M. Shiono

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).

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 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.

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.

Rapid Spectrophotometric Determination of Boron in Biological Tissue with Alkali Fusion Decomposition

During our clinical applications of neutron capture therapy (NCT), after administration of 10B-p-Boronophenylalanine (BPA), 10B concentration in the melanoma and the skin near the melanoma are determined by the prompt γ method. From the data obtained, it is possible to calculate the boron concentration in melanoma during neutron irradiation, and irradiation time was determined. If the prompt γ method is not available, it is difficult to estimate the concentration in melanoma at the time of the irradiation.

In Vivo Cellular Pharmacology on the Selective Affinity of 10B1-BPA for Malignant Melanoma

We have previously shown that 10B1-paraboronophenylalanine (10B1-BPA) has selective affinity for both melanotic and amelanotic melanomas in vitro and in vivo1). We have also shown complete suppression of implanted melanoma in hamster by thermal neutron capture therapy (NCT) using 10B1- BPA1). Further, we have already treated succesfully six human melanoma cases by NCT using 10B1-BPA1,2).

Further in Vitro Radiobiological Analysis on 10B-BPA BNCT of Malignant Melanoma: Correlation of Determined 10B-Content and Cell Killing Effect

The successful application of boron neutron capture therapy (BNCT) for melanoma depends on the following points, (1) high accumulation of 10B in target melanoma cells (approcimately 20 ppm) and (2) high tumor/normal tissue10B ratio, theoretically greater than 5.