Improving chemotherapeutic drug penetration in melanoma by imatinib mesylate.
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.
Ogawa
Youichi
Y
Department of Dermatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
Kawamura
Tatsuyoshi
T
Furuhashi
Masao
M
Tsukamoto
Katsuhiko
K
Shimada
Shinji
S
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001549:Benzamides; D001693:Biological Transport, Active / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D000068877:Imatinib Mesylate; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D003606:Dacarbazine; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta