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Natural products, as a gift of nature to humanity, have long been used as drugs or pharmacological actives to help people cure various diseases. Yet we still know comparatively little about their ability to be materials. In recent years, some small molecule natural products isolated from traditional Chinese medicines have been found to have new features, namely, self-assembly to form gels (i.e., natural product gels, NPG). However, the application development of these natural products is seriously lacking, which greatly weakens their practical value and delays the maturity of the field. Here, a series of self-assembled triterpenoid natural products are used as materials (gel scaffolds) to construct drug delivery systems. Surprisingly, these NPG not only exhibit the excellent self-healing, controlled gelation, good safety and sustained release, but also achieve synergistic treatment of tumors through bioactive natural products. Compared with non-bioactive gel scaffolds, NPG scaffolds show great advantages in tumor therapy, including optimal tumor inhibition, preferable health, better body recovery, stronger immune function, less toxic side effects and longer survival. The successful construction of NPG scaffolds not only takes full advantage of the self-assembled natural products, but also takes an important step in the development of new applications for natural products., Graphical abstract Self-assembled small molecule natural products isolated from traditional Chinese medicine are constructed into injectable gel scaffolds. These natural product gel (NPG) scaffolds not only exhibit the excellent self-healing, controlled gelation, good safety and sustained release, but also achieve synergistic treatment of tumors through bioactive natural products.Image 1

[Objective]: Although great progress has been made in the field of siRNA gene therapy, safe, efficient, and targeted delivery of siRNA are still major challenges in siRNA therapeutics., [Methods]: We developed an up-conversion nanoparticle-based nanocage system. This system protected the siRNA from being degraded by nucleases in organisms and selectively delivered the siRNAs to the tumor sites, due to modifications of targeted molecules on the surfaces of nanocages and local inhalation., [Results]: The siRNAs delivered by the up-conversion nanoparticle nanocages were protected from degradation in transit to the tumor sites, where they accumulated. Compared with the passive target and control groups, the up-conversion nanoparticles based on the nanocage system showed a tumor suppressive effect after approximately 3 weeks of treatment., [Conclusions]: The up-conversion nanoparticle nanocages efficiently delivered vascular endothelial growth factor siRNAs to tumor sites. Mice with lung tumors treated with tumors targeting up-conversion nanoparticle nanocages showed steady body weight changes, high tumor inhibition ratios, and longer survival times., This work is supported by the National Key Basic Research Program (973 Project) (Grant Nos. 2015CB931802 and 2017FYA0205301), the Special Fund for Science and Technology Innovation of Shanghai Jiao Tong University (Grant Nos. YG2017MS70, YG2015MS62, and AF0300179), the Shanghai Municipal Bureau of Economy and Information Technology (Grant No. XC-ZXSJ-02-2016-05), the National Natural Scientific Foundation of China (Grant Nos. 8202010801, 81921002, 81225010, 81028009, and 31170961), the 863 Project of China (Grant No. 2014AA020700), and the Shanghai Science and Technology Fund (Grant No. 13NM1401500).

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.

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.

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.

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.

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.

A novel series of tetrahydroquinolines containing acetohydrazide, oxopyrazole, oxothioxodihydropyrazole, and thioxotriazole have been synthesized. Antileishmanial, antitumor, and cytotoxicity activities of synthesized compounds were evaluated in vitro. Antileishmanial activity of the most synthesized compounds showed tremendous activity towards Leishmania major. Most of the test compounds exhibited significant level of tumor inhibition. The tetrahydropyrano[2,3-b]quinolin-2-one 6 and 4-oxo-4H-pyrazol-3-yloxytetrahydroquinoline-3-carbonitrile derivatives 18 showed 100% tumor inhibition comparable with standard drug vincristine (100% tumor inhibition). Tetrahydroquinolines under investigation showed cytotoxicity with LD50 values in the range 0.56–3.01 μg/mL compared with standard drug MS-222 with LD50 value of 4.30 μg/mL. The presence of a pyrazole ring markedly improved the activity profiles of tetrahydroquinoline. All newly synthesized compounds were characterized by IR, 1H NMR, and MS.

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.

Poly(vinyl pyrrolidone) (PVP) and stearoyl chloride (SC) double-grafted chitosan (PCS) nanoparticles (NPs) were prepared for paclitaxel (PTX) delivery. PTX could be effectively loaded into PCS NPs with encapsulation efficiency of 92.8%. PTX-loaded PCS NPs (PTX/PCS NPs), which possessed particle sizes of 144 nm and Zeta potentials of −7.5 mV, exhibited a sustained release behavior. In H-22 tumor bearing mice, significantly enhanced antitumor efficacies were achieved by PTX/PCS NPs with the tumor inhibition ratio (TIR) of 76.1% as compared with PTX injection. Furthermore, no signs of sub-acute toxicity were detected in healthy mice, indicating the safety of PCS NPs. Therefore, PCS NPs could be served as an effective and safe carrier for PTX delivery.

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

Metastasis constantly occurs in the majority of cases of primary breast cancer at late stage or following surgical treatment. Survivin, a member of the inhibitor of apoptosis protein family, has long been recognized as a promising anticancer target, but its antitumor effects remain largely unexplored. In order to elucidate the role of survivin in breast cancer metastasis, short interfering RNA (siRNA) was used in the present study to specifically downregulate survivin expression in the murine breast cancer cell line 4T1. The results demonstrated that blocking the expression of survivin by siRNA inhibited the proliferation, migration and invasion abilities of murine breast cancer cells in vitro. Vascular endothelial growth factor (VEGF)-C is a lymphatic endothelial cell-stimulating factor that may lead to the formation of lymphatic vessels in lymph nodes. In the present study, the inhibition of survivin by siRNA was able to reduce the overexpression of VEGF-C in 4T1 cells. Furthermore, intratumoral injections of the survivin-siRNA significantly inhibited the growth of orthotopically transplanted 4T1 tumors in vivo. In addition, the number of pulmonary metastases and the microlymphatic vessel density were significantly reduced in vivo, following transfection with survivin-siRNA. The results of the present study suggested that the Akt/hypoxia-inducible factor-1α signaling pathway participates in the survivin-mediated downregulation of VEGF-C expression observed in breast cancer cells treated with survivin-siRNA. Therefore, the use of siRNA specifically targeting survivin may be a potential anticancer method in the future.

Bioinspired tryptophan-rich peptide dendrimers (TRPDs) are designed as a new type of dendritic peptide drugs for efficient tumor therapy. The TRPDs feature a precise molecular structure and excellent water solubility and are obtained in a facile process. Based on the unique features of peptide dendrimers, including highly branched structures, abundant terminal groups, and globular-protein-like architectures, the therapeutic dendrimers show significant supramolecular interactions with DNA through the tryptophan residues (indole rings and amino groups). Further experimental results indicate that TRPDs are efficient antitumor agents both in vitro and in vivo.

There is a pressing need for a ubiquitously expressed antigen or receptor on the tumor surface for successful mitigation of the deleterious side effects of chemotherapy. Phosphatidylserine (PS), normally constrained to the intracellular surface, is exposed on the external surface of tumors and most tumorigenic cell lines. Here we report that a novel PS-targeting liposome, phosphatidylcholine-stearylamine (PC-SA), induced apoptosis and showed potent anticancer effects as a single agent against a majority of cancer cell lines. We experimentally proved that this was due to a strong affinity for and direct interaction of these liposomes with PS. Complexation of the chemotherapeutic drugs doxorubicin and camptothecin in these vesicles demonstrated a manyfold enhancement in the efficacies of the drugs both in vitro and across three advanced tumor models without any signs of toxicity. Both free and drug-loaded liposomes were maximally confined to the tumor site with low tissue concentration. These data indicate that PC-SA is a unique and promising liposome that, alone and as a combination therapy, has anticancer potential across a wide range of cancer types.

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.

In this paper, we used microcapsules releasing liposome-protamine-hyaluronic acid nanoparticles (LPH-NP) with/without carboplatin in response to radiation to image and treat MM48 breast cancer in C3He/N mice in two radiation sessions. The micro-particle-induced X-ray emission (PIXE) camera and quantitative PIXE were used to image and measure the release of nanoparticles from the microcapsules. In session one, iopamiron and computed tomography (CT)-detectable microcapsules containing P-selectin and LPH-NP were mixed with a solution of alginate, hyaluronate, ascorbate, and P-selectin. This solution was sprayed into an FeCl2 solution containing VEGFR-1/2 antibodies (Abs). The microcapsules obtained were injected intravenously into mice, and after 9 h, the mice were exposed to 10 or 20 Gy (140 keV) of X-ray radiation. Anti-VEGFR-1/VEGFR-2 microcapsules accumulated around tumors and released P-selectin and the iopamiron-labeled LPH-NP in response to the first radiation. The iopamiron-containing nanoparticles were detected by CT, allowing detection of MM48 tumors by CT. In the second session, the microcapsules released LPH-NH that delivered carboplatin into the tumor cells. This treatment had a significant antitumor effect [Formula: see text]. The micro-PIXE camera and quantitative PIXE successfully imaged and measured the release of contents from microcapsules. Our results indicate that targeted nanoparticles allow for accurate detection and treatment of tumors.

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.

Our previous reports demonstrated that i.p. administration of Korean red ginseng acidic polysaccharide (RGAP) exerts antitumor activity in mice. The present study was carried out to compare the effects of i.p. and p.o. routes of administration of RGAP on either normal or tumor-bearing BALB/c mice. RGAP was administered either i.p. or p.o. at doses of 100, 300, 500, 1000 ㎎/㎏ for 1 or 5 weeks. Peritoneal macrophages from mice treated with RGAP p.o. at a dose of 300 ㎎/㎏either for 1 or 5 weeks did not exhibit growth inhibition activity toward WEHI-164 tumor cells. However, administration of RGAP at a dose of 600 ㎎/㎏ for both 1 and 5 weeks increased the antitumor activity of macrophages. Oral administration of RGAP (600 ㎎/㎏) for 5 weeks and i.p. administration of RGAP (300 ㎎/㎏) for 1 week resulted in antitumor activities of 40% and 45%, respectively, indicating that the effect of i.p. injection is more potent 2 and 5 times than that of p.o. one in terms of dose and duration, respectively. Tumor inhibition rates of RGAP at doses of 300, 500, 1000 ㎎/㎏ in mice transplanted with B16-F10 melanoma were 4.4, 12.0, and 45.4%, respectively, meaning that p.o. dose higher than 500 ㎎/㎏ possess marked antitumor activity. The results above suggests that p.o. administration of RGAP also show antitumor activity in vivo depending on the dose.

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.

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.

Liposomal formulations of a potent antitumor drug, etoposide were prepared by ethanol injection method successfully. The characteristics of the etoposide liposomes, for particle size, encapsulation efficiency, leakage ratio, ? potential and physical stability, were evaluated. In vivo pharmacokinetics and tumor inhibition ratio of mice were also examined. The liposomes were characterized by high entrapment efficiency, uniform size distribution and moderate ? potential. In addition, the liposomes modified by PEG2000-DSPE could raise the AUC and prolonged the resident time of etoposide in the blood circulating system as compared to conventional liposomes containing etoposide and free etoposide solutions, and improve the tumor inhibition ratio demonstrated by anti-tumor activity experiments.

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.

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.

The anticancer activities of (C5H5)2NbCl2 (NDC) and (C5H5)2WCl2 (WDC) are investigated against Ehrlich ascites tumor in CF1 mice. Whereas with the W(IV) metallocene WDC only sporadic tumor inhibition is observed, the paramagnetic Nb(IV) derivative NDC proves to be a potent cancerostatic agent causing 100% cures in doses of 20 and 25 mg/kg. The side effects of NDC (LD50 = 35 mg/kg) are considerable and unique in the series of cancerostatic metallocene dihalides. Air oxidation of NDC yields the diamagnetic binuclear Nb(V) complex [(C5H5)2NbCl2]2O which has reduced toxic, but also diminished tumor-inhibiting properties.

The antitumor activity of vanadocene dichloride is investigated against Ehrlich ascites tumor in CFi mice. The application of 80 or 90 mg/kg 24 h after transplantation achieves 100% tumor inhibition until day 30. On treatment with higher doses death of an increasing number of animals is caused by substance toxicity. The results of this study indicate that vanadocene dichloride exhibits antineoplastic properties similar to those found for titanocene dichloride and cis-dichlorodiammine-platinum(II).

The antitumor activity of molybdocene dichloride is tested against Ehrlich ascites tumor in CF1 mice. The application of 75 or 100 mg/kg 24 h after transplantation achieves 100% tumor inhibi­tion until day 30. Following the d0 and d1 metallocene dichlorides of titanium and vanadium, molybdocene dichloride is the First analogous d2 system revealing similar antineoplastic properties.

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.

From structure--anti-L1210 relationships developed earlier for the 4'-(9-acridinylamino)alkanesulfonanilides it was predicted that congeners bearing both lipophilic 3-acridine substituents and compensatory hydrophilic function(s), together providing an overall molecular lipophilic--hydrophilic balance close to optimum, should have augmented antitumor properties. The acceptability of a variety of hydrophilic functions, and optimum positioning of these, has now been investigated. A variety of sterically demanding, hydrophilic functions may be acceptably appended to the acridine 4(5) position suggesting considerable site bulk tolerance. A variant with both a lipophilic 3-acridine substituent (3-iodo) and a hydrophilic 5-(2,3-dihydroxypropoxy) function is markedly more active than previous examples in the early treated, intraperitoneally (ip) dosed, ip implanted L1210 system, the assay system employed in the structure--activity analyses. However, this latter compound, on ip administration, failed to significantly inhibit subcutaneously implanted L1210 whereas earlier variants, under the same conditions, provided significant tumor inhibition. In this drug series the observed order of relative drug effectiveness alters with changing site of tumor implantation.

The chemotherapeutic action of Bleomycin, applied at a dosage which induced only a non-specific tumor inhibition on HRS-sarcoma, was potentiated by combination with inosine. This combination, without increasing toxicity, effected both a significant tumor inhibition and a significant curative action.

Lipopolysaccharide (LPS) was shown to prevent tumor growth in BALB/c mice when administered either prior to or after the inoculation of lethal doses of tumor cells. An attempt to elucidate the mechanism of this phenomenon utilizing in vivo protocols was made by the adoptive transfer of tumor protection with peritoneal cells as well as with cell-free peritoneal fluids obtained from non-tumor-bearing, LPS-stimulated syngeneic mice. The in vivo-activated peritoneal cells from LPS-treated mice were capable of adoptively transferring tumor protection at peritoneal cell to tumor cell ratios ranging from 1,000:1 to 100:1. Experiments were also performed that indicate that: (i) LPS exerts no direct toxic or inhibitory effect on the tumor cells, and (ii) that residual LPS present in cell and fluid preparations was not responsible for such protection.

The hypothesis that stimulated this investigation is that cyclic AMP may be a regulator of cell division and therefore may control the growth of tumors. Some inhibition of the 6C3HED, L5178Y, and L1210 tumors results from daily administration of 3 μmoles of cyclic AMP or 5.5 μmoles of theophylline. Treatment of the mice with cyclic AMP 48 hr prior to tumor inoculation produced the greatest tumor inhibition. 5′-AMP, if given during or before tumor transplantation, accelerates tumor growth. Intraperitoneal injection of 3 μmoles of cyclic AMP elevates the cyclic AMP level in the tumor for only 2 hr. The reversibility of the inhibition found in cell culture suggests that this is probably inadequate for producing tumor inhibition. The stimulation of tumor growth by 5′-AMP, a metabolite of cyclic AMP, makes multiple injections of cyclic AMP ineffective in tumor inhibition.

The sum total of inhibition of growth capacities of spontaneous tumors in mice obtained with three nucleosides used separately is similar to, if not identical, with the amount of inhibition obtained by the use of the original liver emulsion. There is also clear evidence that most of this tumor inhibition is brought about by 5 methyl cytidine (0.02 molar concentration administered intraperitoneally three times weekly with a maximum injection of a volume of 0.05 cc). Adenosine is not only an inhibitor of cancer in mice but, under certain conditions, also a stimulator (0.05 molar percentage solution with maximal injections at any one time of 0.05 cc volume). This conversion of an inhibitor of cancer to a stimulator has been brought about by aging of the solution but how the conversion takes place is not known. However, this conversion of the effect of adenosine was obtained by the same procedure that the inhibitor of cancer in the liver emulsion can be converted to a stimulator of cancer.

Summary1. The per cent tumor inhibition, change in carcass weight, and concentration of nonprotein methionine in the liver, resulting from administration of ethionine to normal, castrated, and testosterone-treated castrated male rats, has been determined. 2. Tumor inhibition by ethionine, and the toxi-city of this substance, was greater in castrated than in normal or testosterone-treated castrated male rats and closely resembled that observed in female rats. 3. The concentration of free nonprotein methionine in the liver of castrated male rats was similar to that found in female rats and differed from that observed in normal male or testosterone-treated castrated male rats. The presence of a methionine conjugate was indicated in the liver of castrated male and normal female rats following ethionine administration while such a conjugate was lacking in the liver of normal male or testosterone-treated castrated male rats. 4. It was concluded that the sex difference observed in tumor inhibition, toxicity, and...

dl-C-allylglycine inhibited the growth of Rd/3 sarcoma in male rats. The percentage tumor inhibition ranged from about 10–50 in a series of experiments carried out during an 18 month period.