Cis-diamminedichloroplatinum(II) (CDDP) is proving to be of great use in improving the clinical response rate achievable in several common tumors. The goal of this work is: (1) to explore the utility of covalently combining organic radiosensitizing moieties with bivalent platinum in an effort to develop new drugs with increased sensitizer efficiency and (2) to study the biological interactions of platinum compounds with cellular components. Platinum complexes of known radiosensitizers such as cis-di (2-amino-5-nitrothiazole)dichloroplatinum(II), cis-di(2-nitroimidazole)dichloroplatinum(II), and cis-(1,2-diamino-5-nitrobenzene)dichloroplatinum(II) will be prepared along with derivatives containing sulfate and malonate instead of the chloride leaving groups. The compounds will be tested in vitro for their radiosensitizing ability under oxygenated and hypoxic conditions. Fluorescent analogs of CDDP such as cis-di(fluoresceinaminemethoxymethyl ester)dichloroplatinum(II), cis-di(coumarin 340)dichloroplatinum(II), and cis-di(coumarin 151)-dichloroplatinum(II) will be prepared as well as their sulfato- and malonato- derivatives. These compounds will be used to examine the intracellular localization, uptake and retention of platinum complexes in cell lines and primary cultures of normal and malignant human cells. We will also compare the ability of CDDP sensitive and resistant L1210 cell lines to accumulate and retain the fluorescent platinum analogs. A principal advantage of the use of fluorescent analogs over existing methods is our ability to observe the interactions of platinum complexes with living cells. Using several transplantable mouse tumor models the antitumor activity of the compounds alone and in combination with x-irradiation will be examined and compared with CDDP, organic radiosensitizers and organic fluorescent compounds not complexed to platinum. By alkaline elution methods the interaction of the new platinum compounds with cellular DNA will be analyzed. These two classes of analogs of CDDP will allow us to explore different modes of improving the tumor specificity and therapeutic ratio of platinum-containing drugs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA036508-02
Application #
3174127
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1984-01-01
Project End
1986-12-31
Budget Start
1985-01-01
Budget End
1985-12-31
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
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