The goal is: 1) to develop new platinum drugs with increased tumor selectivity and increased cytocidal efficiency in combination with therapeutic radiation and 2) to study the biological interactions of platinum complexes with cellular components, especially DNA. A selected series of tetrachloroplatinum (II) nuclear staining (+)- charged molecule complexes will be prepared by the reaction of potassium tetrachloroplatinate with two molar equivalents of the dyes. Cytotoxicity, radiation sensitization and post-irrradiation effects of the platinum complexes will be studied under oxygenated and hypoxic conditions. Special attention will be given to potential lethal damage repair inhibition of x-irradiation, bleomycin and adriamycin. A murine and two human cell lines will be used for these experiments. In vivo studies will center on the efficacy of these agents in combination with radiation therapy. Drugs will be administered either 1 hr prior to or immediately following radiation treatment. The experiments will first be carried out at the maximum non-toxic dose of the drug and with single dose (10, 20 or 30 Gy) radiation treatment. The most promising agents will also be examined ina fractionated x-ray protocol with drug administered before or after each fraction. Antitumor activity of the complexes will be assessed in three murine tumors. To study drug penetration and to determine if these agents are producing true dose modification in combination with x-rays, tumor excision-cell survival assays will be performed. Density gradient separation of tumor subpopulations will be used to assess the effect of the treatment combinations on the hypoxic cell subpopulation of the tumor. Bone marrow survival will be determined by CFU-GM. Kidneys will be examined histologically. The binding of these complexes to DNA and the effects of these complexes on DNA repair in the presence and absence of x-rays will be assessed by two methods: 1) DNA alkaline elution of cells treated in vitro, and 2) digestion with T4 DNA polymerase (3' - 5') associated exonuclease of 5'-labelled, drug-treated DNA fragments of defined sequence.
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