Transforming growth factor-beta3 protection of epithelial cells from cycle-selective chemotherapy in vitro.
The transforming growth factor-beta (TGF-beta) family of regulatory growth factors can reversibly arrest cell division in the G1 phase of the cell cycle. Previously, TGF-beta3 was shown to protect epithelial cells and hematopoietic cells from cytotoxic damage in vitro and in vivo, and to reduce the severity and duration of oral mucositis induced by 5-fluorouracil (5-FU) in vivo. In the present study, we tested whether TGF-beta3 can protect epithelial cells from a range of chemotherapy drugs with differing mechanisms of action, using the CCL64 cell line as a model system. We report that preincubation of cells with TGF-beta3 for 24 hr resulted in enhanced clonogenicity following exposure to vinblastine, vincristine, etoposide, taxol, ara-C, methotrexate, or 5-FU. Protection was measured in colony-forming assays, which demonstrated that the protected cells could re-enter the cell cycle and undergo multiple rounds of cell division. At high cytotoxic drug concentrations, absolute colony counts were increased for the cultures prearrested by TGF-beta3, as compared with the proliferating control cultures. The effects of TGF-beta3 were reduced for cisplatin and doxorubicin, drugs that are toxic to cells throughout the cell cycle. Thus, TGF-beta3 can effectively reduce the cytotoxicity of anticancer drugs that act predominantly in S or M phase of the cell cycle.
McCormack
E S
ES
Oncogene Science Inc., Pharmaceuticals Division, Uniondale, NY 11553-3649, U.S.A.
Borzillo
G V
GV
Ambrosino
C
C
Mak
G
G
Hamablet
L
L
Qu
G Y
GY
Haley
J D
JD
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000187:drug effects; D008907:Mink; D016196:S Phase; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D016212:Transforming Growth Factor beta