Cisplatin‐induced enhancement of radioresponse in a murine mammary carcinoma: Test of a role for apoptosis

Abstract

SUMMARYProgrammed cell death or apoptosis has recently been recognized as an important mode of cell death in the response of tumor cells to cytotoxic treatments associated with chemotherapy or radiation therapy (RT). We previously showed that both cisplatin and radiation induced substantial apoptosis in the murine mammary tumor MCA-4 when administered as single agents in vivo. Moreover, the levels of apoptosis correlated with tumor response measured as tumor growth delay. In the current study a role for apoptosis in a combined treatment with cisplatin and radiation was evaluated. Mice bearing MCA-4 tumors were irradiated at different times following an injection with cisplatin, and tumor growth delay was assessed. Apoptosis was scored from histological sections of the tumors. The results showed that whereas the cisplatin sensitized the MCA-4 tumor to a subsequent irradiation in terms of the growth delay, the apoptotic index never rose above the maximum level characteristic of either agent when used singly. Thus, there was no indication that cisplatin sensitized the tumor cells to radiation-induced apoptosis. We conclude that apoptosis is not the only important mechanism for cell killing in tumors following cytotoxic treatment and that tumor response is a complex composite of many different factors.

Enhancement of radiation-induced regrowth delay by gemcitabine in a human tumor xenograft model

“…Treatment groups were compared using the log-rank test. The absolute tumor growth delay (ATGD) was calculated as the difference between the estimated median times required for the vehicle control group and each treatment group to reach 200% of their pretreatment volumes [20][21][22]. The expected tumor growth delay (ETGD) under an additive model for each gemcitabine plus radiation group was determined by adding the ATGD in the gemcitabine alone and radiation alone groups [23].…”

“…The ATGD and the ETGD were compared using normal approximations. Normalized tumor growth delay (NTGD) was defined as the ATGD in the gemcitabine plus radiation group minus the ATGD in the gemcitabine alone group [20,22], thus providing an estimate of the tumor growth delay (TGD) induced by the combined treatment without the contribution of the drug. The regrowth delay enhancement was defined as the ratio of NTGD for combined drug and radiation over ATGD for radiation alone [20].…”

“…The volumes were then expressed as a percentage of the pretreatment volume on day 1, which was designated as 100%. Apoptosis Apoptosis was assessed by microscopic examination [16,20] …”

“…Apoptosis was assessed by microscopic examination [16,20] of tumors at two time points on the first day in the once weekly schedule. The mice received either 430 mg/kg gemcitabine at time zero, or 2 Gy irradiation at 0.5 and 7.5 hr, or the combination of gemcitabine and radiation.…”

“…Paclitaxel, when given prior to a single dose of radiation, can potentiate radiation-induced apoptotic cell death in murine tumors in vivo, with the effect being dependent on the interval between paclitaxel and radiation [19]. In contrast, although the administration of cisplatin prior to radiation resulted in sensitization of a murine mammary carcinoma in vivo, no potentiation of apoptosis by cisplatin was observed [20]. Single fractions of radiation are rarely used for the treatment of human cancers, however, and whether increased apoptosis is a true consequence of a drugradiation interaction needs to be examined using lower radiation doses.…”