Hypoxia of human solid tumors is associated with reduced cure rates with radiotherapy and with and with increased distant metastases. However, hypoxia also represents an attractive therapeutic target, since drugs can be designed that are activated to become cytotoxic only in the hypoxic environment as solid tumors. The first such drug to enter clinical trial based on this rationale is tirapazamine (TPZ), and it has already demonstrated efficacy in Phase II and III trials with cisplatin in patients with non-small cell lung cancer. TPZ, however, is limited in efficacy, particularly with fractionated irradiation by systemic toxicity. We have recently discovered that the enzymes probably responsible for anti-tumor efficacy and for systemic toxicity are different and occur in different cellular components. This provides a powerful biological rationale for developing new analogs with increased anti-tumor efficacy and reduced systemic toxicity Project 2 will perform studies on the TPZ analogs synthesized in Project 1 and will combine the data with data from Project 3 test hypotheses involved in the development of superior second generation TPZ analogs for combination, radiotherapy, and with cisplatin. We will test the hypothesis that targeting of compounds to DNA, or having them with high metabolism by the nuclear matrix enzyme(s), will improve their hypoxic cytotoxicities and reduce the effects on mitochondria, the latter probably being responsible for the dose-limiting toxicity of TPZ with fractionated irradiation. We will use both mouse and human cells in vitro to measure the aerobic and hypoxic cytotoxicities of the compounds, their potentiation of cisplatin cytotoxicity, their metabolism by the purified nuclear matrix enzyme complex and by mitochondria, and also measure with tumors in vivo the potentiation form both single and fractionated doses of irradiation and of single doses of cisplatin. Data from Project 3, particularly on the diffusability through multicellular layers and the in vivo pharmacokinetics of the drugs, will allow the hypothesis to be tested that anti-tumor efficacy on the differential hypoxic cytotoxicities of the compounds.
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