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. Despite advances in the management of cancer with radiotherapy, chemotherapy and surgery, many solid tumors remain incurable. There is an urgent need for treatments with new mechanisms of action, which may act synergistically with chemotherapy and radiotherapy. Tumor vasculature has become a recent target in the development of new cancer therapies, with the focus aimed primarily on compounds that prevent the formation and growth of new blood vessels (i.e., anti-angiogenesis therapy). An alternative approach is therapy targeted against the existing vasculature of tumors (i.e., anti-vascular therapy) using vascular destructing agents (VDAs). Through this approach, tumor blood flow is impeded, leading to extensive tumor cell death as a consequence of oxygen and nutrient deprivation. Several agents have been shown in animal models to cause marked tumor vascular shutdown, but at doses that cause prohibitive toxicity. Combretastatin A-4 Phosphate (CA4P) is a novel anti-cancer agent that displays potent and selective toxicity towards tumor vasculature. CA4P is a synthetic, water soluble, phosphorylated prodrug of the natural product combretastatin A-4 (CA4), which was originally isolated from the bark of the African bush willow, Combretum caffrum. In vitro, the parent CA4 is a strong tubulin-binding agent that has potent activity in preventing tubulin polymerization. Although the exact mechanism for the anti-vascular effects of CA4P remain under investigation, preclinical evidence suggests that it may be a consequence of endothelial cell damage. Clinically, CA4P was evaluated in three Phase I trials as of January 2002, which included 96 patients with advanced malignancies. Due to the range of Phase II recommendations from these Phase I trials, it remains difficult to choose a best dose for Phase II studies with chemotherapy. Taken together, the interpreted Phase I trials suggests the real maximum tolerated dose (MTD) is approximately 67 mg/m2 (75 mg/m2 salt form) and may be even greater in subsets of patients. Points of further consideration involved in the choice of doses are the non-overlapping toxicities of CA4P and chemotherapy. Since the optimal biologic dose may not necessarily coincide with the MTD, Phase I data for changes in tumor perfusion were reviewed. It appears that doses between 47 mg/m2 and 61 mg/m2 (52 and 68 mg/m2 salt form, respectively) are effective in reducing tumor perfusion based on DCE (dynamic contrast imaging)-MRI from 20-50%, so the optimal biologic dose may be close to the MTD. There exist PET data that suggest the effects may occur at even lower doses. For these reasons, this study is evaluating doses of 45 mg/m2 (50 mg/m2 salt form) and 63 mg/m2 (70 mg/m2 salt form) in an effort to resolve the divergent recommendations made by these Phase I studies.
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