Preclinical studies of etoposide and [formula omitted]-diamminedichloroplatinum(II) in combination with radiation and hyperthermia in the fsaiic fibrosarcoma

Abstract

a growth delay of 1.6 + 0.4 days. The combination of the drugs resulted in a FSaIIC tumor growth delay of 6.9 + 0.9 days. Cisplatin followed by 43C, 30 min (which produced a tumor growth delay of 1.4 + 0.9 days by itself) resulted in a growth delay of 5.9 + 1.1 days and etoposide followed by 43C, 30 min resulted in a growth delay of 2.2 + 0.4 days. The combination followed immediately by hyperthermia produced 8.6 + 1.7 days of tumor growth delay. Radiation (5x3 Gy) administered in daily fractions resulted in 6.3 + 1.5 days of tumor growth delay. With cisplatin or etoposide administered on day 1 of radiation treatment, only the tumor growth delay increased to 11.7 + 1.8 and 8.2 + 1.4 days, respectively. protocol produced 18.3 + 2.3 days of tumor growth delay. The combination of drugs in the same treatment increasing tumor cell kill was obtained. Over the dosage range from 10 to 30 mg/kg of etoposide The addition of hyperthermia (43C, 30 min) to the treatment resulted in an increased tumor cell kill from 2.5-fold to 5.8-fold with increasing drug dose. Tumor cell kill by cisplatin was examined over the dosage range from 5 to 30 mg/kg and increased with drug dose in a log-linear manner. With hyperthermia following cisplatin administration, there was a 1.5-2.0 log increase in tumor cell kill. The addition of etoposide (20 mg/kg) to cisplatin over a dosage range resulted in a 3.3-fold increase in tumor cell kill with 5 mg/kg of cisplatin which increased to 5.0-fold with 20 mg/kg of cisplatin. Under hyperthermic conditions etoposide increased the tumor cell killing by cisplatin 1.8-fold at 5 mg/kg of cisplatin, which increased to 4.0-fold at 20 mg/kg of cisplatin. The survival of Hoechst 33342 diffusion selected bright and dim tumor subpopulations was used to examine the effectiveness of these combinations in cells near to and distal from the tumor vasculature. Cisplatin (10 mg/kg) was 1.8-fold less cytotoxic toward the dim cells than toward the bright cells. Etoposide (20 mg/kg) was 1.5-fold less cytotoxic toward the dim cells than toward the bright cells. The combination resulted in 2.3-fold sparing of the dim cells and about 6fold greater than additive tumor cell kill in both the bright cells and dim cells. The effect of the addition of hyperthermia to cisplatin, etoposide and radiation is now being investigated in the tumor growth delay and Hoechst diffusion assays. Preliminary results indicate markedly prolonged tumor growth delay and increased killing of dim (presumably hypoxic) cells is accomplished by hyperthermia. This data may have significant implications to the local control of a variety of human tumors. [This work was supported by NC1 grants 1 ROl CA47379-01, 5 PO1 CA38493 and a grant from Bristol-Myers Co., Inc.]