C. Honda

In vivo diagnosis of human malignant melanoma with positron emission tomography using specific melanoma-seeking 18F-DOPA analogue.

Detection and diagnosis of human malignant melanoma byPositron Emission Tomography (PET) using 18F-10B-L-BPA, a specificmelanogenesis-seeking compound synthesized for use in Boron NeutronCapture Therapy for malignant melanoma (NCT), has beendeveloped. This resulted in a novel, highly effectivemethodology for the selective three dimensional imaging ofmetastatic malignant melanomas, and for accurate determination of10B concentration in the tumor and surrounding tissue,providing almost all diagnostic information necessary for completenon-invasive radiation dose planning in the treatment ofmalignant melanoma both for NCT as well asother therapeutic modalities.

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

Differing in principle from boron neutron capture therapy (NCT) of brain tumors using passive accumulation of 10B, since 1972 our ideal) has been to develop a new 10B delivery system actively targeting cancers by utilizing their enhanced specific metabolic activity. As a prototype, we have been working with melanoma using 10B1-p-boronophenylalanine (10B1-BPA), a 10B-dopaanalogue, melanogenesis-seeking melanin polymer substrate2).

4-Borono-2-[18F]fluoro-d,l-phenylalanine: a possible tracer for melanoma diagnosis with PET

The potential of 4-borono-2-[18F]fluoro-D,L-phenylalanine ([18F]FBPA), a flurodinated derivative of a target compound for boron neutron capture therapy, for melanoma imaging by positron emission tomography (PET) was studied using animal models. A high uptake of [18F]FBPA was found in murine B16 melanoma or in Greenes melanoma No. 179, a melanotic cell line in hamsters, for the first 6 h after injection. Whole body autoradiography using [18F]FBPA gave a clear image of the B16 tumor. The acid-insoluble 18F in the B16 increased to 27% by 6 h, and most of the free 18F was detected as [18F]FBPA in both B16 and plasma. In the hamster models, No. 179 showed a 1.7 times higher uptake than amelanotic Greenes melanoma No. 178 at 6 h post-injection, although both melanomas indicated similar metabolic activities when examined by a tracer uptake study using L-[14C]methionine, 2-deoxy-D-[14C]glucose and [3H]thymidine. [18F]FBPA may be a very promising PET tracer for melanoma imaging.

Increased Selective 10B-Uptake by Malignant Melanoma Using Systemic Administration of 10B1-BPA·Fructose Complex

10B1-para-Boronophenylalanine(10B1-BPA) has selective affinity for malignant melanoma. In our first human case, we succeeded in obtaining complete regression of a metastatic subcutaneous melanoma lesion by neutron capture therapy (NCT) using distant perilesional injections of 10B1-BPA hydrochloride.

Selective Thermal Neutron Capture Therapy and Diagnosis of Malignant Melanoma: From Basic Studies to First Clinical Treatment

As melanoma genesis occurs in pigment cells, accentuated melanogenesis concurrently occurs in principlel. Thus, harnessing this accentuation of melanogenesis, we developed a new mutually-dependent two-step therapy, in which melanogenesis-seeking compounds first specifically target melanoma cells, enabling the powerful second step to selectively destroy the targeted cells. Our new thermal neutron capture therapy2,3,4,5(NCT) uses a 10B-dopa(melanin substrate) analogue, 10B1-p-boronophenylalanine (10B1-BPA) which accumulates preferentially in melanoma cells6,7. The cells then are irradiated with thermal neutrons to induce the 10B(n, α)7Li reaction which releases energy of 2.33MeV to a distance of 10~14μ, the diameter of melanoma cells. Extensive in vitro and in vivo radiobiological analysis8 confirmed the highly enhanced killing effect of 10B1-BPA. Measurements of the accumulating capacity of 10B1-BPA into melanoma cells in vitro and in vivo using both chemical and prompt gamma ray spectrometry7 assay showed its high affinity for these cells9.

Selective Melanoma Thermal Neutron Capture Therapy for Lymph Node Metastases

The success of treatment of tumors with NCT lies primarily with the development of suitable vectors to optimally carry 10B to the tumor site, efficient methods of their administration, and effective neutron beam delivery.

Synthesis of o - and m -Boronophenylalanine

p-Boronophenylalanine (p-BPA) has been used for Boron Neutron Capture Therapy (BNCT). The synthetic route to p-BPA was developed by Snyder et al. 1. o- and m-Boronophenylalanine (o- and m-BPA) are the isomers of p-BPA, and they may be incorporated into melanoma cells such as p-BPA and used for BNCT. Even if this incorporation dose not happen, this will give us informations about the relationship between structure and incorporation. Therefore, we have developed a way of synthesizing o-BPA and m-BPA.

BNCT of Malignant Melanoma-Radiobiological Analysis and Data Comparison with Conventional Radiotherapy

Research on selective melanoma neutron capture therapy was initiated by Y. Mishima and his associates, consisting of physicists, chemists, pharmacologists, radiobiologists, and medical scientists. Following basic research of 13 years, this team started the first clinical. trial of melanoma BNCT using10B-paraboronophenylalanine (BPA) in 1987 and have treated 16 patients with various types of melanoma1−4.

Deuteriation Trials for Neutron Capture Therapy of Deep-Seated Melanoma Lesions

We have succeeded in curing primary cutaneous malignant melanomas of human patients by neutron capture therapy (NCT) using 10B1-para-boronophenylalanine (10BPA)1,2. Since primary cutaneous melanomas are usually within l0mm in thickness, we can irradiate the whole primary lesions with thermal neutrons in a sufficient dose for eradication. In further applying our NCT to deep-seated melanoma lesions, especially those metastasizing into the lymph nodes, partial replacement of hydrogen (H) with deuterium (D) (deuteriation or deuteration) is expected to improve the penetration of thermal neutrons into the depth of the tumors due to the decreased H(n,g)D reaction and very low cross section of D for neutron capture.

Determination of p-Boronophenylalanine in Biological Tissues with High Performance Liquid Chromatography

Many ways of determining 10B in biological tissues have been developed1-4. These methods are adequate for the trial of neutron capture therapy, because 10B concentration and tumor/blood 10B ratio are key points for success. But, we want to know the concentration of 10B-compound itself in tissues to answer following questions.