Topotecan selectively enhances the radioresponse of human small-cell lung carcinoma and glioblastoma multiforme xenografts in nude mice

Purpose: To evaluate the therapeutic efficacy of different combinations of the DNA topoisomerase I-targeting drug, topotecan (TPT), with radiation for treatment of two human tumor xenografts, Methods and Materials: The small cell lung carcinoma 54A and glioblastoma multiforme U87 were transplanted i nto nude mice. Equal i,p. injections of TPT and/or equal fractions of tumor irradiation were administered daily, for 5 consecutive days. When combined , TPT was injected at different constant time intervals prior to or after e ach radiation fraction. The tumor growth delay and changes in skin radiatio n reaction by TPT were evaluated. Tumor oxygenation was measured using the Eppendorf pO(2) histography, Results: The tumor growth delay induced by suc h chemoradiotherapy was independent of interval and sequencing of the agent s for either tumor model. The efficacy of TPT alone or in combination with radiation was always dose-dependent, although of different magnitude in the two xenografts, In 54A xenografts, TPT alone induced longer growth delay, but its combined effect with radiation was not more than additive, In contr ast, U87 responded less to TPT alone, however the drug and radiation intera cted synergisticly in this tumor model, Using both a radiobiological approa ch (tumor irradiation under normoxia vs. clamp hypoxia conditions) and the polarographic electrode measurements, it was shown that TPT did not modify tumor oxygenation and, thus, unlikely modulated oxygen-related tumor radios ensitivity. In contrast to tumors, TPT virtually unchanged skin radiation r eaction. Conclusions: Our data suggest that TPT, when combined with radiati on treatment of tumors, provides a therapeutic gain without substantial loc al and systemic adverse effects. (C) 2001 Elsevier Science Inc.