Platinum-dye complexes inhibit repair of potentially lethal damage following bleomycin treatment

Abstract

Summary Several new complexes of platinum with positively charged cellular dyes have been synthesised in an effort to find chemotherapeutic drugs with increased antitumour cytotoxicity. As part of this effort, the direct cytotoxicities of some of these complexes as well as their ability to inhibit bleomycin potentially lethal damage repair (PLDR) was studied in vitro in a squamous cancer cell line of human origin . All of the new agents were more cytotoxic against exponentially growing than against plateau phase cell cultures. Exposure of cells to non-lethal drug concentrations for between 1 and 6h led to measurable inhibition of bleomycin PLDR in the case of each drug tested. In order of decreasing ability to inhibit bleomycin PLDR, Pt(fast black)2, Pt(thioflavin)2 and Pt(thionin)2 were more effective than CDDP, while Pt(methylene blue)2, Pt(Rh-123)2 and Pt(pyronin y)2 were less effective. The most directly cytotoxic agents were Pt(thioflavin)2, Pt(pyronin Y)2 and Pt(Rh-123)2 which also proved to be the least selectively toxic drugs towards exponential versus plateau phase cells. These results indicate that several of the new platinum complexes may be effective cytotoxic agents as well as effective inhibitors of DNA repair process following exposure of cells to other DNA interactive modalities.The glycopeptide antibiotic bleomycin has demonstrated clinical usefulness in the treatment of squamous cell cancer of the head and neck (SCCHN) (Turrisi et al., 1978), testicular tumours (Einhorn & Donahue, 1977) and lymphomas (Coltman et al., 1978). It is used in combinations with other agents because bleomycin does not exhibit dose limiting haematopoietic toxicity (Hubbard et al., 1975). When used as a single agent, however, complete response rates are relatively low and the emergence of drug resistance is a common problem (Crooke & Bradner, 1976).To various extents, mammalian tumour cells have the capacity to repair drug-and radiation-induced damage. The ability of cells to recover from potentially lethal damage has been modelled in vitro by maintaining cells in conditions which prevent them from proliferating for various times and thereby allowing time for repair processes to take place (Barranco & Townsend, 1986).Solid tumours and slow growing lymphomas are likely to contain large populations of non-cycling cells, which may have the capacity to repair potentially lethal damage and contribute to regrowth of the tumour. An in vitro system containing cells in stationary phase may be more analogous to the in vivo situation than are cells in exponential growth. Such an experimental model can be created by growing monolayer cell cultures to confluency under conditions of constant medium renewal without subculture. These stationary phase cultures contain a large fraction of non-cycling, but potentially clonogenic, cells (Hahn & Little, 1972). In such model systems, time dependent enhancement of cell survival observed with longer pre-subculture intervals following exposure to cytotoxic agents can be inferred as due to poten...

Interaction of topoisomerase I inhibitors with radiation in cis‐diamminedichloroplatinum(II)‐sensitive and ‐resistantcells In Vitro and in the fsaiic fibrosarcoma In Vivo

“…Repair of sub-lethal damage is reflected in the breadth of the shoulder of the radiation survival curve and occurs within a brief period after radiation. Repair of potentially lethal damage occurs slowly, usually being complete by 6 to 12 hr after irradiation and is reflected by the increased survival of cells under constant condition presubculture for those intervals (Hall, 1978;Wang et aL, 1989).…”