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Objective: The efficacy of anlotinib as a treatment for head-and-neck squamous cell carcinoma (HNSCC) has been little explored. Here, we used patient-derived xenografts (PDXs) to this end.Methods: Fresh tumor tissues of HNSCC patients were screened in terms of in vitro drug sensitivity using the MTT assay. Patient PDXs were used to confirm the anti-tumor effects of anlotinib in vivo. After the medication regimen was complete, the tumor volume changes in mice were calculated. Apoptosis was measured using the TUNEL assay. The cell proliferation and apoptosis levels of PDXs yielded data on the utility of anlotinib treatment in vivo.Results: Anlotinib suppressed the in vitro proliferation of nine tumor tissues by an average of 51.05 ± 13.74%. Anlotinib also significantly inhibited the growth of three PDXs in mice (tumor growth inhibition 79.02%). The expression levels of Ki-67 and proliferating cell nuclear antigen after anlotinib treatment were significantly lower than those in the controls. The negative and positive controls exhibited no and some apoptosis, respectively, whereas the anlotinib group evidenced extensive apoptosis.Conclusion: Anlotinib suppressed HNSCC growth in vitro and in vivo (by inhibiting cell proliferation and promoting apoptosis), suggesting that anlotinib can potentially treat HNSCC.

Aim: This study aimed to develop indocyanine green- and doxorubicin-loaded liposomes (DILPs) as theranostic nanoplatform for the detection of hepatocellular carcinoma (HCC) and as an efficient chemotherapeutic to enhance microwave ablation. Materials & methods: DILPs were synthesized and thoroughly characterized. Biocompatibility, tumor uptake and accumulation, and synergistic ablation-chemotherapeutic efficiency were systematically explored in them. In addition, human HCC surgical samples were used to test the affinity of DILPs for HCC. Results: The combination of microwave ablation and DILPs enhanced the ablation efficiency of HCC with apparent tumor inhibition. DILPs exhibited excellent diagnostic ability and could detect 2.5-mm HCC lesions via optoacoustic tomography imaging. DILPs had better affinity for human HCC surgical samples compared with normal liver tissue. Conclusion: Theranostic DILPs could serve as promising nanoparticles for treatment and management of HCC in the clinic.

Pea-like nanocabins (HA@APT§DOX) were designed for deep tumor inhibition. The AS1411 aptamer (APT) constituted "core shelf" which guaranteed DOX "beans" could be embedded, while the outer HA acted as "pea shell" coating. During the circulation (primary orbit), HA@APT§DOX could autonomously cruise until leak through tumor vasculature. Upon tumor superficial site, the "pea shell" could be degraded by highly expressed hyaluronic acid enzymes (HAase) and peel-off, resulting in orbit changing of released APT§DOX to reach the deep tumor tissue. Furthermore, APT§DOX could be specifically uptaken into A549 tumor cells (secondary orbit). Finally, DOX was released under the acidic environment of lysosome, and delivered into nuclear (targeting orbit) to achieve drug pushing for deep tumor inhibition. More importantly, the in vivo imaging and anti-tumor effects evaluations showed that these nanocabins could effectively enhance drugs accumulation in tumor sites and inhibit tumor growth, with reduced systemic toxicity in 4T1 tumor-bearing mice.

Nanoparticles, presenting catalytic activity to induce intracellular oxidative species, have been extensively explored for tumor treatment, but suffer daunting challenges in the limited intracellular H2O2 and thus suppressed therapeutic efficacy. Here in this study, a type of composite nanoparticles, consisting CaO2 core and Co-ferrocene shell, is designed and synthesized for combinational tumor treatment. The findings indicate that CaO2 core can be hydrolyzed to produce large amounts of H2O2 and calcium ions at the acidic tumor sites. Meanwhile, Co-ferrocene shell acts as an excellent Fenton catalyst, inducing considerable ROS generation following its reaction with H2O2. Excessive cellular oxidative stress triggers agitated calcium accumulation in addition to the calcium ions released from the particles. The combined effect of intracellular ROS and calcium overload causes significant tumor inhibition both in vitro and in vivo. Supplementary Information The online version contains supplementary material available at 10.1186/s12951-021-01055-4.

Significance Cullin-RING E3 ubiquitin ligases (CRLs) direct protein degradation to impact a myriad of physiological and pathological processes including cancer. This work reports the small-molecule compounds 33-11 and KH-4-43 as inhibitors of E3 CRL4 with anticancer potential. These compounds have provided an opportunity for developing tool compounds to address mechanistic and phenotypic questions about CRL4 in biochemical, cell-based, and animal studies. The results of correlation studies between cullin4 protein level and the compounds’ cytotoxic response as well as cullin4 depletion experiments suggest a role for low E3 abundance in sensitizing tumor cells for apoptosis. Collectively, the 33-11/KH-4-43–based CRL4 inhibitors may provide new exploitable therapeutic opportunities to target a subset of tumor lines characterized by low CUL4 expression., Cullin-RING (really intersting new gene) E3 ubiquitin ligases (CRLs) are the largest E3 family and direct numerous protein substrates for proteasomal degradation, thereby impacting a myriad of physiological and pathological processes including cancer. To date, there are no reported small-molecule inhibitors of the catalytic activity of CRLs. Here, we describe high-throughput screening and medicinal chemistry optimization efforts that led to the identification of two compounds, 33-11 and KH-4-43, which inhibit E3 CRL4 and exhibit antitumor potential. These compounds bind to CRL4’s core catalytic complex, inhibit CRL4-mediated ubiquitination, and cause stabilization of CRL4’s substrate CDT1 in cells. Treatment with 33-11 or KH-4-43 in a panel of 36 tumor cell lines revealed cytotoxicity. The antitumor activity was validated by the ability of the compounds to suppress the growth of human tumor xenografts in mice. Mechanistically, the compounds’ cytotoxicity was linked to aberrant accumulation of CDT1 that is known to trigger apoptosis. Moreover, a subset of tumor cells was found to express cullin4 proteins at levels as much as 70-fold lower than those in other tumor lines. The low-cullin4–expressing tumor cells appeared to exhibit increased sensitivity to 33-11/KH-4-43, raising a provocative hypothesis for the role of low E3 abundance as a cancer vulnerability.

Excretory/Secretory Products (ESPs) of the nematode Trichinella spiralis contain antitumor-active substances that inhibit tumor growth. Mature dendritic cells (DCs) play a critical role in the antitumor immunity of the organism. As pathogen-derived products, it ought to be discussed whether T. spiralis ESPs will reduce the antitumor effect of mature DCs from the host before it is applied to patients' tumors. Therefore, the aim of this work was to evaluate the immunological effect of DCs stimulated by T. spiralis ESPs in H22 tumor-bearing mice. H22 tumor model mice in this study were randomly divided into four groups according to the treatment: PBS control group, ESP group, DCs group, and DCs stimulated with T. spiralis ESP (ESP+DCs group). The antitumor effect was evaluated by tumor inhibition rate and cytokine detection using ELISA. The results showed significant inhibition in tumor growth in the ESP+DCs, DCs and ESP groups when compared with the PBS control group (p 0.01, p 0.01, and p 0.05, respectively). However, no significant difference was observed on tumor inhibition rates between the ESP+DCs and DCs groups. The decrease in IL-4, IL-6, and IL-10, and the increase in IFN-γ between the DCs and ESP+DCs groups were also not significant. Therefore, DCs stimulated by ESP did not reduce the antitumor effect of mature DCs, which demonstrated that the T. spiralis ESP would not affect the antitumor effect of mature DCs by modulating the immune response of the host, and that ESPs are safe in antitumor immunology when applied in a tumor model mice.Traitement des hépatomes murins avec des cellules dendritiques mûres stimulées par des produits d’excrétion-sécrétion de Trichinella spiralis.Les produits d’excrétion-sécrétion (PES) du nématode Trichinella spiralis contiennent des substances actives antitumorales qui inhibent la croissance tumorale. Les cellules dendritiques (CD) mûres jouent un rôle essentiel dans l’immunité anti-tumorale de l’organisme. En tant que produits dérivés d’agents pathogènes, il convient de déterminer si les PES de T. spiralis réduisent l’effet antitumoral des CD mûrs de l’hôte, avant leur application aux tumeurs des patients. Par conséquent, l’objectif de ce travail était d’évaluer l’effet immunologique des CD stimulées par les PES de T. spiralis chez des souris porteuses de tumeurs H22. Les souris modèles à tumeurs H22 dans cette étude ont été réparties au hasard en quatre groupes selon le traitement : groupe témoin PBS, groupe PES, groupe CD et groupe CD stimulés par les PES de T. spiralis (CD+PES). L’effet antitumoral a été évalué par le taux d’inhibition des tumeurs et la détection des cytokines en utilisant un dosage ELISA. Les résultats ont montré une inhibition significative de la croissance tumorale dans les groupes CD+PES, CD et PES par rapport au groupe témoin PBS (p 0,01, p 0,01 et p 0,05, respectivement). Cependant, aucune différence significative n’a été observée sur le taux d’inhibition de la tumeur entre les groupes CD+PES et CD. La diminution de l’IL-4, de l’IL-6, de l’IL-10 et l’augmentation de l’IFN-γ entre les groupes CD et CD+PES n’étaient pas non plus significatives. Ainsi, les CD stimulées par les PES n’ont pas réduit l’effet antitumoral des CD mûrs, ce qui a démontré que les PES de T. spiralis n’affectaient pas l’effet antitumoral des CD mûrs en modulant la réponse immunitaire de l’hôte et que les PES sont sûrs en immunologie antitumorale quand ils sont appliqués à des souris modèles tumorales.

The Fe element is essential for human beings, but overdose of Fe leads to unwanted toxicity. However, overwhelming Fe accumulation in tumor cells could arouse strong oxidative stress for cancer therapy. Therefore, the fast and specific accumulation of Fe in tumor cells without systemic toxicity is critical for this purpose. Herein, we report that a carbon nanoparticles-Fe(II) complex (CNSI-Fe) could efficiently load Fe into tumor cells and inhibit tumor growth with low toxicity in H22 tumor-bearing mice. Upon intratumoral injection, CNSI-Fe only induced meaningful Fe increase in the tumor to significantly inhibit tumor growth with competitive efficiency to cis-dichlorodiammineplatinum(II). Fe accumulation stimulated the hydroxyl radical generation and serious oxidative stress in the tumor. Due to the lack of Fe accumulation in other tissues, CNSI-Fe was of low systemic toxicity to tumor-bearing mice. With the clinical success of CNSI for decades, CNSI-Fe might be used for cancer therapy through "off label" use to benefit patients immediately.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer without effective targeted drugs. While breast cancer patients often use acupuncture for the relief of cancer-induced pain or the side effects of chemo- or radiation therapy, little information is known regarding the direct effects of electroacupuncture on TNBC tumor and its potential mechanisms. Here, we created a mice model of TNBC and electroacupuncture with encircled needling around the tumors was given to the animals daily for 3 weeks at 15-20 Hz (3 min, each time). For sham electroacupuncture control, the skin was punctured to a depth of 5 mm and then the needle was quickly withdrawn without electrical stimulation or manual needle manipulation. We found that electroacupuncture significantly inhibited TNBC tumor growth and the inhibitory rate increased gradually overtime. Mechanistic analysis showed that electroacupuncture inhibited tumor angiogenesis by reducing the expression of vascular endothelial growth factor A (VEGF-A), its receptor VEGF-R and neuropilin 1 (NRP-1). Electroacupuncture also led to a significant decrease of matrix metalloproteinase-2 (MMP-2) expression and an increase of tissue inhibitor of MMP (TIMP-2) expression. Additionally, the expression of semaphorin 3A (Sema3A) and nerve growth factor receptor (NGFR) p75 in TNBC tissue was significantly upregulated in response to electroacupuncture. Furthermore, tumor necrosis factor (TNF)-alpha level in the serum was dramatically reduced after electroacupuncture. These results showed that electroacupuncture could directly inhibit TNBC tumor growth through the inhibition of proteins related to tumor angiogenesis and extracellular matrix, the suppression of TNBC-induced inflammation and the upregulation of nerve growth factor receptors.

Background Gegen Qinlian decoction (GQT), is a classic traditional Chinese medicine formula chronicled in Shang Han Lun, and is widely used to treat diarrhea and inflammation symptoms in various gastrointestinal disorders. Although it has been found to inhibit delayed-onset mice diarrhea resulted from irinotecan (CPT-11) administration in preliminary experiments, the underlying mechanisms and chemical components remain elusive. Methods The effective fraction of GQT by macroporous resin elution was obtained and screened using a diarrhea mouse model induced by CPT-11 and quantified by UPLC analysis. The protective effect of GQT extract towards alleviating diarrhea in mice following CPT-11 administration was further investigated. The levels of inflammatory cytokines and intestinal tight junction related proteins in colonic tissues were determined. The inhibitory effect of GQT extract against hCE2 was evaluated by a fluorescence-based method. Lastly, the synergistic effect of GQT extract combined with CPT-11 against tumor growth in a colorectal tumor mouse model, induced by HT-29 colon cancer cells xenograft subcutaneously, was investigated. Results The obtained GQT extract, which profoundly ameliorated the gut toxicity induced by CPT-11, contained puerarin, liquiritin, berberine, and baicalin of 27.2 mg/g, 4.6 mg/g, 491.4 mg/g, and 304.2 mg/g, respectively. After 5 days of administration of GQT extract to mice with diarrhea induced by CPT-11, aberrantly elevated levels of pro-inflammatory cytokines, including IL-1β, COX-2, ICAM-1, and TNF-α, were significantly decreased. Meanwhile, GQT extract also exhibited a remarkable anti-oxidative stress effect, involving activating the Keap1/Nrf2 pathway, and up-regulating the intestinal barrier function by enhancing the expression of tight junction proteins ZO-1, HO-1, and occludin. Additionally, a potent inhibitory effect of GQT extract against hCE2 was observedin vitro, with its IC50 value of 0.187 mg/ml, suggesting alleviating activity on hCE2-mediated severe diarrhea in patients suffered from CPT-11. Moreover, GQT extract was shown to improve inhibition of the colonic tumor growth synergistically with CPT-11. Conclusion The present study indicates that GQT extract can ameliorate CPT-11 induced gut toxicity in mice and improve CPT-11 efficacy in colorectal cancer treatment.

Photodynamic therapy (PDT) is commonly employed in clinics to treat the cancer, but because of the hypoxic tumor microenvironment prevalent inside tumors, PDT therapeutic efficiency is not adequate hence limiting the effectiveness of PDT. Therefore, we designed a nanocomposite consisting of reduced nanographene oxide (rGO) modified with polyethylene glycol (PEG), manganese dioxide (MnO2), upconversion nanoparticles (UCNPs), and Chlorin e6 (Ce6) to spark oxygen production from H2O2 with the aim of relieving the tumor hypoxic microenvironments. For in vivo tumor PDT and photothermal therapy (PTT), UCNPs-Ce6-labeled rGO-MnO2-PEG nanocomposites were used as a therapeutic agent, augmenting the therapeutic efficiency of PDT via redox progression through the catalytic H2O2 decomposition pathway and further achieving excellent tumor inhibition. It is important to mention that degradation of MnO2 in an acidic cellular microenvironment leads to the creation of a massive volume of Mn2+ which was employed as a contrast mediator for magnetic resonance imaging (MRI). Our research postulates an approach to spark O2 formation through an internal stimulus to augment the efficiency of MRI- and computerized tomography (CT)-imaging-guided PDT and PTT.

Pd nanosheets (Pd NSs) have attracted extensive attention due to their promising application in photothermal therapy. However, their photodynamic properties have rarely been reported. Herein, holey Pd NSs (H-Pd NSs) with intrinsic photodynamic and hypoxia-resistant capacities are fabricated for the first time using an anisotropic oxidative etching strategy, which introduces one-dimensional nanoholes with active (100) facets on the hole walls. Gradual degradation of H-Pd NSs is observed in simulated physiological media due to the oxidative etching. In vitro and in vivo studies indicate that the single-component H-Pd NSs can act as a photothermal/photodynamic agent for imaging-guided hypoxic tumor therapy, with a high tumor inhibition rate of 99.7%. This work provides ideas for introducing active facets in metallic pore walls, broadening the application of Pd NSs and the design of biodegradable noble metal nanotheranostic agents for cancer therapy.

Conjugation of cisplatin to macromolecular carriers has been extensively studied for reducing systemic side effects. Here, a cisplatin-stitched α-poly(glutamatic acid) nanoconjugate with reduced adverse reactions and effective anti-tumor efficacy was synthesized via ionic interaction between platinum ion of cisplatin with carboxylic groups of α-poly(glutamatic acid). The nanoconjugate exhibited good water solubility, suitable size and polydispersity, almost spherical morphologies, and a sustained release profile without burst release. In vitro cytotoxicity and cell apoptosis assays performed in MCF-7 cells showed significantly decreased cytotoxicity of nanoconjugate compared with free cisplatin, and larger ratio of early apoptosis than late apoptosis. Quantitative cellular uptake assay also supported that conjugation of cisplatin to α-poly(glutamatic acid) reduced its cytotoxicity. Further studies revealed that the unique space structure of nanoconjugate acted as a shield for cisplatin against GSH detoxification under physiological conditions. In vivo studies regarding maximum tolerated dose, hematological parameters evaluation and histopathology assay demonstrated the superior safety of nanoconjugates. Furthermore, the nanoconjugates also achieved comparable antitumor efficacy with no apparent weight loss and death at a high equivalent cisplatin dose of 25 mg/kg. Moreover, the survival rate of mice treated with nanoconjugate was greatly larger than that of free cisplatin. These findings suggest that the cisplatin-stitched α-poly(glutamatic acid) nanoconjugate may hold great potential in clinical application for cancer therapy.

One of the major challenges in vaccine design has been the over dependence on incorporation of abundant adjuvants, which in fact is in violation of the "minimalist" principle. In the present study, a compact nanovaccine derived from a near whole antigen (up to 97 wt %) was developed. The nanovaccine structure was stabilized by free cysteines within each antigen (ovalbumin, OVA), which were tempospatially exposed and heat-driven to form an extensive intermolecular disulfide network. This process enables the engineering of a nanovaccine upon integration of the danger signal (CpG-SH) into the network during the synthetic process. The 50 nm-sized nanovaccine was developed comprising approximately 500 antigen molecules per nanoparticle. The nanovaccine prophylactically protected 70% of mice from tumorigenesis (0% for the control group) in murine B16-OVA melanoma. Significant tumor inhibition was achieved by strongly nanovaccine-induced cytotoxic T lymphocytes. This strategy can be adapted for the future design of vaccine for a minimalist composition in clinical settings.

The development of robust photothermal agents for near-infrared (NIR) imaging is a great challenge. Herein, we report the design and synthesis of a new photothermal agent, based on the aza-boron-dipyrromethene framework (azaBDP). This compound possessed excellent photostability and high photothermal-conversion efficiency (50 %) under NIR laser irradiation. When the photothermal properties of this compound were utilized for tumor inhibition, stable long-term fluorescence was observed in living animals. Photothermal treatment efficiently suppressed tumor growth, as evidenced by in vitro and in vivo experiments. Furthermore, NIR emission could be detected by using an imaging system and therapeutic self-monitoring was achieved by using NIR imaging.

Inhibiting the formation of new tumor blood vessels (so-called antiangiogenesis) and obstructing the established ones are two primary strategies in tumor vasculature targeted therapy. However, the therapeutic outcome of conventional methodologies relying on only one mechanism is rather limited. Herein, the first example of ultrasmall responsively aggregatable nanochelators that can intrinsically fulfill both antivasculature functions as well as high renal clearable efficiency is introduced. The nanochelators with sub-6 nm sizes exhibit not only systemic copper depletion activity for tumor antiangiogenesis but also, more surprisingly, the capability to transform from a "dispersed" state to an "aggregated" state to form large secondary particles in response to tumor microenvironment with elevated copper and phosphate levels for blood vessel obstruction. Compared to a benchmark antiangiogenic agent that can only inhibit the formation of tumor blood vessels, the nanochelators with unprecedented synergistic functions demonstrate significantly enhanced tumor inhibition activity in both breast cancer and colon cancer tumor models. Moreover, these ultrasmall nanochelators are noncytotoxic and renal clearable, ensuring superior biocompatibility. It is envisaged that the design of nanomaterials with ground-breaking properties and the synergistic antivasculature functions would offer a substantial conceptual advance for tumor vasculature targeted therapy and may provide vast opportunities for developing advanced nanomedicines.

Supramolecular protein nanodrugs provide opportunities for improving antitumor therapeutic efficiency and lowering toxicity. However, protein nanodrugs that have robust structural stability and enhanced therapeutic efficiency are still in infancy. In this study, photothermal protein nanodrugs are constructed through a supramolecular approach along with heating by using proteins, photosensitizers, and metal ions as the building blocks. The metal coordination and heating improve not only the structural stability but also photothermal performance of the resulting nanodrugs. By virtue of the first integration of coordination- and heating-enhanced photothermal effects, the nanodrugs show superior photothermal conversion efficiency, enhanced tumor accumulation, and improved tumor inhibition. Metal coordination and heating are versatile to be applied for various protein nanodrugs. Hence, this study provides insights for the construction of highly efficient photothermal nanodrugs and thus will be beneficial to precision theranostics.

Mesenchymal stem cells (MSCs) intrinsically possess unique features that not only help in their migration towards the tumor-rich environment but they also secrete versatile types of secretomes to induce nerve regeneration and analgesic effects at inflammatory sites. As a matter of course, engineering MSCs to enhance their intrinsic abilities is growing in interest in the oncology and regenerative field. However, the concern of possible tumorigenesis of genetically modified MSCs prompted the development of non-viral transfected MSCs armed with nanotechnology for more effective cancer and regenerative treatment. Despite the fact that a large number of successful studies have expanded our current knowledge in tumor-specific targeting, targeting damaged brain site remains enigmatic due to the presence of a blood–brain barrier (BBB). A BBB is a barrier that separates blood from brain, but MSCs with intrinsic features of transmigration across the BBB can efficiently deliver desired drugs to target sites. Importantly, MSCs, when mediated by nanoparticles, can further enhance tumor tropism and can regenerate the damaged neurons in the central nervous system through the promotion of axon growth. This review highlights the homing and nerve regenerative abilities of MSCs in order to provide a better understanding of potential cell therapeutic applications of non-genetically engineered MSCs with the aid of nanotechnology.

Objectives: To investigate the tumor-suppressive properties of enzalutamide in androgen-driven ovarian cancer. Methods: Mice were implanted subcutaneously with OVCAR-3 cells and treated with dihydrotestosterone in combination with enzalutamide or vehicle control. Tumor volumes were measured twice weekly until day 56. Results: Dihydrotestosterone exposure led to a significant increase in tumor growth, while concomitant treatment with enzalutamide led to significant reductions in tumor volume compared to the androgen-exposed groups. Conclusions: We present the first evidence that the second-generation anti-androgen enzalutamide may possess efficacy in the treatment of ovarian cancer, paving the way for the future clinical trials.

International audience; Cancer chemotherapeutic drug containing PEGylated lipidic nanocapsules (D-LNCs) were formulated by the controlled addition of organic phase (combined solution of paclitaxel and curcumin in a mixture of oleic acid and MPEG2000-DSPE (90:2.5 molar ratio) in acetone) to the aqueous phase (consist of Poloxamer 407 as emulsifying agents and glycerol as a co-solvent) at a temperature of 55-60°C followed by evaporation of organic solvent. The obtained pre-colloidal dispersion of D-LNCs was processed through high pressure homogenization to get more uniformly and nano-sized particles. Effect of concentration of emulsifying agent and process variables of high pressure homogenization (pressure and number of cycles) on average particle size and entrapment efficiency was further investigated by constructing Box-Behnken experimental design to achieve the optimum manufacturing process. D-LNCs were characterized by dynamic light scattering, scanning and transmission electron microscopy, Fourier transform infrared spectroscopy, and differential scanning calorimetry. In vitro release studies showed a sustained release pattern of drug from the PEGylated D-LNCs, whereas in vivo pharmacokinetic studies after a single-dose intravenous (i.v.) administration of paclitaxel (15mg/kg) in Ehrlich ascites tumor (EAT)-bearing female Swiss albino mice showed a prolonged circulation time and slower elimination of paclitaxel from D-LNCs as compared with marketed formulation (Paclitec®). From the plasma concentration vs. time profile, i.v. bioavailability (AUC0-∞) of paclitaxel from D-LNCs was found to be increased approximately 2.91-fold (P

// Zhong Liu 1, * , Ge Liu 1, * , Guang-Lin Zhang 1, * , Jun Li 1 , Yan-Qing He 2 , Shu-Shu Zhang 3 , Yi Wang 1 , Wei-Yi He 1 , Guo-Hua Cheng 4 , Xuesong Yang 2 , Jun Xu 3 , Ju Wang 1 1 Institute of Biomedicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China 2 Key Laboratory for Regenerative Medicine of the Ministry of Education, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou 510632, China 3 Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China 4 College of Pharmacy, Jinan University, Guangzhou 510632, China * These authors contributed equally to this work Correspondence to: Ju Wang, email: wangju1688@163.com Keywords: heterocomplex, FGF-2, soluble FGFR2, tumor inhibition, angiogenesis Received: April 03, 2016 Accepted: August 24, 2016 Published: September 16, 2016 ABSTRACT FGFRs are considered essential targets for cancer therapy. We previously reported that msFGFR2c, a Ser252Trp mutant soluble ectodomain of FGFR2IIIc, inhibited tumor growth by blocking FGF signaling pathway. However, the underlying molecular mechanism is still obscure. In this study, we reported that msFGFR2c but not wild-type soluble ectodomain of FGFR2IIIc (wsFGFR2c) could selectively bind to c subtype of FGFRs in the presence of FGF-2. Thermodynamic analysis demonstrated that msFGFR2c bound to wsFGFR2c in the presence of FGF-2 with a K value of 6.61 × 10 5 M −1 . Molecular dynamics simulations revealed that the mutated residue Trp252 of msFGFR2c preferred a π-π interaction with His254 of wsFGFR2c. Concomitantly, Arg255 of msFGFR2c and Glu250 of wsFGFR2c adjusted their conformations and formed three H-bonds. These two interactions therefore stabilized the final structure of wsFGFR2c and msFGFR2c heterocomplex. In FGFR2IIIc-positive/high FGF-2-secreted BT-549 cells, msFGFR2c significantly inhibited the proliferation and induced apoptosis by the blockage of FGF-2-activated FGFRs phosphorylation, also the growth and angiogenesis of its xenograft tumors implanted in chick embryo chorioallantoic membrane model. While weaker the above inhibitory effects of msFGFR2c were observed on FGFR2IIIc-negative/low FGF-2-secreted MCF-7 and MDA-MB-231 cell lines in vitro and in vivo . Moreover, msFGFR2c significantly inhibited the proliferation of FGFR1IIIc-positive NCI-H1299 lung cancer cells by the suppression of FGF-2-induced FGFR1 activation and suppressed the growth of NCI-H1299 transplanted tumors in nude mice. In sum, msFGFR2c is a potential anti-tumor agent targeting FGFR2c/FGFR1c-positive tumor cells. These findings also provide a molecular basis for msFGFR2c to disrupt the activation of FGF signaling.

The combination of Endostatin (ES) and Herpes Simplex Virus thymidine kinase (HSV‐TK) gene therapy is known to have antitumor activity in bladder cancer. The potential effect of ES and TK therapy in glioma has not yet been investigated. In this study, pTK‐internal ribosome entry site (IRES), pIRES‐ES, and pTK‐IRES‐ES plasmids were constructed; pIRES empty vector served as the negative control. The recombinant constructs were transfected into human umbilical vein endothelial cells (HUVECs) ECV304 and C6 rat glioma cell line. Ganciclovir (GCV) was used to induce cell death in transfected C6 cells. We found that ECV304 cells expressing either ES or TK‐ES showed reduced proliferation, decreased migration capacity, and increased apoptosis, as compared to untransfected cells or controls. pTK‐IRES‐ES/GCV or pTK‐IRES/GCV significantly suppressed cell proliferation and induced cell apoptosis in C6 cells, as compared to the control. In addition, the administration of pIRES‐ES, pTK‐IRES/GCV, or pTK‐IRES‐ES/GCV therapy improved animal activity and behavior; was associated with prolonged animal survival, and a lower microvessel density (MVD) value in tumor tissues of C6 glioma rats. In comparison to others, dual gene therapy in form of pTK‐IRES‐ES/GCV had a significant antitumor activity against C6 glioma. These findings indicate combined TK and ES gene therapy was associated with a superior antitumor efficacy as compared to single gene therapy in C6 glioma.

BPAP is a potent enhancer substance with catecholaminergic and serotoninergic activity in the brain. It was discovered that it is also effective against certain types of experimental cancers, showing the most promising results in case of lung cancer. That is why we tested its efficacy in two different doses in a newly developed EGFR wild type mouse lung adenocarcinoma xenograft model. Experiments were conducted on FVB/N and SCID mouse strains treated with low and high dose of BPAP. Body weight, survival, and tumor volumes were recorded. Furthermore, the activity of major signaling pathways of NSCLC such as MAPK and Akt/mTOR as well as cell cycle regulation were determined. Significant inhibition of tumor growth was exerted by both doses, but the mechanism of action was different. High dose directly inhibited, whereas low dose activated the main signaling pathways. Exposure to low dose BPAP resulted in elevated activity of the mTOR pathway together with p16INK-induced cell cycle arrest, a typical feature of geroconversion, a senescent state characterized by loss of cell proliferation. Finally the events culminated in cell cycle inhibition point in case of both doses mirrored by the decrease of cyclin D1, CDK4 and PCNA. In addition, BPAP treatment had a beneficial effect on bodyweight suggesting that the compound at least in part is able to compensate the cancer-related wasting. In view of the low toxicity and confirmed antitumor effect of BPAP against experimental lung adenocarcinoma, this novel compound deserves further attention. Electronic supplementary material The online version of this article (10.1007/s12253-019-00603-6) contains supplementary material, which is available to authorized users.

Angiogenesis is a prerequisite of tumor growth and metastasis and, thus, anti-angiogenesis treatment has become an important part of cancer therapy. A 15-amino acid peptide of the fibrinogen α chain, fibrinostatin, was previously found in serum samples of gastric cancer patients. Herein we demonstrated that fibrinostatin has anti-angiogenesis activity in several angiogenesis models and it reduces tumor growth in mouse xenografts and allografts. Increased tumor necrosis and reduced microvessel density in tumors were observed in mouse xenograft models. Fibrinostatin inhibited proliferation and induced apoptosis in HUVEC, but not in cancer cells. In addition, fibrinostatin specifically entered HUVEC. Fibrinostatin also prevented migration, adhesion and tubule formation of HUVEC in vitro. A single-dose acute toxicity testing and a repeated-dose chronic toxicity study in the mouse, rat and monkey indicated that fibrinostatin had a wide margin of safety. Taken together, fibrinostatin shows promise as a potential anti-angiogenesis therapeutic agent.

Endohedral metallofullerenes exhibit combined properties from carbon cages as well as internal metal moieties and have great potential in a wide range of applications as molecule materials. Along with the breakthrough of mass production of metallofullerenes, their applied research has been greatly developed with more and more new functions and practical applications. For gadolinium metallofullerenes, their water-soluble derivatives have been demonstrated with antitumor activity and unprecedented tumor vascular-targeting therapy. Metallofullerene water-soluble derivatives also can be applied to treat reactive oxygen species (ROS)-induced diseases due to their high antioxidative activity. For magnetic metallofullerenes, the internal electron spin and metal species bring about spin sensitivity, molecular magnets, and spin quantum qubits, which have many promising applications. Metallofullerenes are significant candidates for fabricating useful electronic devices because of their various electronic structures. This Review provides a summary of the metallofullerene studies reported recently, in the fields of tumor inhibition, tumor vascular-targeting therapies, antioxidative activity, spin probes, single-molecule magnets, spin qubits, and electronic devices. This is not an exhaustive summary and there are many other important study results regarding metallofullerenes. All of this research has revealed the irreplaceable role of metallofullerene materials.

Hydroxycamptothecin (HCPT) has shown activity against a broad spectrum of cancers, but its therapeutic efficacy is impaired by its poor solubility and delivery challenges. In this study, HCPT nanosuspensions were prepared with precipitation-combined ultrasonication and characterized by dynamic light scattering (DLS), scanning electron microscopy (SEM) and X-ray powder diffraction (XRD). The HCPT nanosuspensions were spherical with a smooth surface and a small size of 150-200 nm. The lyophilized powders for the HCPT nanosuspensions were amorphous and displayed sustained release in vitro. Compared to commercial HCPT injection, in vivo experiments with HCPT nanosuspensions showed significantly increased HCPT concentrations in the blood and all tissues of the tested as well as improved tumor targetability and liver targetability. Meanwhile, nanosuspensions displayed better anticancer efficacy than injection on H22 bearing mice (81.20% vs. 56.39%, in tumor inhibition rate). Therefore, HCPT nanosuspensions seem very promising for the treatment of hepatic cancer.

Withania somnifera, commonly known as Ashwagandha, is an important medicinal plant that has been used in Ayurvedic and indigenous medicine for over 3,000 years. In view of its varied therapeutic potential, it has also been the subject of considerable modern scientific attention. The major chemical constituents of the Withania genus, the withanolides, are a group of naturally occurring C28-steroidal lactone triterpenoids built on an intact or rearranged ergostane framework, in which C-22 and C-26 are appropriately oxidized to form a six-membered lactone ring. In recent years, numerous pharmacological investigations have been carried out into the components of W. somnifera extracts. We present here an overview of the chemical structures of triterpenoid components and their biological activity, focusing on two novel activities, tumor inhibition and antiangiogenic properties of withaferin A and the effects of withanolide A on Alzheimer's disease. The most recent attempts in biotechnological production of withanolides are also discussed.

Endostatin, a 20-kDa C-terminal proteolytic fragment of collagen XVIII, is a specific endogenous angiogenesis inhibitor discovered more than a decade. The structure, stability, and mechanism of actions of endostatin have been extensively investigated during the past 12 years, among which controversial reports remain unclarified. The mysteries include the following: 1) Why controversial efficacies were observed with endostatin regarding tumor inhibition? Particularly, why does an N-terminal modified endostatin show good clinical responses in China, whereas the clinical trials of the wild type endostatin were terminated at the early stage of phase II in the USA? 2) What is the contribution of zinc-binding to the stability and biological functions of endostatin? 3) Why does insoluble endostatin shrink tumors? 4) How to ensure that endostatin is correctly refolded? 5) How does endostatin exert its biological functions? Recent progress regarding the biophysical properties, biological functions, signaling pathways, and clinical trials of endostatin are reviewed here. Surprising findings show that the integrity of the N-terminal sequence, the capability of zinc-binding, and the correct folding are three essential elements for assurance of structural stability and biological functions of endostatin. This review provides clues to understand the mysteries of endostatin and its derivatives.

Oxaliplatin (OXP) was reported to show low anti-tumor activity when used alone and to display side effects; this low activity was attributed to high partitioning to erythrocytes and low accumulation in tumors. Thermosensitive liposomes (TSL) were considered able to specifically deliver drugs to heated tumors and to resolve the OXP distribution problem. Regretfully, TSL encapsulating doxorubicin did not demonstrate significant improvement in progression-free survival. Drug release below 41°C and significant leakage were considered major reasons for the failure. The purpose of this study was to acquire OXP TSL with rapid release at the triggered temperature and high stability at body temperature and at storage temperatures. A small quantity of poloxamer 188 was introduced into the TSL formulation to stabilize the encapsulated drug. It was shown that the addition of poloxamer 188 had no influence on the TSL characteristics. More than 90% of OXP was released within 10 min at 42°C, and less than 15% was released within 60 min at temperatures below 39°C. TSL were stable at 37°C for 96 h and at 4°C for 6 months. The anti-tumor activity of TSL at the dose of 2.5 mg/kg was certified to be equal to those of OXP injection and non-thermosensitive liposomes (NTSL) at the dose of 5 mg/kg, and significant improvement of tumor inhibition was observed in TSL compared with injection and NTSL at the same dose. It was also shown from the histological transmutation of tumors that TSL had stronger anti-tumor activity. Therefore, it could be concluded that TSL composed of a proper amount of poloxamer had rapid release and high stability, and OXP TSL would be anticipated to exert prominent anti-tumor activity in the clinic.

Chan Feng,1,* Xiaoyan Li,2,* Chunyan Dong,1 Xuemei Zhang,1 Xie Zhang,1 Yong Gao11Department of Oncology, Shanghai East Hospital, Tongji University, Shanghai, 2Shanghai Tenth People’s Hospital, Tongji University, Shanghai, People’s Republic of China*These authors contributed equally tothis workAbstract: In this study, long-circulating Arg-Gly-Asp (RGD)-modified aclacinomycin A (ACM) liposomes were prepared by thin film hydration method. Their morphology, particle size, encapsulation efficiency, and in vitro release were investigated. The RGD-ACM liposomes was about 160 nm in size and had the visual appearance of a yellowish suspension. The zeta potential was -22.2 mV and the encapsulation efficiency was more than 93%. The drug-release behavior of the RGD-ACM liposomes showed a biphasic pattern, with an initial burst release and followed by sustained release at a constant rate. After being dissolved in phosphate-buffered saline (pH 7.4) and kept at 4°C for one month, the liposomes did not aggregate and still had the appearance of a milky white colloidal solution. In a pharmacokinetic study, rats treated with RGD-ACM liposomes showed slightly higher plasma concentrations than those treated with ACM liposomes. Maximum plasma concentrations of RGD-ACM liposomes and ACM liposomes were 4,532 and 3,425 ng/mL, respectively. RGD-ACM liposomes had a higher AUC0–∞ (1.54-fold), mean residence time (2.09-fold), and elimination half-life (1.2-fold) when compared with ACM liposomes. In an in vivo study in mice, both types of liposomes inhibited growth of humanlungadenocarcinoma (A549) cells and markedly decreased tumor size when compared with the control group. There were no obvious pathological tissue changes in any of the treatment groups. Our results indicate that RGD-modified ACM liposomes have a better antitumor effect in vivo than their unmodified counterparts.Keywords: RGD, aclacinomycin A, long-circulating liposomes, pharmacokinetic, tumor inhibition

The leaves of Chenopodium ambrosioides L. [Chenopodiaceae] ('mastruz') have been indicated for the treatment of several diseases, among which the cancer. There are no results focusing the effect of C. ambrosioides treatment on tumor development in vivo. The aim of this study was to investigate the effect of treatment with C. ambrosioides on Ehrlich tumor development. Swiss mice were treated by intraperitoneal route (i.p.) with hydroalcoholic extract from leaves of C. ambrosioides (5 mg/kg) or with PBS (control group) 48 h before or 48 h later the Ehrlich tumor implantation. The tumor cells were implanted on the left footpad (solid tumor) or in the peritoneal cavity (ascitic tumor). To determine the solid tumor growth, footpad was measured each 2 days until the fourteenth day, when the feet were weighed. Ascitic tumor development was evaluated after 8 days of tumor implantation by quantification of the ascitic fluid volume and tumor cell number. The i.p. administration of C. ambrosioides extract before or after the tumor implantation significantly inhibited the solid and ascitic Ehrlich tumor forms. This inhibition was observed in ascitic tumor cell number, in the ascitic volume, in the tumor-bearing foot size and foot weight when compared to control mice. The treatments also increased the survival of tumor-bearing mice. In conclusion, C. ambrosioides has a potent anti-tumoral effect which was evident with a small dose and even when the treatment was given two days after the tumor implantation. This effect is probably related with anti-oxidant properties of C. ambrosioides.

A Streptomyces strain was isolated from soil and the sequence of 1471 nucleotides of its 16S rDNA showed 99% identity to Streptomyces sp. HV10. This newly isolated Streptomyces strain produced an extracellular polysaccharide (EPS) composed mainly of glucose and mannose in a ratio of 1:4.1, as was characterized by Fourier transform infrared spectroscopy (FTIR), HPLC and 1H-NMR. The antioxidant activities of the partially purified MOE6-EPS were determined by measuring the hydroxyl free radical scavenging activity and the scavenging of 2,2-diphenyl-2-picryl-hydrazyl (DPPH) radicals. In addition, the partially purified MOE6-EPS showed high ferrous ion (Fe2+) chelation activity which is another antioxidant activity. Interestingly, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays that were colorimetric assays for NAD(P)H-dependent cellular oxidoreductases and a proxy of the number of viable cells, showed that the partially purified MOE6-EPS inhibited the proliferation of the human breast cancer cells (MDA-MB-231). The scratch wound assay showed that MOE6-EPS reduced the migration of mouse breast cancer cells (4T1). This study reports the production of EPS from Streptomyces species with promising antioxidant, metal chelating and mammalian cell inhibitory activities.

Our previous cellular experiments demonstrated that 100 Hz magnetic field (MF) was effective at enhancing apoptosis of liver cancer cells BEL-7402 induced by X-ray irradiation. This study was performed to further explore the possible synergism between 100 Hz MF and X-ray in treatment of hepatoma-implanted Balb/c mice. 100 Hz MF exposure with a mean flux density of 0.7 mT was performed inside an energized solenoid coil. Six MV X-ray irradiation was generated using a linear accelerator. Tumor growth and survival of mice implanted with H22 cells were evaluated by measuring the tumor diameters and overall days of survival. Six groups treated with 100 Hz MF or X-ray alone or a combination of MF and X-ray were examined. Furthermore, the effects of different numbers of MF exposure periods on tumor growth and mice survival were examined when combined with 4 Gy X-ray. Data referring to overall survival days and tumor diameters of the above groups were compared using log-rank test and Student's t-test. Our results showed that five periods of combined 100 Hz MFs and 4 Gy X-ray could significantly extend the overall days of survival and reduce the tumor size compared to MF or X-ray alone. Also, a greater number of 100 Hz MF exposure periods could further improve the survival and inhibit tumor growth in hepatoma-implanted mice when combined with 4 Gy X-ray. In conclusion, these findings suggested that 100 Hz MF could possibly synergize with 4 Gy X-ray in terms of survival improvement and tumor inhibition in hepatoma-implanted mice. Bioelectromagnetics 32:322–324, 2011. © 2011 Wiley-Liss, Inc.

Taxol is currently one of the most effective anticancer agents available. However, limitations due to multidrug-resistance (MDR) susceptibility and lack of aqueous solubility render it less than an ideal drug. These limitations, coupled with taxol's unique mechanism of tumor inhibition, involving the stabilization of microtubule assembly, have spurred the search for more effective chemotherapeutic agents. This review will discuss the chemistry and biology of some of the most promising new molecules with "taxol-like" activity. The extended family of microtubule-stabilizing agents now includes the epothilones, eleutherobins, discodermolide, laulimalide and WS9885B. The epothilones have emerged as one of the most exciting new candidates for detailed structure-activity-related studies. A review of our efforts in the synthetic and biological aspects of this research is presented, as are the latest developments reported from other laboratories in academia and the pharmaceutical industry. The synthesis and structure-activity studies of eleutherobins, as well as recent progress with discodermolide, laulimalide and WS9885B are also reviewed. An abundance of exciting advances in chemistry and biology have emerged from these studies, and it is hoped that it will ultimately result in the development of new and more effective chemotherapeutic agents in the fight against cancer.

Tea catechins exhibit a broad range of pharmacological activities that impart beneficial effects on human health. Epigallocatechin-3-gallate (EGCG), one of the major tea catechins, has been widely associated with cancer prevention and treatment. In addition, tea catechins in combination with anticancer drugs are being evaluated as a new cancer treatment strategy. However, the interactions of anticancer drugs with tea catechins are largely unknown. Accumulated data indicate significant interactions between anticancer drugs and tea catechins, such as synergistic tumor inhibition or antagonist activity. Therefore, it is critical to understand comprehensively the effects of tea catechins on anticancer drugs. Focusing on evidence from preclinical studies, this paper will review the interactions between anticancer drugs and tea catechins, including pharmacodynamics and pharmacokinetics effects. We hope that by detailing the interactions between anticancer drugs and tea catechins, more attention will be directed to this important therapeutic combination in the future.

Background Melanoma represents one of the most aggressive and therapeutically challenging malignancies as it often gives rise to metastases and develops resistance to classical chemotherapeutic agents. Although diverse therapies have been generated, no major improvement of the patient prognosis has been noticed. One promising alternative to the conventional therapeutic approaches currently available is the inactivation of proteins essential for survival and/or progression of melanomas by means of RNA interference. Survivin and cyclin B1, both involved in cell survival and proliferation and frequently deregulated in human cancers, are good candidate target genes for siRNA mediated therapeutics. Methods We used our newly developed sticky siRNA-based technology delivered with linear polyethyleneimine (PEI) to inhibit the expression of survivin and cyclin B1 both in vitro and in vivo, and addressed the effect of this inhibition on B16-F10 murine melanoma tumor development. Results We confirm that survivin and cyclin B1 downregulation through a RNA interference mechanism induces a blockage of the cell cycle as well as impaired proliferation of B16-F10 cells in vitro. Most importantly, PEI-mediated systemic delivery of sticky siRNAs against survivin and cyclin B1 efficiently blocks growth of established subcutaneaous B16-F10 tumors as well as formation and dissemination of melanoma lung metastases. In addition, we highlight that inhibition of survivin expression increases the effect of doxorubicin on lung B16-F10 metastasis growth inhibition. Conclusion PEI-mediated delivery of sticky siRNAs targeting genes involved in tumor progression such as survivin and cyclin B1, either alone or in combination with chemotherapeutic drugs, represents a promising strategy for melanoma treatment.

Personalized oncology significantly relies on the development of cancer theranostic agents to integrate cancer therapeutics and diagnostics. Current most common strategy for development of such multifunctional agents requires multistep chemical conjugation with cancer targeted ligands, contrast agents and therapeutic agents. Here we report the chemical synthesis and biological characterization of a new heptamethine dye, termed as IR-808DB, natively with multifunctional characteristics of cancer targeting, near-infrared fluorescence imaging, and efficient anticancer activity. The tumor inhibition effect of IR-808DB is higher than that of cyclophosphamide (CTX) toward a broad spectrum of tumor xenograft models. These findings provide IR-808DB a promising prospect as a new cancer theranostic agent that would enable integration of cancer targeted therapeutics and diagnostics without requirement of multi-component chemical conjugation.

By using the two-hybrid system with basic fibroblast growth factor (FGF-2) as bait, we isolated and characterized fibstatin, an endogenous Mr 29,000 human basement membrane-derived inhibitor of angiogenesis and tumor growth. Fibstatin, a fragment containing the type III domains 12–14 of fibronectin, was produced as a recombinant protein and was shown to inhibit the proliferation, migration, and differentiation of endothelial cells in vitro. Antiangiogenic activity of fibstatin was confirmed in a Matrigel angiogenesis assay in vivo, and electrotransfer of the fibstatin gene into muscle tissue resulted in reduced B16F10 tumor growth. Taken together, these results suggest that fibstatin could act as a powerful molecule for antiangiogenic therapy.

The effects of gallium and lanthanum compounds on DS sarcoma growth were studied. Under the stated experimental conditions gallium showed no tumor inhibition while lanthanum did. The probable mechanisms of action which explain this behavior are discussed on the basis of their pharmacological properties (calcergens) and of the influence of treatment procedure.

Retinoids--vitamin A and its analogues--have been recognized for more than half a century to be potent agents in the control of cellular differentiation and proliferation. Only recently, however, have there been concerted efforts to exploit this observation, with particular emphasis on cancer prevention. Experimental findings of tumor inhibition and suppression are reviewed.

The antiproliferative activity of divers ferricenium complexes [Cp2Fe]+X- (X-= [CCl3COO]- · CCl3COOH (I); X- = [CCl3COO]- · 2 CCl3COOH (II); X- = ½ [Cl3FeOFeCl3]2- (III); X- = [FeCl4]- (IV); X = [2 ,4, 6-(NO2)3C6H2O]- (V)) was investigated against solid, subcutaneously growing Ehrlich ascites tumor (EAT) in vivo as well as against EAT cells cultivated in vitro as permanent suspension culture. In vivo, triple intraperitoneal injections of the complexes II (3 × 200 mg/kg), III (3 × 100, 140, 180 mg/kg) or IV (3 × 160 mg/kg) markedly suppressed tumor development thus that the sizes of treated tumors were reduced to 42-48% related to control tumors (100%); these results point to the systemic character of the antitumor action by ferricenium complexes in vivo. In vitro, all ferricenium complexes inhibited cellular proliferation to an equal extent; application of 10-5 ᴍ diminished the increase in cell number by 20-40%, application of 10-4 ᴍ resulted in a total cessation of cellular proliferation. In comparison to cis-diamminedichloroplatinum(II), the cell growth-inhibiting effect of ferricenium complexes was less pronounced and required 10-to 50-fold higher concentration levels to evoke equivalent cytostasis.

The cytotoxicity of combined antitumor drugs and lymphotoxin (LT)-containing supernatants was studied on target cells. Marked reduction of L cells was observed after combined use of LT-containing supernatants with actinomycin D, adriamycin or aclacinomycin A but not with mitomycin C or vincristine sulphate. Similar effects were observed in Sarcoma 180 cells and Ehrlich ascites tumor cells in vitro. The survival of mice injected i.p. with Ehrlich ascites tumor cells was prolonged by the combined use of LT-containing supernatants and actinomycin D (0.1 or 0.3 μg/mouse). The mechanisms of the synergistic effect are discussed in regard to the mode of action of antitumor drugs.

Twenty-two new esters of natural (-)-cephalotaxine with synthetic acids possessing widely divergent structural features have been synthesized. Murinichloroethyl carbonate (27) esters of cephalotaxine are the most active of this group; this activity is less than that of harringtonine and other naturally occurring cephalotaxine esters. Other synthetic esters exhibiting activity are methyl cephalotaxylfumarate (4) and the trichloroethyl carbonate of cephalotaxyl-L-mandelate (21). The specificity of this experimental tumor system apparently requires esters of (-)-cephalotaxine for tumor inhibition because methyl cephalotaxylitaconate (7b) prepared from the synthetic (+) enantiomer of cephalotaxine is inactive.

The antitumor activity of two representatives of the metallocene dihalides, titanocene dichloride (TDC) and vanadocene dichloride (VDC), is investigated by the use of various experimental tumor systems. Against the lymphoid leukemia L1210 and the lymphocytic leukemia P388, TDC and VDC induce significant increases of life span corresponding to T/C values which exceed 125%. On treating advanced stages of fluid EAT with single doses, TDC causes, when applied within 5 days after transplantation, the survival of 80–100% of the treated animals, whereas VDC cures progressed stages of fluid EAT to a much minor extent. Investigations using a solid EAT subcutaneously growing in the nuchal region show that the intraperitoneally applied metallocene dihalides are able to inhibit tumor growth in a highly significant manner so that the minimum tumor sizes attain 14% (TDC) or 31% (VDC) of the control values. This result indicates that the antiproliferative activity of the metallocene dihalides is based on a systemic effect.

Previous findings show that experimental tumors of the mouse, such as Ehrlich carcinoma and Sarcoma 180, transplanted in different sites, elicit a different sensitivity to the same drug according to the site of tumor implantation. Cyclophosphamide is highly active on intraperitoneal or subcutaneous tumors, but is ineffective on intracerebral tumors. However, the opposite is true for drugs such as nitroso-derivatives, which are active only on intracerebral tumors. The studies presented in this report were performed in order to elucidate whether different concentrations of drugs at the three tumor sites are related to the different antitumoral effects. It was found that measurements of blood and tissue concentrations explain fairly well the different activities of the drugs being tested.

SummaryTwo experiments were conducted using rats of the Marshall 520 strain depleted in vit. B6 by the use of a deficient diet and 4-desoxypyridoxine. Osteogenic Sarcoma 344 was transplanted into the deficient animals, a pair-fed group and an ad libitum group. Desoxypyridoxine was removed from the diet of the deficient animals on the day of tumor transplant. In Exp. 1 daily measurements of the tumor showed a marked inhibition of the growth of the tumor in the deficient animals as compared to the control groups. The mean weight of the tumor and also the mean weight as a percentage of final mean total body weight were also decreased. In a second experiment larger, more mature animals were used. Tumor inhibition in the deficient animals was again observed, although it was not so striking as in the first experiment. No histological differences in the tumor were noted in either experiment with the exception of increased hemorrhage and necrosis in the neoplasms of the ad libitum animals.

Investigation of the cytotoxic principles of Annona purpurea L. resulted in the isolation and characterization of four new alkaloids of the aporphine variety. One of the four is an oxoaporphine which shows borderline activity in vitro against the 9-KB tumor test system. The known aporphine isocorydine, oxoaporphine O-methylatheroline, and the proaporphines glaziovine and stepharine were also obtained. Glaziovine and O-methylatheroline also showed limited tumor inhibition.

SummaryImmature AKD2F1 mice were examined for possible estrogenic inhibition of Sarcoma 1. Large doses of estradiol benzoate inhibited growth of tumor in intact animals and in hysterectomized castrates. It was concluded that this estrogenic effect can be achieved in absence of uterus, and that the tumor-inhibitory properties of endometrial secretions act by a mechanism different from that of estrogen.