No abstract available

[en] Thermal neutrons are easily absorbed by the nonradioactive isotope ¹⁰B, resulting in the emission of alpha particles and lithium atoms, which release an energy of 2.33 MeV for up to a 14-μm-diam melanoma cell. Thus, if ¹⁰B can be selectively accumulated in melanoma, it can be destroyed without injury to the surrounding normal tissues by concentrating high linear energy transfer particles. The authors have synthesized seven melanoma-seeking ¹⁰B compounds, two of which, ¹⁰B12-chlorpromazine(¹⁰B¹²-CPZ) and ¹⁰B₁-p-boronophenylalanine(¹⁰B₁-BPA), are found to be highly effective. The enhanced melanoma-killing effect of the ¹⁰B compounds is found by in vitro radiobiological analysis. A chemical assay and alpha-track analysis 28 h after systemic administration to melanoma-bearing hamsters reveals a ¹⁰B melanoma/blood ratio of 11.5 and a melanoma/liver ratio of 15. Establishment of a clinical therapeutic method for curing human melanoma without failure is underway by correlating biophysical, biochemical, biological, and therapeutic data analysis. Recently, the authors have also been working to develop neutron capture therapy using ¹⁰B-monoclonal antibodies for melanoma and were able to make some ¹⁰B conjugates with the specific m259-0 antibody

[en] A non-sensitive, 8-yr-old male patient (termed UV81KO) with only acute recurrent sunburns and without any other physical or neuromental retardations was studied. The patient's skin exhibited lowered minimal erythema doses between 280 and 300 nm monochromatic wavelengths without delayed peaking of erythema. UV81KO skin fibroblasts in culture was 5-fold more sensitive to 254 nm UV killing than normal cells, though the response of obligatory heterozygotes was normal. UV81KO cells were also more sensitive to killings by fluorescent sunlamp (295-300 nm UV-B) radiation, 4-nitroquinoline-1-oxide, and N-hydroxy-acetyl aminofluorene, but not by monofunctional decarbamoyl mitomycin C, bifunctional mitomycin C, and alkylating agents (methyl methanesulfonate, ethyl methanesulfonate, N-methyl-N-nitrosourea). Assays for unscheduled DNA synthesis, T4 endonuclease V-susceptible sites (pyrimidine dimers), endogenous excision-break accumulation by arabinofuranosyl cytosine-plus-hydroxyurea, single-strand-break rejoining, and molecular-weight increase of pulse-chased DNA in irradiated cells indicated no apparently detectable defects in nucleotide-excision repair processes and in replicative bypass in UV81KO cells. Despite the repair proficiency as such, UV81KO cells showed the defective recovery of DNA synthesis after 254 nm UV irradiation with 1 and 5 J/m2, at which dose the recovery occurred in normal cells. The base line level of sister-chromatid exchanges (SCEs) was higher in UV81KO cells (10-12 SCEs/cell) than in normal cells (5 SCEs/cell), although the induction rate of SCEs by 254 nm UV in UV81KO cells was the same as in normal cells. Such clinical, cellular and molecular characteristics and comparison to those in the other photodermatoses (xeroderma pigmentosum, Cockayne's syndrome, the 11961 disorder, Bloom's syndrome) can make a clear distinction of UV81KO from the others

[en] Excision repair of DNA damage by UV has been assessed in normal human fibroblasts in culture by measuring unscheduled DNA synthesis. Dose response experiments indicated that the same chromophore was involved in UV-induced damage and excision repair at three different wave-lengths between 260 and 300 nm. Action spectra for unscheduled DNA synthesis were determined at wavelengths between 260 and 320 nm 30 min after irradiation using 2 doses of UV. 100 Jm^-2 and 10 Jm^-2. Experiments at the lower dose were carried out because it appeared that repair was saturated with the higher dose at 260 and 280 nm. To explore this part of the spectrum further, experiments were performed with different doses at 260 and 280 nm and unscheduled DNA synthesis assessed 30 min and 24 h after irradiation. At 24 hr after irradiation a significantly greater amount of unscheduled DNA synthesis occurred at 280 nm. It is suggested, therefore, that both DNA and protein are concerned in the absorption of UV which leads to DNA damage and excision repair. (author)

[en] Tonicity shock or caffeine postirradiation treatment makes evident fast-type potentially lethal damage (PLD). Caffeine expresses fast-type PLD more efficiently than tonicity shock in X-irradiated B-16 mouse melanoma cells, compared with V79 Chinese hamster cells. The survival curves of thermal neutrons for either V79 or B-16 cells exhibit no shoulder. Neither V79 nor B-16 cells show the sublethal damage (SLD) repair of thermal neutrons. Caffeine-sensitive fast-type PLD repairs exist in X-irradiated B-16 cells, as well as V79 cells. The fast-type PLD repair of B-16 cells exposed to thermal neutrons alone is rather less than that of X-irradiated cells. Furthermore, an extremely low level of fast-type PLD repair of B-16 cells with 10B1-paraboronophenylalanine (BPA) preincubation (20 hours) followed by thermal neutron irradiation indicated that 10B(n,alpha)7Li reaction effectively eradicates actively growing melanoma cells. The plateau-phase B-16 cells are well able to repair the slow-type PLD of X-rays. However, cells can not repair the slow-type PLD induced by thermal neutron irradiation with or without 10B1-BPA preincubation. These results suggest that thermal neutron capture therapy can effectively kill radioresistant melanoma cells in both proliferating and quiescent phases

[en] Since the success of human melanoma treatment by a single NCT application using ¹⁰B-dopa analogue, ¹⁰B₁-paraboronophenylalanine, a metabolic substrate for melanin, the authors have been investigating other melanoma-seeking ¹⁰B agents which could in principle be applicable to other cancers. In order to accumulate a sufficient number of ¹⁰B atoms on target cells, they first synthesized new ¹⁰B-avidin compounds. These compounds can be effectively targeted on human melanoma cells by biotinated monoclonal antibodies (MoAbs) specific for the cells. The precise quantification of ¹⁰B atoms accumulated on a target cell has been successfully carried out Inductively Coupled Plasma Mass Spectrometry (ICP-MS)

[en] The effect of chlorpromazine (CPZ) and UVA on lysosomes of cultured normal human fibroblasts has been investigated. Acid phosphatase (ACPase) activity in 12000 g pellet of cells treated with CPZ (10 μg/ml) and UVA (6 x 10⁴ J/m²) was found to be decreased as compared with non-treated, CPZ or UVA treated control cells. This decrease, however, was not accompanied by a concomitant increase in ACPase activity in the 12000 g supernatant. The addition of Triton X-100 to cells pre-treated with CPZ + UVA resulted in only a moderate increase in ACPase activity of the 12000 g supernatant. ACPase activity of the cells incubated in media containing pre-irradiated CPZ was also found to be decreased. These results indicate that CPZ + UVA directly inactivate lysosomal enzymes, possibly without affecting the membrane. (author)

[en] Thermal neutrons are absorbed easily by ¹⁰B resulting in the emission of α-particles and lithium atoms, which share an energy of 2.3 MeV, and have a travelling range of 14 μm. This is equal to the diameter of melanoma cells. Therefore if we can selectively accumulate ¹⁰B in melanoma cells, we can destroy them without serious injury to the surrounding tissue. We have synthesized ¹⁰B compounds having a selective affinity for melanoma cells, such as ¹⁰B₁-chlorpromazine (¹⁰B₁-CPZ), ¹⁰B sodium undecahydrododecaborate (¹⁰B₁₂-CPZ), and ¹⁰B₁-p-boronophenylalanine (¹⁰B₁-BPA). We irradiated melanoma subcutaneously proliferating in hamster. The maximum and longest suppressive effect has been obtained by neutron and administration of ¹⁰B₁₂-CPZ or ¹⁰B₁-BPA before irradiation, compared to neutron alone and to X-ray treatment. The enhanced melanoma killing effect of the ¹⁰B-compounds is also shown by in vitro radiobiological analysis. The D₀ value of thermal neutron only is 2.8 x 10¹² nvt, ¹⁰B-boric acid, 5 μg ¹⁰B present: 0.9 x 10¹² nvt; ¹⁰B₁₂-CPZ, 1.2 μg ¹⁰B pre-incubation: 0.9 x 10¹² nvt; and ¹⁰B₁-BPA, 0.38 μg ¹⁰B pre-incubation: 0.9 x 10¹² nvt. The chemical assay of melanoma bearing hamsters revealed a ¹⁰B tumor to blood ratio of 11.5 and a tumor to liver ratio of 15, twenty-eight hours after administration. Pre-clinical experiments on spontaneous melanoma in Duroc pig skin have shown marked regression and depigmentation after the combined treatment of ¹⁰B₁-BPA and irradiation, without obvious side effects. (author)

[en] A 10B-dopa analogue, 10B1-para-boronophenylalanine (10B1-BPA) has been found to have a marked melanoma killing effect as expressed by the Do value, 0.9-1.2 X 10(12) n/cm2. The Do value of the neutron alone is 2.8 X 10(12) n/cm2. After the introduction of high LET irradiation into radiotherapy, its higher energy deposition in the target cancer cells is one of the major problems currently to be solved. This can be achieved by our thermal neutron capture therapy in the order of cellular dimensions when we have highly tumor-seeking 10B-compounds available. Our present evidence seems to indicate that our new 10B1-BPA can highly concentrate 10B into melanoma cells, to as much as 11 times the level of the medium in the in vitro system

[en] Solar radiation induces acute and chronic reactions in human and animal skin. Chronic repeated exposures are the primary cause of benign and malignant skin tumors, including malignant melanoma. Among types of solar radiation, ultraviolet B (290-320 nm) radiation is highly mutagenic and carcinogenic in animal experiments compared to ultraviolet A (320-400 nm) radiation. Epidemiological studies suggest that solar UV radiation is responsible for skin tumor development via gene mutations and immunosuppression, and possibly for photoaging. In this review, recent understanding of DNA damage caused by direct UV radiation and by indirect stress via reactive oxygen species (ROS) and DNA repair mechanisms, particularly nucleotide excision repair of human cells, are discussed. In addition, mutations induced by solar UV radiation in p53, ras and patched genes of non-melanoma skin cancer cells, and the role of ROS as both a promoter in UV-carcinogenesis and an inducer of UV-apoptosis, are described based primarily on the findings reported during the last decade. Furthermore, the effect of UV on immunological reaction in the skin is discussed. Finally, possible prevention of UV-induced skin cancer by feeding or topical use of antioxidants, such as polyphenols, vitamin C, and vitamin E, is discussed