The STAMP program is a closely integrated multidisciplinary laboratory and clinical effort to design curative high dose combination chemotherapy regimens with hematopoietic stem cell support for the treatment of cancer. Alkylating agents serve as the building blocks of most high dose regimens because they exhibit steep dose-response relationships, relative non-cross resistance, some degree of therapeutic synergy, and broad cytotoxicity in a variety of tumors. Moreover they are generally non-cell cycle specific and can be substantially dose-escalated with hematopoietic support before dose-limiting organ toxicity intervenes. To the extent that other classes of antineoplastic agents share these properties and possess complementary activity, they can be incorporated into clinical regimens. The rational design and rigorous clinical evaluation of more effective dose intense regimens for common solid tumors (with specific focus on breast cancer, small cell lung cancer, and lymphomas) is based on close collaboration between clinical, statistical, and basic research components of this grant. The STAMP program has designed and implemented an orderly progression of phase I/II high dose trials, leading to disease-specific phase II/III trials. Specific themes include the development of new agents for high dose combinations, agents which overcome specific mechanisms of resistance (such as hypoxia and angiogenesis), and enhanced delivery of activated metabolites of alkylating agents. The study of resistance has been expanded to include characterization of the """"""""high-dose tumor cell survivor"""""""" persisting in preclinical models and in patient tissues and stem cell sources after intensive therapy. We will explore the significance of the expression of several in situ markers persisting or developing after therapy and the expression of novel targets before and after therapy. We ultimately hope to develop specific targeted therapy against these residual cells.
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