Improving chemotherapeutic drug penetration in melanoma by imatinib mesylate

• Published in: Journal of dermatological science 2008-09, Vol.51 (3), p.190-199
• Main Authors: Ogawa, Youichi, Kawamura, Tatsuyoshi, Furuhashi, Masao, Tsukamoto, Katsuhiko, Shimada, Shinji
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Benzamides; Biological Transport, Active - drug effects; Dacarbazine; Dacarbazine - administration & dosage; Dacarbazine - pharmacokinetics; Dermatology; Drug delivery; Female; Imatinib Mesylate; Melanoma; Melanoma, Experimental - drug therapy; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Melanoma, Experimental - secondary; Mice; Mice, Inbred C57BL; Piperazines - administration & dosage; Platelet-derived growth factor receptors; Protein Kinase Inhibitors - administration & dosage; Pyrimidines - administration & dosage; Receptor, Platelet-Derived Growth Factor beta - antagonists & inhibitors; Receptor, Platelet-Derived Growth Factor beta - metabolism
• ISSN: 0923-1811; 1873-569X
• DOI: 10.1016/j.jdermsci.2008.03.011

Summary Background Imatinib mesylate has specific activity in inhibiting select tyrosine kinase receptors, including platelet-derived growth factor receptors (PDGFRs) and c-kit. In general, melanomas widely express PDGFR and c-kit, and their in vivo resistance to chemotherapy is attributable to high tumor interstitial fluid pressure (IFP). Recent studies have suggested that PDGFR-β inhibition reduces tumor IFP, and thus increases the uptake of concomitantly administered drugs. Objective The present study was designed to investigate the potential of imatinib mesylate as a therapy for melanoma or as an adjuvant to chemotherapeutics. Methods Using in vivo mouse models, the effect of imatinib mesylate on the growth of melanoma with or without dacarbazine was studied. Results Imatinib mesylate enhanced the antitumor effect of dacarbazine on in vivo growth and lung metastases of melanoma cells, although treatment with only imatinib mesylate had no effect. We could detect perivascular expression of PDGF β-receptor in melanoma tumors. Interestingly, dacarbazine uptake in melanoma was more than three-times increased by treatment with imatinib mesylate, while its uptake in serum or bone marrow was not affected by imatinib mesylate. Conclusions These data suggest interference with PDGF receptors, or their ligands, as a novel strategy to increase drug uptake and therapeutic effectiveness of chemotherapy for melanoma.