Advances in the Control of Human Cutaneous Primary and Metastatic Melanoma by Thermal Neutron Capture Therapy

Mishima, Yutaka; Ichihashi, M.; Honda, C.; Shiono, M.; Nakagawa, Toshio; Obaral, H.; Shirakawa, Jun; Hoshino, Junichi; Kanda, Keiji; Kobayashi, Takao; Nozaki, Tetsuya; Aizawa, Otohiko; Satô, Tadashi; Karashima, Hiroshi; Yoshino, Kazuo; Fukuda, Hiroshi

doi:10.1007/978-1-4615-3384-9_126

Cited by 24 publications

(8 citation statements)

References 7 publications

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“…This should be noted in the application of experimental data to making clinical protocol for individual human cases of melanoma brain metastases. In fact, these current data also correlate with our long standing experience treating a large number of human cutaneous melanoma cases (5–10), in which the therapeutic prognosis often corresponds to the initial growth rate of primary melanoma lesions even if we compare melanoma cases among same melanoma types, same stage, and similar therapeutic regime.…”

Section: Discussionsupporting

confidence: 75%

“…Our previous studies have revealed that the major mechanism of high BPA affinity to melanotic melanoma is likely the formation of a chemical complex between BPA and melanin monomers which are actively synthesized within melanoma cells (10, 50, 51). Further, we have previously reported that such a stepwise increase of boron concentration parallel to the increase of BPA administration also occurred in the skin (7, 9).…”

Section: Resultsmentioning

confidence: 78%

“…However, Mishima et al. developed a melanoma‐specific BNCT and succeeded in treating 18 human patients (5–10). Mishima et al.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Boron Neutron Capture Therapy for Melanotic and Amelanotic Melanoma Transplanted into Mouse Brain

Iwakura

Kondoh²,

Hoshino

et al. 2002

Pigment Cell Research

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In order to develop a protocol to treat brain metastatic melanoma using our 10B-p-boronophenylalanine (BPA) boron neutron capture therapy (BNCT), we initiated the following studies (i), Comparative analyses of boron biodistribution between melanoma proliferating in the brain and skin among melanotic and amelanotic types, and (ii) Therapeutic evaluation of BPA-BNCT for brain melanoma models of both types, using survival times. Our present data have revealed that boron concentration in melanoma proliferating in the brain, the major prerequisite for successful BNCT, showed a positive correlation to melanin synthesizing activity in the same way as melanoma proliferating in skin. Further, the boron concentration ratio of melanoma to normal surrounding tissue for brain melanoma models was considerably higher than that for subcutaneous (s.c.) ones because of the existence of the blood-brain barrier (BBB). Additionally, from analyses of median and mean survival times following BNCT using low, middle, and high neutron doses, the therapeutic effect of BNCT for the amelanotic A1059 melanoma appeared at first glance to be higher than that for the highly BPA attracting and highly relative biological effect equivalent dose obtaining B15b melanoma. As the survival time was dependent on both regression and regrowth curves, and because the brain melanoma model in small animals made it difficult to evaluate these curves separately, we further examined the in vivo growth curve of both types of melanomas following implantation in s.c. tissue. The melanotic B15b melanoma was indeed found to possess much higher growth rate as compared with that of the amelanotic A1059 melanoma. The significance of boron biodistribution studies and BNCT survival curve analyses in forming an effective clinical protocol for individual human cases of melanoma brain metastasis is discussed.

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Section: Discussionsupporting

confidence: 75%

Section: Resultsmentioning

confidence: 78%

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Effect of Boron Neutron Capture Therapy for Melanotic and Amelanotic Melanoma Transplanted into Mouse Brain

Iwakura

Kondoh²,

Hoshino

et al. 2002

Pigment Cell Research

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“…8). This concentration is 3 times higher than normal skin and blood 2-3 hrs after final systemic 10 B administration (17). We subsequently were able to successfully treat 18 patients suffering various types of malignant melanoma by 10 B-BPA-BNCT.…”

Section: First Clinical Bnct Of Melanoma Patientmentioning

confidence: 89%

“…Note marked selective accumulation of 10 B into melanoma as compared to skin and blood. PGS: prompt g-ray spectrometry(17).…”

mentioning

confidence: 99%

Dual Control of Melanogenesis and Melanoma Growth: Overview

Mishima¹,

Kondoh²

2000

Pigment Cell Research

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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.

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Boron neutron capture therapy for cancer. Realities and prospects

Barfh

Soloway

Fairchild

et al. 1992

Cancer

271

104

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Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when a stable isotope, boron‐10 (10B), is irradiated with low‐energy thermal neutrons (nth) to yield (4He) α‐particles and 7Li nuclei (10B + nth→ [11B] → 4He + 7Li + 2.31 MeV). The success of BNCT as a tumoricidal modality is dependent on the delivery of a sufficient quantity of 10B and nth to individual cancer cells to sustain a lethal 10B(n, α) 7Li reaction. The current review covered the radiobiologic considerations on which BNCT is based, including a brief discussion of microdosimetry and normal tissue tolerance. The development of tumor‐localizing boron compounds was discussed, including the sulfhydryl‐containing polyhedral borane, sodium borocaptate (Na2 B12 H11 SH), and borono‐phenylalanine [BPA], both of which are currently being used clinically in Japan as capture agents for malignant brain tumors and melanomas, respectively. Compounds currently under evaluation, such as boronated porphy‐rins, nucleosides, liposomes, and monoclonal antibodies (MoAbs), were also considered. Nuclear reactors have been used as the exclusive source of neutrons for BNCT. The use of low‐energy (0.025 eV) thermal neutrons and higher‐energy 1–10, 000 eV) epithermal beams, beam optimization, and possible alternative neutron sources (accelerators) were also discussed. Clinical studies performed in the United States during the 1950s and 1960s for the treatment of malignant brain tumors were reviewed. Current studies in Japan and future studies in Europe and the United States concerning the treatment of glioblastomas and melanomas by BNCT were discussed, as were critical issues that must be addressed if BNCT is ever to be a useful therapeutic modality.

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Advances in the Control of Human Cutaneous Primary and Metastatic Melanoma by Thermal Neutron Capture Therapy

Cited by 24 publications

References 7 publications

Effect of Boron Neutron Capture Therapy for Melanotic and Amelanotic Melanoma Transplanted into Mouse Brain

Effect of Boron Neutron Capture Therapy for Melanotic and Amelanotic Melanoma Transplanted into Mouse Brain

Dual Control of Melanogenesis and Melanoma Growth: Overview

Boron neutron capture therapy for cancer. Realities and prospects

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