Effect of tumor type, size, and endpoint on tumor radioprotection by WR-2721.

Experiments are reported showing that the degree of tumor radioprotection afforded by WR-2721 varies with the type of tumor and assay endpoint, and that for a given tumor system, microaggregates are protected better than larger cell masses. The tumors used were a methylcholanthrene-induced fibrosarcoma (FSa), and two tumors of spontaneous origin, another fibrosarcoma (NFSa), and a mammary carcinoma (MCa-4), all syngeneic to C3Hf/Kam mice. WR-2721 was given in a dose of 400 mg/kg 30 minutes before irradiation in all experiments. In TCD50 assays, WR-2721 protected 5 mm diameter and impalpable 3 day-old transplants of 5 X 10(5) FSa cells growing in the leg by factors of 1.11 and 1.13, respectively. Using the tumor latency endpoint, 3 day-old s.c. transplants of 10(3) FSa in the abdominal wall were protected by a factor of 1.27, a degree of protection similar to that reported earlier for sterilization of lung micrometastases of the same tumor. MCa-4 tumors growing in the leg were protected better than FSa in TCD50 assays with protection factors of 1.3 for 4 day-old transplants, 1.24 for 5 mm tumors, and 1.23 for 8 mm tumors. MCa-4 tumors recurrent after irradiation as 4 day-old transplants grew more rapidly in mice that had received WR-2721, and this was shown to be most likely due to protection by the drug against expression of the tumor bed effect. Using the lung micrometastases assay, NFSa was protected by a factor of 1.22. This variability in protection with different tumor types, sizes, and assay endpoints is discussed in terms of drug delivery and uptake, and also in relation to the influence of tumor hypoxia on the radioprotective ability of WR-2721.