Improving chemotherapeutic drug penetration in melanoma by imatinib mesylate.

Abstract

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-beta 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 beta-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.

• Authors: Youichi Ogawa, Tatsuyoshi Kawamura, Masao Furuhashi, Katsuhiko Tsukamoto, Shinji Shimada
• Journal: Journal of dermatological science (J Dermatol Sci) Vol. 51 Issue 3 Pg. 190-9 (Sep 2008) ISSN: 0923-1811 [Print] Netherlands
• PMID: 18485676 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Benzamides
• Piperazines
• Protein Kinase Inhibitors
• Pyrimidines
• Dacarbazine
• Imatinib Mesylate
• Receptor, Platelet-Derived Growth Factor beta

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• Benzamides
• Biological Transport, Active (drug effects)
• Dacarbazine (administration & dosage, pharmacokinetics)
• Female
• Imatinib Mesylate
• Melanoma, Experimental (drug therapy, metabolism, pathology, secondary)
• Mice
• Mice, Inbred C57BL
• Piperazines (administration & dosage)
• Protein Kinase Inhibitors (administration & dosage)
• Pyrimidines (administration & dosage)
• Receptor, Platelet-Derived Growth Factor beta (antagonists & inhibitors, metabolism)