Search

Background Transplant related toxicity is a major therapeutic challenge. We have previously reported that the toxicity of chemotherapy is largely not directly because of the drugs themselves; rather it is mainly due to DNA damage, apoptosis and hyper-inflammation triggered by cell-free chromatin particles that are released because of drug-induced host cell death. Cell-free chromatin particles can be inactivated by free-radicals which are generated when the nutraceuticals resveratrol and copper are administered orally. We investigated if a combination of resveratrol and copper would reduce transplant related toxicities in an exploratory, prospective dose-escalation study. Patients and methods Twenty-five patients with multiple myeloma were enrolled between March 2017 to August 2019. Patients were divided into 3 groups: control (Group 1, N = 5) received vehicle alone; group 2 (N = 15) received resveratrol-copper at dose level I (resveratrol = 5.6 mg and copper = 560 ng); group 3 (N = 5) received resveratrol-copper at dose level II (resveratrol = 50 mg and copper = 5 μg). The dose was given twice daily with the first dose administered 48 hours before administering melphalan and continued until day +21 post-transplant. Common Terminology Criteria for Adverse Events version 4.02 was used to assess toxicities which included oral mucositis, nausea, vomiting and diarrhea. Measurement of inflammatory cytokines was done by ELISA. Results All patients (100%) in the control group developed grade 3/4 oral mucositis compared to 8/20 (40%) in both resveratrol-copper group 2 plus group 3 combined (P = 0.039). Reduction in inflammatory cytokines: salivary TNF - α (p = 0.012) and IL—1β (p = 0.009) in dose level I but not in dose level II was observed. Conclusions A combination of resveratrol-copper reduced transplant related toxicities in patients with multiple myeloma receiving high dose melphalan. We conclude that relatively inexpensive nutraceuticals may be useful as adjuncts to chemotherapy to reduce its toxicity. Registration The trial was registered under Clinical Trial Registry of India (no.CTRI/2018/02/011905).

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer, improving outcomes in patients with advanced malignancies. The use of ICIs in clinical practice, and the number of ICI clinical trials, are rapidly increasing. The use of ICIs in combination with other forms of cancer therapy, such as chemotherapy, radiotherapy, or targeted therapy, is also expanding. However, immune-related adverse events (irAEs) can be serious in up to a third of patients. Critical questions remain surrounding the characteristics and outcomes of irAEs, and how they may affect the overall risk–benefit relationship for combination therapies. This article proposes a framework for irAE classification and reporting, and identifies limitations in the capture and sharing of data on irAEs from current clinical trial and real-world data. We outline key gaps and suggestions for clinicians, clinical investigators, drug sponsors, patients, and other stakeholders to make these critical data more available to researchers for pooled analysis, to advance contemporary understanding of irAEs, and ultimately improve the efficacy of ICIs.

We recruited 69 consecutive patients with oral cavity squamous cell carcinoma (OSCC) between January 2017 and January 2019 for this study. All patients underwent up-front surgery followed by adjuvant radio- and/or chemotherapy as indicated. Pre-operative serum levels of C-reactive protein (CRP) and cell-free chromatin (cfCh) were estimated by ELISA and post-operative histopathological features were recorded. CRP levels were significantly associated with poor histopathological features, advanced stage, bone erosion, extracapsular spread and pathological nodal status. CRP levels were not associated with survival. CfCh levels were significantly associated with bone erosion and neck nodes and patients with higher cfCh levels had significantly poor overall survival.

Mesorhizobium sp. indirectly promote the growth of plants as a biocontrol agent by inhibiting the growth of pathogens particularly Fusarium wilt of chickpea. Out of 24 Mesorhizobium isolates obtained from chickpea nodules, eight isolates showed antagonistic effect against Fusarium oxysporum. Salinity stress severely affects growth, nodulation and yield of chickpea. Mesorhizobium isolates were tested for their salt tolerance capacity at 1, 2, 4, 6 and 8% NaCl concentrations. Only two Mesorhizobium isolates MCA5 and MCA22 were found salt-tolerant upto 8% of salt concentration. Maximum increase (45.5%) in shoot dry weight was observed by inoculation of isolate MCA20 at 40 days of chickpea growth under chillum jar conditions, whereas isolate MCA23 resulted in 166.2% increase in root dry weight. Likewise, 112.6% increase in shoot dry weight was observed on inoculation of MCA14 isolate at 80th day of observation. Further extensive research is required to understand the mechanism of potential Mesorhizobium isolates of chickpea in controlling Fusarium wilt disease and salt tolerance. Selection of mesorhizobia with twin functional traits (plant growth promoting and biocontrol agent) can be exploited as future biofertilizer in chickpea.

Weeds pose a serious constraint to agricultural production and usually result in average ~37% losses of the world’s agricultural output. Thus, weed control is indispensable in every crop production system. For weed management, chemical herbicides are usually applied due to uncertainty of effects caused by mechanical methods, and it also involves more labour. Although these herbicides are quite effective in controlling the weeds, their indiscriminate use causes environmental problems and human health hazards; moreover continuous use of herbicides may lead to evolution of resistant weed biotypes and shift in the weed flora. These problems necessitated the search for an alternate ecofriendly method of weed management through the biological approach, in which microorganisms or their products could be used to suppress the growth of weed species. Many naturally occurring microorganisms in the rhizosphere have the potential to suppress the growth of weeds through the manipulation of rhizosphere ecosystem. These rhizosphere microorganisms colonize the root surfaces of weed seedlings and suppress the growth of weed plant by reducing weed density, biomass and its seed production. Many rhizosphere bacteria such as Pseudomonas aeruginosa, P. fluorescens, Erwinia herbicola, Alcaligenes sp.; strains of Xanthomonas campestris pv. poannua, Pseudomonas syringae pv. tagetis and P. syringae pv. phaseolicola, Serratia plymuthica and S. marcescens; and the fungi including Colletotrichum gloeosporioides, Aeschynomene virginica, Phomo chenopodicola and Exserohilum monoceras have been characterized as bioherbicides. The mode of action of each biocontrol agent is variable, and it may range from simple compounds like cyanide, organic acids, secondary metabolites (antibiotic 2,4-diacetylphloroglucinol) and plant growth regulators, such as auxins (indole acetic acid and δ-aminolevulinic acid). Bacterial and fungal microbes also produce a wide array of phytotoxins that interfere with metabolism of weed plants and cause plant mortality. Thus, there are immense possibilities for developing microbial bioherbicides that could reduce the application of chemical herbicides for weed control and may increase the production of cereal, oil seeds and legume crops.

Microorganisms in the soils and rhizosphere take part in biogeochemical cycles and improve the soil fertility. Diverse chemical substances in root exudates released through root systems also influence the rhizosphere biology. Moreover, structural and physical heterogeneity of soils affects the interactions of rhizosphere microorganisms with plants. The crosstalk in the rhizosphere among different kinds of microorganisms and plants is undertaken through various biochemical mechanisms. Different signaling molecules involved in crosstalk/communications are secreted for the beneficial and/or harmful interactions in the rhizosphere. The initial signal exchange in plant and microbes occurs through the release of root exudates. Enhanced microbial population in the rhizosphere improves the growth of plants by the recycling of nutrients and production of hormones. Moreover, certain microorganisms provide resistance to microbial diseases and tolerance to toxic compounds and abiotic stresses. Thus, crosstalk/communication in the roots of plant and microbes is very much essential for improving crop productivity. This chapter describes microbial communities in the rhizosphere and the associated biological processes these communities perform to sustain chemical communications. With the discovery and characterization of different kinds of secreted compounds in the rhizosphere and by the use of genomic, transcriptomic, proteomic, and metabolomic techniques, our understanding of the signal exchange between microbes and plants has expanded enormously.

Maintenance of agricultural productivity is currently based mainly on extraneous application of fertilizers and pesticides. However, indiscriminate use of agrochemicals for controlling the pests and diseases led to pollution of soil, water, and food sources, poisoning of nontarget beneficial insects, and development of insect population resistant to insecticides. To obviate the pollution problem and obtain higher yields in a sustainable manner, biological control of insect pests using specific antagonistic microorganisms is an effective alternate approach with minimum deleterious effects. Microorganisms have been obtained from the rhizosphere of different crop plants that inhibited insect pests by producing toxins, bacteriocins, siderophores, hydrolytic enzymes, and other secondary metabolites. Moreover, plant hormones salicylic acid, jasmonic acid, and ethylene orchestrate a complex transcriptional programming that eventually leads to pest-induced SAR (systemic acquired resistance) and ISR (induced systemic resistance) in many plant species. Microbial genes involved in the biosynthesis of secondary metabolites and enzymes have been cloned and transferred to other microorganisms and plants to enhance the suppression and killing of insects. The efficiency of these biocontrol products can be further increased through genetic improvement, manipulation of the soil and plant environment, using mixtures of biocontrol agents, and optimization of formulations and by integration of biocontrol agents with other alternative methods that provide additive and synergistic effects. Thus, the application of effective biocontrol agents may reduce the use of chemical insecticides and support sustainable agriculture in an eco-friendly manner in tandem with improved crop productivity.

Resistance to aromatase inhibitors is a major concern in the treatment of breast cancer. Long-term letrozole cultured (LTLC) cells represent a model of resistance to aromatase inhibitors. The LTLC cells were earlier generated by culturing MCF-7Ca, the MCF-7 human breast cancer cell line stably transfected with human placental aromatase gene for a prolonged period in the presence of letrozole. In the present study the effect of RAMBA, VN/14-1 on the sensitivity of LTLC cells upon multiple passaging and the mechanisms of action of VN/14-1 in such high passage LTLC (HP-LTLC) cells was investigated. We report that multiple passaging of LTLC cells (HP-LTLC cell clones) led to profound decrease in their sensitivity to VN/14-1. Additionally, microarray studies and protein analysis revealed that VN/14-1 induced marked endoplasmic reticulum (ER) stress and autophagy in HP-LTLC cells. We further report that VN/14-1 in combination with thapsigargin exhibited synergistic anti-cancer effect in HP-LTLC cells. Preliminary pharmacokinetics in rats revealed that VN/14-1 reached a peak plasma concentration ( C max ) within 0.17 h after oral dosing. Its absolute oral bioavailability was >100%. Overall these results indicate potential of VN/14-1 for further clinical development as a potential oral agent for the treatment of breast cancer.

The U.S. Food and Drug Administration (FDA) describes the accelerated approval of brentuximab vedotin for patients with relapsed Hodgkin lymphoma and relapsed systemic anaplastic large-cell lymphoma (sALCL). FDA analyzed the results of two single-arm trials, enrolling 102 patients with Hodgkin lymphoma and 58 patients with sALCL. Both trials had primary endpoints of objective response rate (ORR) and key secondary endpoints of response duration and complete response (CR) rate. For patients with Hodgkin lymphoma, ORR was 73% (95% CI, 65–83%); median response duration was 6.7 months, and CR was 32% (95% CI, 23–42%). For patients with sALCL, ORR was 86% (95% CI, 77–95%), median response duration was 12.6 months, and CR was 57% (95% CI, 44–70%). The most common adverse reactions were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting. FDA granted accelerated approval of brentuximab vedotin for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplantation (ASCT) or after failure of at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates, and for the treatment of patients with sALCL after failure of at least one prior multiagent chemotherapy regimen. Clin Cancer Res; 18(21); 5845–9. ©2012 AACR.

Learning Objectives After completing this course, the reader will be able to: Compare the survival benefits of rituximab in combination with fludarabine and cyclophosphamide to those of alemtuzumab, bendamustine, and ofatumumab in patients with CLL.Identify CLL patients for whom rituximab in combination with fludarabine and cyclophosphamide may be an appropriate first-line regimen. CME This article is available for continuing medical education credit at CME.TheOncologist.com Purpose. To describe the clinical studies that led to the FDA approval of rituximab in combination with fludarabine and cyclophosphamide (FC) for the treatment of patients with chronic lymphocytic leukemia (CLL). Materials and Methods. The results of two multinational, randomized trials in CLL patients comparing rituximab combined with fludarabine and cyclophosphamide versus FC were reviewed. The primary endpoint of both studies was progression-free survival (PFS). Results. The addition of rituximab to FC decreased the risk of a PFS event by 44% in 817 previously untreated patients and by 24% in 552 previously treated patients. Median survival times could not be estimated. Exploratory analysis in patients older than 70 suggested that there was no benefit to patients when rituximab was added to FC. The safety profile observed in both trials was consistent with the known toxicity profile of rituximab, FC, or CLL. Conclusions. On the basis of the demonstration of clinically meaningful prolongation of PFS, the FDA granted regular approval to rituximab in combination with FC for the treatment of patients with CLL. The magnitude of the treatment effect in patients 70 years and older is uncertain.

We previously reported that our novel compound 3β-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (VN/124-1) is a potent 17α-hydroxylase/17,20-lyase (CYP17) inhibitor/antiandrogen and strongly inhibits the formation and proliferation of human prostate cancer LAPC4 tumor xenografts in severe combined immunodeficient mice. In this study, we report that VN/124-1 and other novel CYP17 inhibitors also cause down-regulation of androgen receptor (AR) protein expression in vitro and in vivo. This mechanism of action seems to contribute to their antitumor efficacy. We compared the in vivo antitumor efficacy of VN/124-1 with that of castration and a clinically used antiandrogen, Casodex, and show that VN/124-1 is more potent than castration in the LAPC4 xenograft model. Treatment with VN/124-1 (0.13 mmol/kg twice daily) was also very effective in preventing the formation of LAPC4 tumors (6.94 versus 2410.28 mm3 in control group). VN/124-1 (0.13 mmol/kg twice daily) and VN/124-1 (0.13 mmol/kg twice daily) + castration induced regression of LAPC4 tumor xenografts by 26.55% and 60.67%, respectively. Treatments with Casodex (0.13 mmol/kg twice daily) or castration caused significant tumor suppression compared with control. Furthermore, treatment with VN/124-1 caused marked down-regulation of AR protein expression, in contrast to treatments with Casodex or castration that caused significant up-regulation of AR protein expression. The results suggest that VN/124-1 acts by several mechanisms (CYP17 inhibition, competitive inhibition, and down-regulation of the AR). These actions contribute to inhibition of the formation of LAPC4 tumors and cause regression of growth of established tumors. VN/124-1 is more efficacious than castration in the LAPC4 xenograft model, suggesting that the compound has potential for the treatment of prostate cancer. [Mol Cancer Ther 2008;7(8):2348–57]

Novel mutual prodrugs (MPs) of ATRA (all- trans-retinoic acid) and HDIs (histone deacetylase inhibitors) ( 10, 13, 17- 19) connected via glycine acyloxyalkyl carbamate linker (AC linker) or through a benzyl ester linker (1,6-elimination linker) were rationally designed and synthesized. Most of our novel MPs were potent inhibitors of growth of several hormone-insensitive/drug resistant breast cancer cell lines and the hormone-insensitive PC-3 prostate cancer cell line. The novel MPs exhibited differential antiproliferative potencies in both MDA-MB-231 and PC-3 cell lines. Whereas 19 (VNLG/124) [4-(butanoyloxymethyl)phenyl(2 E,4 E,6 E,8 E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoate] with a GI 50 of 10 nM was the most potent MP versus the MDA-MB-231 cells, 13 (VNLG/66) [{ N-[ N-{2-[4-{[3-pyridylmethoxy)carbonyamino]methyl}phenyl) carbonylamino]phenyl} carbamoylcarbamoyloxy}methyl(2 E,4 E,6 E,8 E)-3,7-dimethyl-9-(2,6,6-trimethyl cyclohex-1-enyl)nona-2,4,6,8-tetraenoate] with a GI 50 = 40 nM was the most potent versus the PC-3 cells. MP 19 exhibited the most benefit because its GI 50 of 10 nM versus MDA-MB-231 cells was remarkably 1085-fold lower than that of parent ATRA and over 100000-fold lower than butyric acid (BA).

Combining drugs, which target different signalling pathways, often decreases adverse side effects while increasing the efficacy of treatment. The objective of our study was to determine if the combination of our novel atypical retinoic acid metabolism-blocking agent (RAMBA) VN/66-1 and a promising histone deacetylase inhibitor N-(2-aminophenyl)4-[N-(pyridine-3-yl-methoxy-carbonyl)aminomethyl]benzamide (MS-275) would show enhanced antineoplastic activity on human PC-3 prostate cancer cells/tumours and also to decipher the molecular mechanisms of action. The combination of VN/66-1+MS-275 was found to be synergistic in inhibiting PC-3 cell growth, caused cell cytostaticity/cytotoxicity and induced marked G2/M phase arrest and apoptosis. In mice with well-established PC-3 tumours, VN/66-1 (5 and 10 mg kg(-1) day(-1)) caused significant suppression of tumour growth compared with mice receiving vehicle alone. Furthermore, treatment with VN/66-1 (10 mg kg(-1) day(-1))+MS-275 (2.5 mg kg(-1) day(-1)) for 18 days resulted in an 85% reduction in final mean tumour volume compared with control and was more effective than either agent alone. Mechanistic studies indicated that treatment of PC-3 cells/tumours with VN/66-1+MS-275 caused DNA damage (upregulation of gammaH2AX), hyperacetylation of histones H3 and H4, upregulation of retinoic acid receptor-beta, p21WAF1/CIP1, E-cadherin, and Bad and downregulation of Bcl-2. These data suggest that the mechanism of action of the combination of agents is DNA damage-induced p21 activation, resulting in inhibition of the Cdc2/cyclin B complex and accumulation of cells in G2/M phase. In addition, the combination caused modulation and induction of apoptosis. These results suggest that VN/66-1 or its combination with MS-275 may be a novel therapy for the treatment of prostate carcinoma.

Antitumour effects of retinoids are attributed to their influence on cell proliferation, differentiation, apoptosis and angiogenesis. In our effort to develop useful agents for breast cancer therapy, we evaluated the effects of four representative retinoic acid metabolism blocking agents (RAMBAs, VN/14-1, VN/50-1, VN/66-1 and VN/69-1) on growth inhibition of oestrogen receptor positive (ER +ve, MCF-7 and T-47D) and oestrogen receptor negative (ER -ve, MDA-MB-231) human breast cancer cells. Additionally, we investigated the biological effects/molecular mechanism(s) underlying their growth inhibitory properties as well as their antitumour efficacies against MCF-7 and MCF-7Ca tumour xenografts in nude mice. We also assessed the effect of combining VN/14-1 and all-trans-retinoic acid (ATRA) on MCF-7 tumour xenografts. The ER +ve cell lines were more sensitive (IC(50) values between 3.0 and 609 nM) to the RAMBAs than the ER -ve MDA-MB-231 cell line (IC(50)=5.6-24.0 microM). Retinoic acid metabolism blocking agents induced cell differentiation as determined by increased expression of cytokeratin 8/18 and oestrogen receptor-alpha (ER-alpha). Similar to ATRA, they also induced apoptosis via activation of caspase 9. Cell cycle analysis indicated that RAMBAs arrested cells in the G1 and G2/M phases and caused significant downregulation (80%) of cyclin D1 protein. In vivo, the growth of MCF-7 mammary tumours was dose-dependently and significantly inhibited (92.6%, P0.0005) by VN/14-1. The combination of VN/14-1 and ATRA also inhibited MCF-7 breast tumour growth in vivo (up to 120%) as compared with single agents (P0.025). VN/14-1 was also very effective in preventing the formation of MCF-7Ca tumours and it significantly inhibited the growth of established MCF-7Ca tumours, being as effective as the clinically used aromatase inhibitors, anastrozole and letrozole. Decrease in cyclin D1 and upregulation of cytokeratins, Bad and Bax with VN/14-1 may be responsible for the efficacy of this compound in inhibiting breast cancer cell growth in vitro and in vivo. Our results suggest that our RAMBAs, especially VN/14-1 may be useful novel therapy for breast cancer.

Antibody–drug conjugate (ADC) development started about three decades ago with the hypothesis that toxins conjugated to antibodies would enhance antitumor activity and reduce toxicity by delivering toxins to specific tumor sites. Since then, the field has evolved to include potent small molecule drugs (SMD) and radiolabeled drugs conjugated to antibodies targeting both solid tumors and hematologic malignancies. Improved ADC technology has paved the way for increased drug delivery to the target tumors and decreased normal tissue exposure to cytotoxic agents. Radio-immunoconjugates (RICs) present a different set of challenges leading to unique development pathways. Several factors need to be taken into consideration when developing RICs, such as decay of radioactivity, potentially higher exposure to normal tissue caused by lower specificity, and dehalogenation leading to a loss of signal. This chapter focuses on antibodies conjugated to SMDs.

Most plants grown in fields are colonized by diverse groups of rhizosphere bacteria that form beneficial or pathogenic relationships with their hosts. The root exudates encourage the development of beneficial bacterial communities in the root zone capable of producing secondary metabolites that improve plant growth and crop yield. These beneficial associations facilitate plant growth either by enhancing crop nutrition, releasing plant growth stimulating hormones, reducing damages caused by pathogens/pests by producing antibiotics, bacteriocins, siderophores, hydrolytic enzymes and other secondary metabolites or by improving resistance to environmental pollutants. Rhizosphere bacteria also supply biologically fixed nitrogen, solubilize bound phosphorus and may provide other nutrients, such as, potassium, iron and sulfur to plants. These beneficial associations hence, reduce the requirement of chemical fertilizers used for crop productivity. Moreover, some rhizobacteria are used to relieve the toxicity of metals and organic toxicants, either through stimulation of microbial degradation of pollutants in the rhizosphere, or by uptake of pollutants/toxicants by the plant. The inoculation of the legumes with such rhizosphere bacteria has often been found to increase symbiotic properties, plant biomass and yields under green house or field conditions. Tremendous progress has been made recently in characterizing the process of rhizosphere colonization, identification and cloning of bacterial genes involved in nitrogen fixation, phosphorus solubilization, production of plant growth regulators and in suppression of plant diseases. The interactions/relationships of rhizosphere bacteria with their hosts and performance of wild-type and genetically manipulated beneficial bacterial populations are discussed for their efficient utilization in legume production under sustainable agriculture systems.

We have developed new, simple, and efficient procedures for the synthesis of two promising histone deacetylase inhibitors (HDIs), CI-994, (N-(2-aminophenyl)-4-acetylaminobenzamide), and MS-275 (N-(2-aminophenyl)4-[N-(pyridine-3-yl-methoxycarbonyl)aminomethyl]benzamide) from commercially available acetamidobenzoic acid and 3-(hydroxymethyl)pyridine, respectively. The procedures provide CI-994 and MS-275 in 80% and 72% overall yields, respectively. We found that the combination of four HDIs (CI-994, MS-275, SAHA, and TSA) with retinoids all-trans-retinoic acid (ATRA) or 13-cis-retinoic acid (13-CRA) or our atypical retinoic acid metabolism blocking agents (RAMBAs) 1 (VN/14-1) or 2 (VN/66-1) produced synergistic anti-neoplastic activity on human LNCaP prostate cancer cells. The combination of 2 and SAHA induced G1 and G2/M cell cycle arrest and a decrease in the S phase in LNCaP cells. 2+SAHA treatment effectively down-regulated cyclin D1 and cdk4, and up-regulated pro-differentiation markers cytokeratins 8/18 and pro-apoptotic Bad and Bax. Following subcutaneous administration, 2, SAHA or 2+SAHA were well tolerated and caused significant suppression/regression of tumor growth compared with control. These results demonstrate that compound 2 and its combination with SAHA are potentially useful agents that warrant further preclinical development for treatment of prostate cancer.

The search for novel androgen receptor (AR) down-regulating agents by catalyst HipHop pharmacophore modeling led to the discovery of some lead molecules. Unexpectedly, the effect of these leads on human prostate cancer LNCaP cell viability did not correlate with the ability of the compounds to cause down-regulation of AR protein expression. Through rational synthetic optimization of the lead compound (BTB01434), we have discovered a series of novel substituted diaryl molecules as potent anti-prostate cancer agents. Some compounds ( 1 – 6 ) were shown to be extremely potent inhibitors of LNCaP cell viability with GI 50 values in the nanomolar range (1.45–83 nM). The most potent compound (4-methylphenyl)[(4-methylphenyl)sulfonyl]amine ( 5 ) with a GI 50 value of 1.45 nM is 27,000 times more potent than our lead compound BTB01434 (GI 50 = 39.8 μM). In addition, some of the compounds exhibited modest anti-androgenic activities and one was also a potent inhibitor (GI 50 = 850 nM) of PC-3 (AR-null) cell growth. A clear structure–activity relationship (SAR) has been established for activity against LNCaP cells, where potent molecules possess two substituted/unsubstituted aromatic rings connected through a sulfonamide linker. These novel compounds are strong candidates for development for the treatment of hormone-sensitive and importantly hormone-refractory prostate cancers in humans.

A qualitative 3D pharmacophore model (a common feature based model or Catalyst HipHop algorithm) was developed for well-known natural product androgen receptor down-regulating agents (ARDAs). The four common chemical features identified included: one hydrophobic group, one ring aromatic group, and two hydrogen bond acceptors. This model served as a template in virtual screening of the Maybridge and NCI databases that resulted in identification of six new ARDAs (EC(50) values 17.5-212 microM). Five of these molecules strongly inhibited the growth of human prostate LNCaP cells. These novel compounds may be used as leads to develop other novel anti-prostate cancer agents.

Novel potent C-4 azolyl retinoic acid metabolism blocking agents (RAMBAs)-VN/14-1, VN/50-1, VN/66-1, VN/67-1, and VN/69-1, have been synthesized and investigated for their in vitro and in vivo effects against breast and prostate cancers. These RAMBAs, in addition to being potent inhibitors of all-trans-retinoic acid (ATRA) metabolism have potent anti-cancer properties and in vivo anti-tumor efficacies as characterized in breast and prostate cancer models. Here we determined the toxicity and pharmacokinetics (PK) of these various RAMBAs.Preliminary acute toxicity studies of these RAMBAs were carried out using Swiss NIH mice. The toxicity profile of the RAMBAs was evaluated relative to ATRA. Three different doses (8.3, 33, and 100 micromol/kg/day) of ATRA and RAMBAs were administered on a daily basis subcutaneously for 14 days to the mice. Clinical signs of toxicity alopecia, scaly skin, and loss of body weight in the mice were observed during the study and the maximum tolerated dose was determined. PK of selected agents (VN/14-1, VN/50-1, and VN/66-1) was studied in Balb/C mice after a single dose subcutaneous administration. Plasma concentrations of the agents were quantitatively determined using a high-performance liquid chromatographic method with ultraviolet detection. Plasma concentration versus time profiles were fit to various PK structural models and relevant PK parameters were estimated.VN/66-1 and VN/69-1 were found to be the least toxic even at the highest doses when compared to the other RAMBAs and ATRA. VN/66-1 had the longest half-life, the slowest clearance, and the greatest exposure.Based on PK characteristics and toxicity studies, VN/66-1 appeared to be the most favorable agent. However, both VN/14-1 and VN/66-1 are our leads based on the fact that VN/14-1 has been found to be highly effective in endocrine-sensitive and -resistant breast cancer cells and tumors with little toxicity. Our findings provide valuable information that will be used to select RAMBAs and establish therapeutic regimens that provide optimal efficacy with minimal toxicity.

The naturally occurring retinoids and their synthetic analogs play a key role in differentiation, proliferation, and apoptosis, and their use/potential in oncology, dermatology and a variety of diseases are well documented. This review focuses on the role of all-trans-retinoic acid (ATRA), the principal endogenous metabolite of vitamin A (retinol) and its metabolism in oncology and dermatology. ATRA has been used successfully in differentiated therapy of acute promyelocytic leukemia, skin cancer, Kaposi's sarcoma, and cutaneous T-cell lymphoma, and also in the treatment of acne and psoriasis. However, its usefulness is limited by the rapid emergence of acquired ATRA resistance involving multifactoral mechanisms. A key mechanism of resistance involves ATRA-induced catabolism of ATRA. Thus, a novel strategy to overcome the limitation associated with exogenous ATRA therapy has been to modulate and/or increase the levels of endogenous ATRA by inhibiting the cytochrome P450-dependent ATRA-4-hydroxylase enzymes (particularly CYP26s) responsible for ATRA metabolism. These inhibitors are also referred to as retinoic acid metabolism blocking agents (RAMBAs). This review highlights development in the design, synthesis, and evaluation of RAMBAs. Major emphasis is given to liarozole, the most studied and only RAMBA in clinical use and also the new RAMBAs in development and with clinical potential.