Radiosensitization of hypoxic cells in vivo by SR 2508 at low radiation doses: A preliminary report

Abstract

We have used the RIF-1 tumor implanted intradermally in the lower dorsum of C3H mice to explore to what extent the radiosensitizer SR 2508 is capable of sensitizing hypoxic cells at clinically relevant doses of 1 and 2 Gy per fraction. We injected SR 2508 (1000 mg/kg) 45 min prior to each radiation dose in fractionated regimens of 2 or 4 doses/day for up to 5 days (1 or 2 Gy/fraction) given locally to the tumors, which were clamped to occlude the blood supply prior to each radiation exposure. This necessitated the design of clamps which (a) totally occluded blood flow (b) could be applied to nonanesthetized mice without obvious discomfort, and (c) could be applied up to 20 times without compromising the tumor blood supply on removal of the clamps. We have performed various experiments which confirm the validity of these 3 requirements. The response of the tumor cells with and without clamping and with and without SR 2508 was determined by constructing multifraction cell survival curves using the in vivo-in vitro assay. The initial results demonstrate significant radiosensitization of artificially hypoxic tumor cells at 1 and 2 Gy/fraction by SR 2508 (1000 mg/kg). Using the ratio of the D 0's of the exponential, multifraction survival curves, we obtained an SER for SR 2508 of 1.6 (3 experiments pooled) compared to an OER(D 0 clampled/D 0 air-breathing mice) of 2.3 (4 experiments pooled). These data suggest that SR 2508 (and presumably other electron-affinic sensitizers) can radiosensitize hypoxic cells at low radiation doses, and indicate that this and similar drugs may be useful in the radiotherapy of those tumors for which hypoxis limits curability.