Platelet‐derived growth factor receptor as a prognostic marker and a therapeutic target for imatinib mesylate therapy in osteosarcoma

Abstract

The purpose of this review was to determine whether imatinib mesylate (STI571, Gleevec) has a role in the treatment of osteosarcoma. The expression of plateletderived growth factor (PDGF) receptor and its ligand was examined in a panel of surgical specimens obtained from 54 osteosarcoma patients, and then the expression was compared with prognosis. The effects of imatinib mesylate on growth and molecular events in 10 patient-derived osteosarcoma cell cultures were investigated. Immunohistochemical studies demonstrated frequent expression of PDGF-AA (80.4%) and PDGF-a receptor (79.6%) and their correlation with inferior event-free survival (P < .05). PDGF-B-B and PDGF-b-receptor expressions were also frequent (75.4% and 86%, respectively); however, statistically significant inferior event-free survival was not demonstrated (P 5 .15). In vitro studies demonstrated that imatinib mesylate had a variable cytotoxic effect on various osteosarcoma primary cultures, with an IC 50 of 5.6 lM to 9.5 lM, and blocked the PDGF-induced intracellular signal transduction as well as inhibition of downstream Akt phosphorylation. Mitogen-activated protein kinase (MAPK) was constitutively activated despite PDGF stimulation and imatinib mesylate treatment in 7 of 10 osteosarcoma cultures, perhaps explaining uncontrolled proliferation and relative unresponsiveness to imatinib. Imatinib mesylate could not be viewed as having a role as a single agent at current conventional doses for the treatment of osteosarcoma. These findings predicted activity in osteosarcoma clinical trials and suggested that in vitro model systems predict clinical behavior and that PDGF and its receptor expression could potentially be used for determining prognosis of osteosarcoma.

What Are the Factors That Affect Survival and Relapse After Local Recurrence of Osteosarcoma?

“…It is possible that novel therapeutic approaches may be necessary to improve the outcome of these patients. This might involve the combination of traditional cytotoxic agents with targeted therapies [16] and immunomodulatory agents [18]. Our second question was to determine prognostic factors for survival after local recurrence.…”

In vitro novel combinations of psychotropics and anti-cancer modalities in U87 human glioblastoma cells

“…It is of interest to note that the activation of MAPK by sertraline in hepatoma cells and fluoxetine in rat astrocytes has previously been reported (22,35). It should also be noted that in several osteosarcoma cell lines, imatinib was shown to reduce pAKT, while pMAPK remained constitutively activated (36). In a recent study it has been reported that the flavonoid, n arginine, inhibited vascular smooth muscle proliferation via the activation of the ERK signaling pathway (37).…”

Platelet-Derived Growth Factor-B Normalizes Micromorphology and Vessel Function in Vascular Endothelial Growth Factor-A-Induced Squamous Cell Carcinomas

“…34,35 Imatinib reduced the recruitment of myofibroblasts in mVEGF-164 transfectant transplants, most probably by interfering with signaling of the endogenous, stromal PDGF-B. However, the amount of pericyte-associated blood vessels and the epithelial structure were not altered in the imatinib-treated mVEGF-164 transfectant transplants.…”

“…PDGFR signaling was blocked with imatinib mesylate 34,35 (Glivec; Novartis Pharma, Basel, Switzerland) in nude mice either transplanted with a 1:1 mixture of HaCaT mVEGF-164 and HaCaT hPDGF-B transfectants or with HaCaT mVEGF-164 transfectants alone. Imatinib mesylate was given by oral gavage in 100 l of saline solution at a dose of 150 mg ϫ kg Ϫ1 body weight ϫ day…”