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There is increasing attention directed to the hypothesis that apoptosis plays a role in the response to cancer treatment including chemotherapy. However, the evidence to support this hypothesis has come almost entirely from experiments conducted in cultured cell systems. To extend this hypothesis to the therapeutic setting it is necessary to address this critical question in tumors treated in vivo. We have therefore evaluated the extent of apoptosis induced in murine tumors treated in vivo with cancer chemotherapy agents. Seven different murine tumors, comprising a mammary adenocarcinoma (MCa-4), an ovarian adenocarcinoma (OCa-I), a lymphoma (LY-TH), three sarcomas (FSA, NFSA and SA-NH) and a squamous cell carcinoma (SSC-7), were examined 8 and 24 h after treatment with cisplatin or cyclophosphamide (CY). Apoptosis was scored by morphometric analysis of histological sections of the tumors. The results showed that MCa-4, OCa-1 and LY-TH had a significant apoptotic response to both cisplatin and CY, and the other tumors had essentially no apoptotic response. In addition, two of these tumors, MCa-4 and OCa-1, underwent apoptosis in response to adriamycin, 5-fluorouracil, Ara-C, etoposide, camptothecin and fludarabine. These observations demonstrate that apoptosis may be a feature of tumor response to chemotherapy in vivo, and illustrate the heterogeneity of apoptotic response amongst different tumor types and to different cytotoxic agents.