THE INTERACTION OF CISPLATIN PLUS ETOPOSIDE WITH RADIATION +/- HYPERTHERMIA

The addition of concurrent etoposide and cisplatin to radiation +/- hyperthermia was evaluated in the murine FSaIIC fibrosarcoma tumor system. Tumor growth delay (TGD) demonstrated that when the drugs were tested with radiation (3 Gy daily X 5) plus (43-degrees X 30 min) local hyperthermia, cisplatin/hyperthermia/radiation (TGD approximately 25 days) was significantly more effective than etoposide/hyperthermia/radiation (TGD approximately 14 days). The addition of etoposide to cisplatin/hyperthermia/radiation, however, yielded a significantly longer growth delay (approximately 34 days). Tumor cell survival studies demonstrated that hyperthermia (43-degrees-C, 30 minutes) was dose modifying for etoposide cytotoxicty (dose modifying factor approximately 2.0 as determined by comparisons of the slopes of the curves). The addition of etoposide to cisplatin modified cisplatin killing only slightly at 37-degrees-C or 43-degrees-C. Considerable additional cell kill was observed over a range of radiation doses with cisplatin, hyperthermia, and etoposide added singly or in combination, especially at the lowest radiation dose tested (5 Gy), but essentially no dose modifications was observed. Evaluation of Hoechst 33342 dye-selected tumor subpopulations demonstrated that cisplatin, etoposide, radiation (10Gy), etoposide plus radiation, and cisplatin plus radiation killed significantly fewer dim (presumably hypoxic) cells than bright (presumably normally oxygenated) cells. Hyperthermia killed more dim than bright cells. The combination of hyperthermia with cisplatin and radiation, however, resulted in approximately 5-fold lesser kill in dim cells, and the addition of etoposide increased this differential to 6.4-fold. These results indicate that etoposide adds small but measurable antitumor effects when used with cisplatin alone or with cisplatin in combination with radiation +/- hyperthermia (especially at lower radiation fraction sizes).