We are searching for relatively non-toxic platinum drugs which can be given systemically and which will increase the cytotoxicity and antitumor efficacy of local hyperthermia ionic radiation. A series of coordination complexes of platinum (II) with aromatic heterocyclic molecules and a series of tight ion pairs of tetrachloroplatinum (II) with (+)-charged aromatic cellular dyes will be examined. Representative compounds from both series appear to have the characteristics we are seeking in that several of these drugs are excellent radiosensitizers and are relatively non-toxic so that much more can be given to animals on a molar basis than can cisplatin (CDDP). We have tested some of these drugs in vitro and have found that the cytotoxicity of each compound towards aerobic cells is markedly increased by concomitant hyperthemia (42 degrees C for 1 h). The degree of heat sensitization of cells to these compounds is as great or greater than we have observed with CDDP previously. In the Lewis lung tumor we observed a 2.5-fold increase in growth delay when CDDP was given just prior to 43 degrees C for 30 min, as compared to drug without hyperthermia. Hyperthermia (43 degrees C for 30 min) alone only moderately prolonged growth delay. With Pt(Rh-123)2, however, 5- and 7-fold increases in growth delay were observed when Pt(Rh-123)2 was administered at two dose levels at 43 degrees C for 30 min, as compared to drug without hyperthermia. We propose to continue our in vitro laboratory investigations in order to define optimum drugs of each class for animal testing. In addition, we are seeking to understand the mechanisms responsible for increased cytotoxicity of these drugs at elevated temperatures in order to suggest even better structures for synthesis. Specifically, we will study in vitro cytotoxicity of these and related compounds in EMT6 cells, in a human squamous cell line (SCC-25) and in a subclone of the squamous cells resistant to CDDP (SCC-25/CP). Cellular retention of drugs and DNA damage will also be assessed. These end points will be evaluated as a function of drug concentration, peak temperatures during exposure, rate of heating, stepdown heating, pH and oxygenation of cells during treatment. Also, selected compounds will be evaluate in two mouse tumors (FSaIIC fibrosarcoma and Lewis lung tumor). The in vivo studies will assay the effect of these drugs on tumor growth delay as a function of local tumor temperature and scheduling of drugs with hyperthermia plus or minus fractionated radiation. The bone marrow, renal and hepatic toxicity of the complexes will be examined.
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