A PHASE I STUDY OF OSI-461 IN COMBINATION WITH MITOXANTRONE (NOVANTRONE ) IN

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。米托蒽醌是一种化疗药物，可导致脱氧核糖核酸（DNA）交联和链断裂，干扰核糖核酸（RNA），并抑制增殖和非增殖培养人细胞中的拓扑异构酶II。它已被批准用于治疗难治性前列腺癌和急性非淋巴细胞白血病，并已被广泛研究用于治疗乳腺癌以及各种白血病和淋巴瘤[ - ]。OSI-461是一种细胞生长抑制剂，在多种肿瘤细胞系中选择性诱导凋亡，同时还抑制血管生成和阻断有丝分裂进程。来自OSI-461在29名具有可测量疾病的难治性前列腺癌患者中进行的II期初步研究的初步数据表明，该患者群体具有适度的抗肿瘤活性。在200 mg BID剂量水平下，1例患者在肝转移中出现轻微缓解，1例患者盆腔淋巴结病减轻，1例患者疾病稳定6个周期。在400 mg BID剂量水平下，1名患者具有未经证实的> 50% PSA应答。细胞生长抑制剂与标准细胞毒性疗法的组合目前正在进行深入评价。尽管OSI 461和米托蒽醌的组合的活性的临床前证据仍在产生中，但该组合似乎值得在药理学基础上（抑制拓扑异构酶II并诱导肿瘤细胞凋亡）和从临床角度进行研究，因为这些药剂具有不同的毒性特征。此外，这两种药物在难治性前列腺癌患者中均表现出活性。因此，每日两次口服OSI-461与每个周期第1天剂量的米托蒽醌组合可以证明是可行且有效的药物组合。

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.