nsc-141537 and Disease-Models--Animal

Although fungi produce highly structurally diverse metabolites, many of which have served as excellent sources of pharmaceuticals, no fungi-derived agent has been approved as a cancer drug so far. This is despite a tremendous amount of research being aimed at the identification of fungal metabolites with promising anticancer activities. This review discusses the results of clinical testing of fungal metabolites and their synthetic derivatives, with the goal to evaluate how far we are from an approved cancer drug of fungal origin. Also, because in vivo studies in animal models are predictive of the efficacy and toxicity of a given compound in a clinical situation, literature describing animal cancer testing of compounds of fungal origin is reviewed as well. Agents showing the potential to advance to clinical trials are also identified. Finally, the technological challenges involved in the exploitation of fungal biodiversity and procurement of sufficient quantities of clinical candidates are discussed, and potential solutions that could be pursued by researchers are highlighted.

Topics: Androstadienes; Animals; Antineoplastic Agents; Aphidicolin; Biological Products; Clinical Trials as Topic; Cyclohexanes; Diketopiperazines; Disease Models, Animal; Drug Design; Drug Resistance, Neoplasm; Fatty Acids, Unsaturated; Female; Fungi; Humans; Macrolides; Male; Mice; Neoplasms; Polycyclic Sesquiterpenes; Sesquiterpenes; Trichothecenes; Wortmannin

The trichothecene mycotoxins contaminate cereal grains and have been related to alimentary toxicosis resulted in emetic response. This family of mycotoxins comprises type A to D groups of toxic sesquiterpene chemicals. Diacetoxyscirpenol (DAS), one of the most toxic type A trichothecenes, is considered to be a potential risk for human and animal health by the European Food Safety Authority. Other type A trichothecenes, T-2 toxin and HT-2 toxin, as well as type B trichothecene deoxynivalenol (DON), have been previously demonstrated to induce emetic response in the mink, and this response has been associated with the plasma elevation of neurotransmitters peptide YY (PYY) and serotonin (5-hydroxytryptamine, 5-HT). However, it is found that not all the type A and type B trichothecenes have the capacity to induce PYY and 5-HT. It is necessary to identify the roles of these two emetogenic mediators on DAS-induced emesis. The goal of this study was to determine the emetic effect of DAS and relate this effect to PYY and 5-HT, using a mink bioassay. Briefly, minks were fasted one day before experiment and given DAS by intraperitoneally and orally dosing on the experiment day. Then, emetic episodes were calculated and blood collection was employed for PYY and 5-HT test. DAS elicited robust emetic responses that corresponded to upraised PYY and 5-HT. Blocking the neuropeptide Y2 receptor (NPY2R) diminished emesis induction by PYY and DAS. The serotonin 3 receptor (5-HT3R) inhibitor granisetron totally restrained the induction of emesis by serotonin and DAS. In conclusion, our findings demonstrate that PYY and 5-HT have critical roles in DAS-induced emetic response.

Topics: Animals; Antiemetics; Disease Models, Animal; Female; Granisetron; Mink; Peptide YY; Receptors, Gastrointestinal Hormone; Receptors, Serotonin, 5-HT3; Secretory Pathway; Serotonin; Serotonin 5-HT3 Receptor Antagonists; Trichothecenes; Up-Regulation; Vomiting

Topics: Animals; Anorexia; Appetite Regulation; Behavior, Animal; Cholecystokinin; Disease Models, Animal; Feeding Behavior; Female; Glucagon-Like Peptide 1; Mice; Peptide Fragments; Satiety Response; Signal Transduction; T-2 Toxin; Time Factors; Trichothecenes; Up-Regulation

The use of a tumor colony assay was evaluated for its ability to predict anticancer drug response in an N[4-(5-nitro-2-furyl)-2-thiazolyl] formamide mouse bladder tumor model. One-hour and continuous drug exposure were compared to determine what effect altering drug concentration and time of exposure would have on the predictability of the tumor colony assay in the murine model. Ten anticancer drugs were tested in the murine model, and tumor cells removed from control mice were used for in vitro drug testing. One-hour and continuous drug exposure (using the one-hour drug level) were performed simultaneously and the in vitro and in vivo data compared. Using one-hour drug incubation in the tumor colony assay resulted in a true positive predictive rate of 54 per cent and a true negative predictive rate of 70 per cent. Continuous drug incubation overestimated drug sensitivity resulting in a drop in the predictability of the tumor colony assay. We conclude that using one-hour drug exposure the tumor colony assay is predictive of chemotherapeutic drug response in this murine bladder tumor model.

Topics: Animals; Antineoplastic Agents; Bleomycin; Cell Line; Cisplatin; Colony-Forming Units Assay; Disease Models, Animal; Doxorubicin; FANFT; Female; Fluorouracil; Maytansine; Methotrexate; Mice; Mice, Inbred C3H; Mitomycin; Mitomycins; Podophyllotoxin; Streptozocin; Time Factors; Trichothecenes; Tumor Stem Cell Assay; Urinary Bladder Neoplasms