Natural products are represented among clinically useful antitumor agents. The general goal of this project is to find and identify small molecules that can manipulate function of proteins and other receptors relevant to cancer. Answers to critical questions related to mechanism and site of action of cytotoxic compounds are now desired much earlier in the progression from compound discovery to clinical trial. Truly novel chemotherapeutic agents that are most likely to attract interest are cytotoxic or cytostatic compounds that exhibit activity against solid tumors and also target novel points of intervention in the sequence of events in oncogenesis. Natural products that induce apoptosis in transformed proliferating tumor cells may lead to tumor cell-specific suppressive agents that are useful as cancer chemotherapeutic drugs. Drug-induced apoptosis involves cell-cycle specific events mediated by a family of genes and gene products including p53 and Bcl-2 that may constitute a novel target for cancer chemotherapy. Apoptosis has important implications in the clinical outcome of cancer chemotherapy, not only for arresting tumor growth, but also for solid tumor regression by channeling the disposal of apoptotic tumor cells without problematic inflammatory responses. Pure cytotoxic and cytostatic natural products will be isolated from invertebrates collected from sites of unique marine biodiversity based on bioassay-guided purification. Active compounds will be prioritized based on activity against HCT-116 (colon tumor) and CCRF-CEM (T-cell leukemia), MCF-7 (breast), PC-3 (prostate), SK-MEL-5 (malignant melanoma), A549 (lung carcinoma), and HL-60 (promyelocytic) tumor cell lines. Prioritized cytotoxic compounds that also induce apoptosis in PC-3 and MCF-7 will be evaluated further by cell flow cytometry and drug profiling using DNA-microarray technology to determine the involvement of genes in cell-cycle arrest related to drug-induced apoptotic events. Promising new leads that emerge from this evaluation will be advanced to in vivo trials in animal models to ascertain their potential usefulness as leads in development of novel anticancer drugs active against human solid tumors.
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