Development of acquired multidrug resistance (MDR) is a major challenge in cancer chemotherapy. The possible mechanisms include high levels of mdr 1p-glycoprotein and the glutathione transferase (GST) and glutathione (GSH) repair mechanism. But neither mechanism explains the broad-spectrum nature of acquired MDR. Alteration of the apoptosis rheostat toward survival could explain the cross resistance among drugs that induce apoptosis through different action mechanisms. The clinical relevance of these mechanisms is not known as studies using Pgp or GSH inhibitors or antisense to Bcl-2 have not improved the efficacy of chemotherapy or have not been completed. ? ? We recently demonstrated that two fibroblast growth factors, i.e., acidic and basic FGF (aFGF and bFGF) that are expressed in solid tumors, induce a broad-spectrum resistance (up to 10-fold) to drugs with diverse structures and action mechanisms. Inhibitors of FGF binding to their receptors, including monoclonal antibodies and/or suramin, completely reverse the resistance induced by exogenous FGF. We further found that nontoxic and subtherapeutic doses of suramin enhance the efficacy of paclitaxel and doxorubicin in mice bearing human xenografts. Preliminary results of a phase I trial also suggest that suramin enhanced the efficacy of paclitaxel and carboplatin non-small cell lung cancer patients. ? ? Additional preliminary results indicate that short term (72 hour) and long-term (6 months) drug treatments enhanced the levels of intracellular and/or extracellular aFGF and bFGF, under in vitro and in vivo conditions, such that the post-treatment FGF levels were sufficient to induce drug resistance. The enhanced FGF levels were due to increased FGF production and secretion, and release of protein upon cell lysis. Drug treatment-induced resistance in cultured cells and xenografts was reversed by suramin. Finally, cDNA microarray results show that bFGF treatment altered the expression of GST, Bcl-2 family proteins, drug efflux proteins, and topoisomerases. These preliminary results, together with the literature data indicating that bFGF enhances GST and shifts the apoptosis rheostat toward survival, have led us to hypothesize that drug treatment induces increases in FGF levels, which in turn lead to acquired MDR, and that acquired MDR can be overcome by FGF inhibitors. The four Aims are as follows. (1) Establish that drug treatment enhances extracellular FGF levels. (2) Test the hypothesis that the FGF induction results in acquired MDR. (3) Test the hytpothesis that FGF is an upstream event that triggers several known mechanisms of acquired MDR. (4) Test the hypothesis that suramin can reverse acquired MDR under in vitro and in vivo conditions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA097067-03
Application #
6796273
Study Section
Special Emphasis Panel (ZRG1-CONC (04))
Program Officer
Forry, Suzanne L
Project Start
2002-09-01
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
3
Fiscal Year
2004
Total Cost
$245,219
Indirect Cost
Name
Ohio State University
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Zhao, Liang; Au, Jessie L-S; Wientjes, M Guillaume (2010) Comparison of methods for evaluating drug-drug interaction. Front Biosci (Elite Ed) 2:241-9
Villalona-Calero, M A; Otterson, G A; Wientjes, M G et al. (2008) Noncytotoxic suramin as a chemosensitizer in patients with advanced non-small-cell lung cancer: a phase II study. Ann Oncol 19:1903-9
Walsh, Colin T; Wei, Yong; Wientjes, M Guillaume et al. (2008) Quantitative image analysis of intra-tumoral bFGF level as a molecular marker of paclitaxel resistance. J Transl Med 6:4
Kosarek, Carrie E; Hu, Xiao; Couto, C Guillermo et al. (2006) Phase I evaluation of low-dose suramin as chemosensitizer of doxorubicin in dogs with naturally occurring cancers. J Vet Intern Med 20:1172-7
Gan, Yuebo; Wientjes, M Guillaume; Au, Jessie L-S (2006) Expression of basic fibroblast growth factor correlates with resistance to paclitaxel in human patient tumors. Pharm Res 23:1324-31
Lu, Ze; Wientjes, Trini S-S; Au, Jessie L-S (2005) Nontoxic suramin treatments enhance docetaxel activity in chemotherapy-pretreated non-small cell lung xenograft tumors. Pharm Res 22:1069-78
Song, SaeHeum; Yu, Bei; Wei, Yong et al. (2004) Low-dose suramin enhanced paclitaxel activity in chemotherapy-naive and paclitaxel-pretreated human breast xenograft tumors. Clin Cancer Res 10:6058-65
Zhao, Liang; Wientjes, M Guillaume; Au, Jessie L-S (2004) Evaluation of combination chemotherapy: integration of nonlinear regression, curve shift, isobologram, and combination index analyses. Clin Cancer Res 10:7994-8004