Purpose: We sought to determine whether administration of a MGMT blocker, O 6 -benzyl guanine (O 6 BG), at an optimal biological dose alone or in combination with gemcitabine inhibits human pancreatic cancer cell growth. Experimental Design: Human pancreatic cancer L3.6pl and PANC1 cells were treated with O 6 BG, either alone or in combination with gemcitabine, and the therapeutic efficacy and biological activity of these drug combinations were investigated. Results: O 6 BG sensitized pancreatic cancer cells to gemcitabine. Protein and mRNA expression of MGMT, cyclin B1, cyclin B2, cyclin A, and ki-67 were significantly decreased in the presence of O 6 BG. In sharp contrast, protein expression and mRNA message of p21 cip1 were significantly increased. Interestingly, O 6 BG increases p53-mediated p21 cip1 transcriptional activity and suppresses cyclin B1. In addition, our results indicate that p53 is recruited to p21 promoter. Furthermore, an increase in p21 cip1 and a decrease in cyclin transcription are p53 dependent. The volume of pancreatic tumors was reduced by 27% in mice treated with gemcitabine alone, by 47% in those treated with O 6 BG alone, and by 65% in those mice given combination. Immunohistochemical analysis showed that O 6 BG inhibited expression of MGMT and cyclins, and increased expression of p21 cip1 . Furthermore, there was a significant decrease in tumor cell proliferation and an increase in tumor cell apoptosis. Conclusions: Collectively, our results show that decreased MGMT expression is correlated with p53 activation, and significantly reduced primary pancreatic tumor growth. These findings suggest that O 6 BG either alone or in combination with gemcitabine may provide a novel and effective approach for the treatment of human pancreatic cancer. (Clin Cancer Res 2009;15(19):6087-95)
Abstract:The management of acute lymphoblastic leukemia (ALL) during pregnancy requires treatment with high-dose chemotherapy that can pose risks to both the mother and fetus. Special consideration to chemotherapy regimen and its doses and to fetal gestational age at the time of chemotherapy administration should be taken in order to limit fetal exposure while still providing optimal therapy to the mother. Here we describe a 22-year-old patient who was diagnosed at 26 weeks gestation with ALL and was treated in the third trimester with HyperCVAD (cytoxan, vincristine, adriamycin, dexamethasone) combination chemotherapy giving birth via Caesarean section to a healthy baby girl 4 weeks after induction chemotherapy.
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