Enhanced melanogenesis induced by tyrosinase gene-transfer increases boron-uptake and killing effect of boron neutron capture therapy for amelanotic melanoma.
Specific and powerful cancer killing effect for melanoma by boron neutron capture therapy (BNCT) using DOPA analogue, 10B-p-boronophenylalanine (10B-BPA), has been established, but amelanotic melanoma is insufficiently responsive to 10B-BPA BNCT in comparison with actively melanin-producing melanoma. Although the accumulation mechanism of 10B-BPA within melanoma was not established, we have recently obtained findings suggesting that melanin monomers, key intermediates for melanin polymer formation, play a critical role in 10B-BPA accumulation. In addition, there are some kinds of human amelanotic melanomas, such as MEL2A, in which expression of tyrosinase is repressed or lacking though tyrosinase-related protein (TRP)-1 and TRP-2 are well expressed. Thus, by using a similarly tyrosinase-lacking mouse amelanotic melanoma cell line, A1059, we constructed TA1059 cells by transfecting human tyrosinase-cDNA into these cells. TA1059 cells acquired higher DOPA-oxidase and DOPAchrome tautomerase activity as well as eumelanin content at even higher levels than those of B16F10 cells. TA1059 cells showed about 2.5 times higher P-boronophenylalanine (BPA) uptake than A1059 cells in culture. In animal experiments, by using these cell lines, tumor growth of TA1059 was significantly suppressed by 10B-BPA BNCT as compared with A1059. These findings indicate that the induction of active melanin biosynthesis by melanogenic gene-transfer effectively improves the treatment of amelanotic melanoma by BNCT.
Tsuboi
T
T
Mishima Institute for Dermatological Research, Kobe, Japan.
Kondoh
H
H
Hiratsuka
J
J
Mishima
Y
Y
D000818:Animals; D001896:Boron Compounds / Q000378:metabolism*; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D002478:Cells, Cultured; D015870:Gene Expression; D018014:Gene Transfer Techniques; D045563:Indolequinones; D007211:Indoles / Q000032:analysis; D007700:Kinetics; D008543:Melanins / Q000096:biosynthesis / Q000627:therapeutic use; D018328:Melanoma, Amelanotic / Q000378:metabolism / Q000532:radiotherapy*; D051379:Mice; D014442:Monophenol Monooxygenase / Q000032:analysis / Q000235:genetics*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000378:metabolism; D011809:Quinones / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001896:Boron Compounds; D045563:Indolequinones; D007211:Indoles; D008543:Melanins; D011809:Quinones; C001123:dopachrome; D010649:Phenylalanine; D014442:Monophenol Monooxygenase; C033685:4-boronophenylalanine