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  • Title: Concentration and timing dependence of lethality enhancement between topotecan, a topoisomerase I inhibitor, and ionizing radiation.
    Author: Lamond JP, Wang M, Kinsella TJ, Boothman DA.
    Journal: Int J Radiat Oncol Biol Phys; 1996 Sep 01; 36(2):361-8. PubMed ID: 8892461.
    Abstract:
    PURPOSE: Topotecan (TPT) is a water-soluble Topoisomerase I (Topo I) inhibitor with reported antineoplastic activity against a variety of solid tumors (including nonsmall cell lung, small cell lung, ovarian, breast, esophageal, and head and neck primaries) and leukemias. We sought to determine: (1) if TPT enhanced the lethal effects of ionizing radiation: and (b) the biological and biochemical characteristics of the enhancement. METHODS AND MATERIALS: Quiescent human radioresistant melanoma (U1-Mel) cells were x-irradiated (1-12 Gy) and exposed to various TPT concentrations (0.1-300 microM) either before (for 4 h), during, or after (for 4 h) radiation. Survival was determined via colony forming assays and normalized to correct for drug cytotoxicity. The effects of TPT on radiation-related potential lethal damage repair (PLDR) and sublethal damage repair (SLDR) were measured. A modification of the SDS-KCl assay was used to quantify DNA-Topo I complexes. RESULTS: Enhanced radiation lethality by TPT was observed using quiescent U1-Mel cells. The sensitizer enhancement ratio (SER) after a 4 h postirradiation exposure of 4 microM TPT was 1.6 at 10% survival. The effect was: (A) dependent on drug concentration, with lethality enhancement and minimal drug lethality alone in the 2-10 microM range for a 4 h posttreatment; (b) dependent on timing, with enhancement observed only when drug was present at the time of, or shortly after, radiation; and (c) irreversible, with inhibition of PLDR and SLDR. Exposure to TPT during or after radiation substantially elevated DNA-Topo I complexes (four- to tenfold) over control levels and complex formation correlated to some degree with loss of survival. CONCLUSIONS: TPT enhanced radiation lethality in vitro at low drug concentrations that are clinically feasible. The rationale and design of an ongoing Phase I trial which utilizes concurrent TPT and radiation is discussed.
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