Enhancement of paclitaxel-mediated cytotoxicity in lung cancer cells by 17-allylamino geldanamycin: in vitro and in vivo analysis.
BACKGROUND
It has previously been demonstrated that 17-allylamino geldanamycin (17-AAG) enhances paclitaxel-mediated cytotoxicity and downregulates vascular endothelial factor expression in non-small cell lung cancer. This project was designed to evaluate the tumoricidal and antiangiogeneic effects of 17-AAG and paclitaxel in H358 non-small cell lung cancer cells grown as xenografts in nude mice.


METHODS
In vitro cytotoxic drug combination effects were evaluated by (4, 5-dimethylthiazo-2-yl)-2, 5-diphenyl tetrazolium bromide-based proliferation assays. The combinations of 17-AAG and paclitaxel were administered intraperitoneally in nude mice bearing H358 tumor xenografts. Tumor volumes were measured weekly. Tumor expression of erbB2, vascular endothelial cell growth factor, von Willebrand factor (tumor microvasculature), and activated caspase 3 (apoptosis) were determined by immunohistochemistry.


RESULTS
Five- to 22-fold enhancement of paclitaxel cytotoxicity was achieved by paclitaxel + 17-AAG combination that was paralleled with marked induction of apoptosis. This combination treatment profoundly suppressed tumor growth and significantly prolonged survival of mice bearing H358 xenografts. Immunohistochemical staining of tumor tissues indicated profound reduction of vascular endothelial cell growth factor expression associated with reduction of microvasculature in tumors treated with 17-AAG. Apoptotic cells were more abundant in tumors treated with 17-AAG + paclitaxel than in those treated with 17-AAG or paclitaxel alone.


CONCLUSIONS
Concurrent exposure of H358 cells to 17-AAG and paclitaxel resulted in supraadditive growth inhibition effects in vitro and in vivo. Analysis of molecular markers of tumor tissues indicated that therapeutic drug levels could be achieved with this chemotherapy regimen leading to significant biological responses. Moreover, 17-AAG-mediated suppression of vascular endothelial cell growth factor production by tumor cells may contribute to the antitumor effects of this drug combination in vivo.
Nguyen
D M
DM
Section of Thoracic Oncology and Surgical Metabolism, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. Dao_Nguyen@nih.gov
Lorang
D
D
Chen
G A
GA
Stewart
J H
JH
Tabibi
E
E
Schrump
D S
DS
D000499:Allylamine / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones; D052160:Benzothiazoles; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D016228:Endothelial Growth Factors / Q000032:analysis; D006801:Humans; D047029:Lactams, Macrocyclic; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology*; D008222:Lymphokines / Q000032:analysis; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D011809:Quinones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D020032:Tyrphostins / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D052160:Benzothiazoles; D016228:Endothelial Growth Factors; D047029:Lactams, Macrocyclic; D008222:Lymphokines; D011809:Quinones; D020032:Tyrphostins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C098214:tyrphostin AG825; D000499:Allylamine; D017239:Paclitaxel; C001277:geldanamycin