Dual control of melanogenesis and melanoma growth: overview molecular to clinical level and the reverse.
Utilizing increased melanin pigmentation and accentuated melanogenesis seen in malignant melanoma, we newly developed melanoma-selective boron neutron capture therapy (BNCT) after designing and synthesizing the 10B-DOPA analogue, 10B-p-boronophenylalanine (10B-BPA). After multi-disciplined and extensive basic and pre-clinical investigations, we successfully treated 18 cases of human melanoma. Recently, we found that accentuated synthesis of melanin monomers, richest within coated vesicles (CV) in melanoma cells, plays a critical role in attracting 10B-BPA through chemical complex formation of monomers and 10B-BPA. CV are indeed BPA-localizing organelles. This led us to the new clinical endeavor that BPA may possess the potential ability to suppress melanin polymer formation through 'melanin monomer trapping' out of the melanogenic pathway which is highly regulated by the function of CV in pigment cells. It was soon found that melanin polymer formation can be suppressed by BPA at the chemical and cellular levels, then at the clinical level. Our discovery, that single molecule 10B-BPA possesses the dual nature of eradication of melanoma with BNCT and suppression of melanin hyperpigmentation, resulted from pursuing bilateral feedback at each stage from pure science to clinical application and vice versa. A further example of bilateral feedback is the development of gene-transfer applied BNCT (gBNCT). This also has its roots in clinical hurdles faced in treating amelanotic melanomas by 10B-BPA BNCT. The transfer of tyrosinase and melanin monomer synthesis-related genes into target cancer cells has produced more effective BNCT and may lead to gBNCT for non-melanoma cancers.
Mishima
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Y
Mishima Institute for Dermatological Research, Kobe, Japan. rxm02257@nifty.ne.jp
Kondoh
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H
D000818:Animals; D001896:Boron Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D045563:Indolequinones; D007211:Indoles / Q000378:metabolism; D008543:Melanins / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism / Q000503:physiopathology*; D008548:Melanosis / Q000188:drug therapy; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011809:Quinones / Q000378:metabolism; D012880:Skin Pigmentation / Q000502:physiology*; D013347:Subcellular Fractions
D001896:Boron Compounds; D045563:Indolequinones; D007211:Indoles; D008543:Melanins; D011809:Quinones; C001123:dopachrome; D010649:Phenylalanine; C033685:4-boronophenylalanine