OPTIMIZING CANCER CHEMOTHERAPY

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Despite the recent appearance of an exciting new arsenal of effective anti-cancer therapeutic agents (e.g. liposomal drugs, gene therapies, radiolabeled antibodies, and toxins), selectively delivering adequate concentrations of these new agents to tumor cells making up primary and metastatic cancers larger than 1 - 2 cm remains a problem. We propose that whoel body hyperthermia (WBH), can be used to increase both the delivery and cytotoxicity of drugs to tumors, while sparing normal tissue. WBH can (i) increase the permeability of tumor microvasculature, (ii) increase drug passage across the tumor cell membrane, (iii) stimulate release of drugs from liposomes, (iv) increase direct cytotoxicity by increasing the interaction of drugs with sub-cellular targets such as DNA (v) inhibit the repair of drug-induced cellular damage, and (vi) destroy tumor microvasculature, thereby limiting tumor growth and metastasis. This proposal focuses on aspects (i), (iii), and (vi). The specific aims are A) to use WBH to increase liposome delivery to tumor by increasing tumor microvascular permeability; B) to use WBH once liposomes have accumulated in the tumor to stimulate and synchronize release of drug from the liposome; C) to combine liposomal drug with two heat fractions designed to target microvessel permeability and synchronize drug release from the liposomes in a way which balances tumor control, achieved through direct endothelial cytotoxicity and microvessel destruction, with normal tissue toxicity. We propose to achieve this by administering carefully designed combinations of WBH and Doxil (doxorubicin encapsulated in a pegylated, sterically stabilized liposome) to Fischer rats bearing orthotopically inoculated MTLn3 mammary adenocarcinomas which spontaneously metastasize to lymph nodes. WBH will be administered as LL-WBH [long-duration (6h), low-temperature (fever-like) 39.5-40.0 C) WHB) and SH-WBH [short-duration (1 h), high temperature (41.5 C) WBH]. In order to determine the efficacy of these treatments, we will quantify a) primary and metastatic tumor response, b) normal tissue response, c) plasma drug concentration and drug accumulation in tumor and normal tissues as a function of time (pharmacokinetics), d) microvessel permeability as indicated by VPF/VEGF and Flk-1/KDR levels as a function of time, and e) the time course of tumor microvascular density. The ultimate goal is to develop a treatment, which uses multiple heat fractions, together with liposome-encapsulated agents, to target two different aspects of tumor neovasculature to enhance tumor toxicity. The strategy explored in this proposal has direct relevance to the delivery of many of the innovative, new therapeutic agents. Through such a hyperthermia-mediated multi- pronged attack, we hope to significantly increase the survival and quality of life of patients with common cancers.