Overexpression of Bax enhances antitumor activity of chemotherapeutic agents in human head and neck squamous cell carcinoma.
Overexpression of the Bax protein in human head and neck squamous cell carcinoma A253 cells was reported to result in an increased sensitivity to various chemotherapeutic agents in vitro (Guo et al., Oncol. Res., 11: 91-99, 1999). In the present study, the relationship between Bax expression and response to chemotherapy was further investigated in vitro and in vivo model systems. For in vitro study, A253, A253/Vec (pcDNA3 vector transfectant), and A253/Bax (pcDNA3/Bax transfectant, expressing 50-fold higher Bax protein than A253 and A253/Vec) cells were exposed to various concentrations of raltitrexed (a specific thymidylate synthase inhibitor) and SN-38 (a topoisomerase I inhibitor) for 2 h, and cell growth inhibition was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide clonogenic assay. Compared to A253/Vec, A253/Bax cells exhibited 9.5- and 13.5-fold increases in sensitivity to raltitrexed and SN-38, respectively. For in vivo study, A253/Vec and A253/Bax tumor xenografts were established by s.c. injection of tumor cells into nude mice. The antitumor activity and toxicity of raltitrexed (i.v. push daily for 5 days) and irinotecan (a prodrug of SN-38; i.v. push daily for 3 days) were evaluated. The maximum tolerated doses of raltitrexed and irinotecan were 30 and 100 mg/kg/day, respectively. At the maximum tolerated doses, minimal antitumor activity was observed with raltitrexed, although irinotecan was more active than raltitrexed against A253 or A253/Vec tumors. In contrast, both raltitrexed and irinotecan were significantly more active against A253/Bax xenografts than against A253/Vec xenografts; the yield for complete tumor regression (cure) was 40% and 100% with raltitrexed and irinotecan, respectively, with no significant toxicity. Furthermore, the observed increase of antitumor activity in A253/Bax tumors was associated with an enhanced induction of apoptosis in vivo. The in vivo results demonstrated a proof of the principal concept that selecting up-regulation of the proapoptosis gene Bax can provide the basis for a greater therapeutic efficacy to a variety of chemotherapeutic agents with different structures and mechanisms of action.
Guo
B
B
Department of Pharmacology and Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Cao
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Tóth
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K
Azrak
R G
RG
Rustum
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D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use / Q000633:toxicity; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines / Q000627:therapeutic use* / Q000633:toxicity; D013876:Thiophenes / Q000627:therapeutic use* / Q000633:toxicity; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D059004:Topoisomerase I Inhibitors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; C494826:BAX protein, human; C494827:Bax protein, mouse; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D013876:Thiophenes; D059004:Topoisomerase I Inhibitors; D051028:bcl-2-Associated X Protein; D000077146:Irinotecan; D013940:Thymidylate Synthase; C068874:raltitrexed; D002166:Camptothecin