Imatinib Mesylate (Gleevec) Inhibits Ovarian Cancer Cell Growth through a Mechanism Dependent on Platelet-Derived Growth Factor Receptor α and Akt Inactivation

Abstract

Purpose:We identified the platelet-derived growth factor receptor ␣ (PDGFR␣) as an ovarian cancer-specific gene by microarray hybridization using primary cultures. The purpose of this study is to evaluate whether disruption of the platelet-derived growth factor-regulated growth pathway by Imatinib mesylate (Gleevec), a partially selective PDGFR inhibitor, inhibits growth of ovarian cancer cells expressing PDGFR.Experimental Design: To investigate the effects of Imatinib mesylate in ovarian cancer, we established an in vitro model by immortalizing primary ovarian cells, which express endogenous PDGFR, and we evaluated the effects of Imatinib on cell proliferation. In addition, we investigated the involvement of Akt in mediating Imatinib-inhibited cell growth inhibition.Results: We found that 39% of ovarian tumors express PDGFR by immunohistochemistry. We showed that Imatinib inhibits the growth of ovarian cancer cells in a PDGFR-specific manner, at clinically relevant concentrations (IC 50 < 1 M).

Expression of platelet-derived growth factors and their receptors in ovarian clear-cell carcinoma and its putative precursors

“…22 A recent study has demonstrated that imatinib mesylate inhibits ovarian cancer cell proliferation and PDGF-induced S-phase entry through PDGFR-a and Akt inactivation. 23 Although a phase II trial of imatinib mesylate as a single agent failed to produce satisfactory efficacy against recurrent and platinum-resistant ovarian cancer, 24 cases with clear-cell adenocarcinoma were not enrolled and, therefore, the effect of imatinib or other tyrosine kinase inhibitors on ovarian clear-cell adenocarcinoma remains undetermined.…”

Rationale for the development of IMC‐3G3, a fully human immunoglobulin G subclass 1 monoclonal antibody targeting the platelet‐derived growth factor receptor α

“…2). [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] Several types of cancers, particularly those derived from the ovary, prostate, breast, lung, brain, skin, and bone, express PDGFRa on the malignant cells themselves (Table 1). 22 In 1 experiment in which a human tumor array was probed with a cross-reactive polyclonal rabbit antibody to PDGFRa, PDGFRa expression was noted in approximately 95% of osteosarcomas and chondrosarcomas, in 77% of prostate cancers, in 52% of ovarian cancers, in 65% of breast cancers, and in 51% of lung cancers (N. Loizos, ImClone Systems, unpublished results).…”

Treatment with imatinib improves drug delivery and efficacy in NSCLC xenografts

“…Blocking VEGF prunes immature vessels, increases fraction of pericyte-covered vessels, and decreases vessel permeability, dilation and tortuosity Willett et al, 2004;Jain, 2005). Inhibition of PDGF or PDGFRb also prunes immature vessels, and additionally decreases contraction of the interstitial space and proliferation of stroma (Heuchel et al, 1999;Pietras et al, 2001;George, 2003;Matei et al, 2004;Vlahovic et al, 2006). Imatinib (Gleevec, Novartis Pharmaceuticals Corp., East Hanover, NJ, USA) is a synthetic small molecule that inhibits phosphorylation of a number of tyrosine kinase receptors including PDGFR, c-kit, and bcr-abl (Buchdunger et al, 1995;George, 2003;Matei et al, 2004).…”

“…Inhibition of PDGF or PDGFRb also prunes immature vessels, and additionally decreases contraction of the interstitial space and proliferation of stroma (Heuchel et al, 1999;Pietras et al, 2001;George, 2003;Matei et al, 2004;Vlahovic et al, 2006). Imatinib (Gleevec, Novartis Pharmaceuticals Corp., East Hanover, NJ, USA) is a synthetic small molecule that inhibits phosphorylation of a number of tyrosine kinase receptors including PDGFR, c-kit, and bcr-abl (Buchdunger et al, 1995;George, 2003;Matei et al, 2004). It decreases proliferation of both tumour and stromal cells (George, 2003;Furuhashi et al, 2004;Kim et al, 2004;Matei et al, 2004;Ostman, 2004).…”

“…Imatinib (Gleevec, Novartis Pharmaceuticals Corp., East Hanover, NJ, USA) is a synthetic small molecule that inhibits phosphorylation of a number of tyrosine kinase receptors including PDGFR, c-kit, and bcr-abl (Buchdunger et al, 1995;George, 2003;Matei et al, 2004). It decreases proliferation of both tumour and stromal cells (George, 2003;Furuhashi et al, 2004;Kim et al, 2004;Matei et al, 2004;Ostman, 2004). In colonic xenografts, Pietras et al (2001) demonstrated that imatinib decreases IFP and thereby increases transcapillary transport of small molecules.…”