Article Chemistry Small Boron compounds Year 1989

Treatment of malignant melanoma by single thermal neutron capture therapy with melanoma-seeking 10B-compound

The Lancet, 1989

Authors:   Yutaka Mishima,Chihiro Honda,Masamitsu Ichihashi,Hidefumi Obara,Junichi Hiratsuka,Hiroshi Fukuda,Hiroshi Karashima,Tooru Kobayashi,Keiji Kanda,Kazuo Yoshino
Journal: The Lancet
Abstract: As pigment cells undergo melanoma genesis, accentuated melanogenesis concurrently occurs in principle. Subsequent to the understanding of intrinsic factors controlling both processes, we found our selective melanoma neutron capture therapy (NCT) using lOB-dopa (melanin substrate) analogue, I OBI-p-boronophenylalanine (l°BI-BPA), followed by I OB(n,afLi reaction, induced by essentially harmless thermal neutrons, which releases energy of 2.33 MeV to 14,u, the diameter of melanoma cells. In vitro/in vivo radiobiological analysis revealed the highly enhanced melanoma killing effect of I OBI_BPA. Chemical and prompt gamma ray spectrometry assays of lOB accumulated within melanoma cells after I OBI_BPA administration in vitro and in vivo show high affinity, e.g., lOB melanoma/blood ratio of 11.5. After successfully eradicating melanoma transplanted into hamsters P rinciples of Selective Neutron Capture Therapy Thermal neutrons, generated by an atomic reactor, are absorbed easily by the non-radioactive isotope boron10(IOB). This absorption is known to result in the emission of a-particles and lithium atoms [‘oB(n, a)1Li reactionJ, which share between them an average total kinetic energy of 2.33 MeV [1 J (Fig 1). Due to the limited traveling range of these charged particles, the primary radiation injury is confined to a distance of 10- 14 f.1 from the point of the neutron-activated boron atom. This distance is approximately equal to the diameter of an individual cancer cell. Therefore, if we can selectively accumulate lOB in cancer cells, we can destroy them without serious injury to the surrounding normal tissue [2J (Fig 1). Melanoma is a highly lethal cancerous growth of pigment cells which have the specific function of synthesizing melanin from dopa and tyrosine by the action of tyrosinase. As pigment cells undergo malignant transformation, their tyrosinase activity usually increases, and this results in an increase of its product, melano-protein. If this unique, specific cellular property of melanoma can be utilized to concentrate lOB, then a selective, biological, nonsurgical treatment of melanoma can be realized. Furthermore, because the synthesis of unique, specific proteins is not limited to malignant mel aReprint requests to: Dr. Yutaka Mishima, Special Institute of Cancer Neutron Capture Therapy, Kobe University School of Medicine, 5-1 Kusunoki-Cho 7-Chome, Chuo-ku, Kobe, Japan Abbreviations: BPA: p-boronophenylalanine CPZ: chlorpromazine NCT: neutron capture therapy with NCT, we advanced to preclinical studies using spontaneously occurring melanoma in Duroc pig skin. We cured three melanoma cases, 4.6 to 12 cm in diameter, by single neutron capture treatment. Complete disappearance of melanoma was obtained without substantial side effects. Acute and subacute toxicity as well as pharmacodynamics of IOBI_ BPA have been studied in relation to therapeutic dosage requirements. Clinical radiation dosimetry using human phantom has been carried out. Further preclinical studies using human melanoma transplanted into nude mouse have been a useful model for obtaining optimal results for each melanoma type. We recently treated the first human melanoma patient with our NCT, using essentially the method for Duroc pig melanoma, and obtained similar regression time course leading to cure.