Expression of basic fibroblast growth factor correlates with resistance to paclitaxel in human patient tumors.
BACKGROUND
Preclinical results indicate acidic fibroblast growth factor (aFGF) and basic FGF (bFGF) present in solid tumors as a cause of broad-spectrum chemoresistance, whereas earlier clinical studies suggest that bFGF expression is associated with opposing outcomes in patients. We investigated the relationship between FGF expression and paclitaxel activity in tumors from bladder, breast, head and neck, ovarian, and prostate cancer patients.


METHODS
Tumors (n = 96) were maintained in three-dimensional histocultures, retaining tumor-stromal interaction. Bladder tumors were treated with paclitaxel for 2 h, and the other tumors for 24 h. Antiproliferative and proapoptotic effects of paclitaxel were quantified and correlated with expression of aFGF, bFGF, P-glycoprotein (Pgp), p53, and bcl-2.


RESULTS
Fifty-one percent (49/96) and 63% (61/96) of tumors showed aFGF and bFGF staining, respectively. aFGF expression was positively correlated with tumor stage (p < 0.01), and bFGF expression with tumor grade and Pgp expression (p < 0.05). Paclitaxel inhibited antiproliferation in 86% of tumors (83/96), with an average inhibition of 46 +/- 19% (mean +/- SD) in the responding tumors. Paclitaxel also induced apoptosis in 96% of tumors (92/96), with an average apoptotic index of 12 +/- 7% in the responding tumors. aFGF expression did not correlate with tumor sensitivity to paclitaxel, whereas bFGF expression showed an inverse correlation (p < 0.01). bFGF expression was a stronger predictor of paclitaxel resistance compared to Pgp, p53, or Bcl-2.


CONCLUSIONS
These results support a role of bFGF in paclitaxel resistance in human patient tumors.
Gan
Yuebo
Y
College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA.
Wientjes
M Guillaume
MG
Au
Jessie L-S
JL
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006801:Humans; D008297:Male; D010051:Ovarian Neoplasms; D017239:Paclitaxel / Q000494:pharmacology*; D011379:Prognosis; D046509:Tissue Culture Techniques; D014407:Tumor Cells, Cultured / Q000187:drug effects; D001749:Urinary Bladder Neoplasms
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D017239:Paclitaxel