EFFECT OF RADIATION AND PACLITAXEL ON P53 EXPRESSION IN MURINE TUMORSSENSITIVE OR RESISTANT TO APOPTOSIS INDUCTION

Purpose: Tumors are thought to differ in their response to cytotoxic a gents for a variety of reasons including cell cycle kinetics, degree o f hypoxia, differential repair, and ability to survive when stressed. Our previous studies showed that murine mammary carcinoma MCA-4 tumors are relatively sensitive to both radiation and paclitaxel and exhibit a significant apoptotic response following treatment in vivo. In cont rast, murine squamous cell carcinoma SCC-VII tumors are relatively res istant to radiation and paclitaxel and exhibit relatively little apopt osis following treatment. Since dysfunctional p53 has been shown to be associated with tumor resistance, perhaps through a dysregulated cell loss mechanism, we examined the role of p53 expression in the differe ntial apoptotic response of these two tumors following cytotoxic treat ment in vivo. Methods and Materials: Mice bearing 8-mm tumors were tre ated with 40 mg/kg paclitaxel i.v. or 15 Gy local tumor irradiation, a nd tumors were harvested at several time points up to 2 days following treatment. Histological sections of the tumors were then assessed mic romorphometrically for mitotic arrest and apoptosis and immunohistoche mically for p53 and p21 expression. Results: In the apoptosis-sensitiv e MCA-4 tumors, p53 expression increased rapidly following radiation f rom 13% at baseline to a peak of 45% within 3 h, and expression remain ed elevated for more than 24 h. Radiation also upregulated p21 suggest ing that radiation-induced apoptosis in MCA-4 tumor is p53 dependent. Paclitaxel also induced an increase in both p53 and p21 expression in MCA-4 cells; however, the increase was delayed compared to that after irradiation. This upregulation occurred after the onset of apoptosis w hich would suggest that paclitaxel-induced apoptosis is p53 independen t. Both radiation and paclitaxel caused p53 upregulation in the apopto sis-resistant SCC-VII tumors. The untreated SCC-VII tumor has 25% cell s p53 positive and has a very high level of p21 (87% cells positive) w hich suggests a downstream defect in p53 response. Conclusion: These r esults show that tumor responsiveness to paclitaxel and radiation, mea sured by tumor growth delay, was associated with apoptotic response. H owever, although both agents upregulated p53 expression in these tumor s, the association between this upregulation and induction of apoptosi s was not clear. Additional studies using these and other tumors are w arranted to elucidate the role of p53 and its downstream effecters in the in vivo responsiveness of tumors to paclitaxel and radiation. (C) 1997 Elsevier Science Inc.