SUPRAADDITIVE APOPTOTIC RESPONSE OF R3327-G RAT PROSTATE TUMORS TO ANDROGEN ABLATION AND RADIATION

Purpose: Androgen ablation is often combined with radiation in the tre atment of patients with prostate cancer, yet, the optimal sequencing a nd the mechanisms governing the interaction are not understood, The ob jectives were to determine if cell killing via apoptosis is enhanced w hen the combined treatment is administered and to define the relations hip of changes in this form of cell killing to tumor volume growth del ay, Materials and Methods: Dunning R3327-G rat prostate tumors, grown in the flanks of Copenhagen rats, were used at a volume of approximate ly 1 cc. Androgen ablation was initiated by castration, and androgen r estoration was achieved with 0.5 cm silastic tube implants containing testosterone, Co-60 was used for irradiation, The terminal deoxynucleo tidyl transferase (TUNEL) histochemical assay was used to quantify apo ptosis, Results: Tumors from intact and castrate unirradiated control rats had average apoptotic indices (percent of apoptotic cells) of 0.4 and 1.0%, respectively. The apoptotic index varied only slightly over time (3 h to 28 days) after castration (range 0.75-1.43%). Irradiatio n of intact rats to 7 Gy resulted in a peak apoptotic response at 6 h of 2.3%, A supraadditive apoptotic response was seen when castration w as initiated 3 days prior to 7 Gy radiation, with peak levels of about 10.1%, When the radiation was administered at increasing times beyond 3 days after castration, the apoptotic response gradually diminished and was back to levels seen in intact rats by 28 days after castration . Tumor volume growth delay studies were consistent with, but not conc lusive proof of, a supraadditive effect when the combination was used, Discussion: A supraadditive apoptotic response was seen when androgen ablation and radiation were used to treat androgen sensitive R3327-G rat prostate tumors, This supraadditive effect was dependent on the ti ming of the two treatments, Further studies are required to more fully define the optimal timing and administration of androgen ablation and radiation. (C) 1997 Elsevier Science Inc.