This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mitoxantrone is a chemotherapy agent that causes crosslinks and strand breaks in deoxyribonucleic acid (DNA), interferes with ribonucleic acid (RNA), and inhibits topoisomerase II in both proliferating and nonproliferating cultured human cells. It has been approved for use in hormone-refractory prostate cancer and acute nonlymphocytic leukemia, and has been extensively studied in the treatment of breast cancer as well as various leukemias, and lymphomas [ - ]. OSI-461 is a cytostatic agent that selectively induces apoptosis in a variety of tumor cell lines while also inhibiting angiogenesis and blocking mitotic progression. Preliminary data from a Phase II pilot study of OSI-461 in 29 hormone-refractory prostate cancer patients with measurable disease demonstrate modest antitumor activity in this patient population. At the 200 mg BID dose level, one patient had a minor response in a liver metastasis, one patient had a reduction in pelvic lymphadenopathy, and one patient had stable disease for 6 cycles. At the 400 mg BID dose level, one patient had an unconfirmed > 50% PSA response. The combination of cytostatic agents with standard cytotoxic therapies is currently under intensive evaluation. Though preclinical evidence of activity for the combination of OSI 461 and mitoxantrone is still being generated, the combination seems worthwhile to investigate both on a pharmacological basis (inhibition of topoisomerase II coupled with induction of apoptosis in tumor cells) and from a clinical perspective since these agents have differing toxicity profiles. In addition, both agents demonstrate activity in hormone-refractory prostate cancer patients. Therefore, OSI-461 orally twice daily combined with a Day 1 dose of mitoxantrone every cycle may prove a feasible and efficacious combination of drugs.
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