Plant derived antitumor agents and their modified compounds are excellent sources of new drugs for cancer chemotherapy. This is clearly exemplified by the Vinca alkaloids, vincristine and vinblastine, and the semisynthetic podophyllotoxin derivatives, etoposide (VP-16) and teniposide (VM-26). These new leads as well as numerous additional novel plant cytotoxic antitumor agents have also contributed significantly to a mechanistic understanding of antitumor action, which in turn will be useful for future synthetic anticancer drug design. We propose continuously to isolate and determine the structures of novel cytotoxic antitumor compounds from selected active plant extracts. The isolated novel active principles will be further modified for enhanced activity and reduced toxicity. Extracts of 49 previously unexplored species mostly of Chinese origin in 31 families, which have shown potent cytotoxic activity in the new human cancer cell lines including the human lung carcinoma cell A-549, the human colon HCT-8, MCF-7, KB, P-388, or L-1210, depending upon the initial selective cytotoxicity demonstrated by the crude extracts. Those extracts which demonstrate the most potent activity in A-549, HCT-8 or MCF-7 will receive the top priority for investigation and possible uncovering of novel potential new drugs for the treatment of refractory solid tumors. The in vitro active compounds will be submitted to National Cancer Institute for further panels of human cancer cell line as well as in vivo evaluations. Modern physical methods, such as UV, IR, NMR, ORD, CD, mass spectroscopy and X-ray crystallographic analysis, as well as elemental analysis will be used to elucidate and confirm the complete structures of the isolated active principles. Studies on the structure modification in the course of structural elucidation and synthesis of analogs for the potent cytotoxic agents with novel structures will be added in order to investigate the structure-activity relationships as well as to produce compounds which might ultimately become clinically useful in cancer treatment and become novel biochemical probes for the investigation of tumor cell biology.
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