THE BIOLOGICAL-ACTIVITY OF CISPLATIN AND DIBROMODULCITOL IN COMBINATION THERAPY

The efficacy and modes of action of dibromodulcitol (DBD) and cisplati n (CDDP) were studied in several model systems. Combination treatments produced a longer survival rime in mice bearing P388 solid lymphomas than either of the drugs alone. In the human metastatic melanoma HT-16 8 xenograft model the combined application of DBD and CDDP was also ve ry effective, inducing a reduction in the number and volume of metasta tic nodules. For V79 spheroids, DBD was mainly cytotoxic against the i nternal, quiescent cells, whereas cisplatin primarily killed cells in the proliferating, external regions of the spheroids. When combined, t he drugs appeared to act synergistically throughout the spheroids. Stu dies on plasmid DNA showed that CDDP primarily generates cross-links, whereas single-strand breaks were dominant after DBD treatment. Upon u sing an assay for cleavage by restriction nuclease, antagonistic actio n of DBD and CDDP in combination may occur, nevertheless more strand b reaks were always observed in these samples. These results suggest tha t the efficacy of combined DBD and CDDP is in part a result of 'spatia l cooperation' by the drugs (i.e. affecting different cells) and in pa rt the result of DNA damage produced by the combination treatments.