astatine and Skin-Neoplasms

3,7-(dimethylamino) phenazathionium chloride [methylene blue (MTB)] labelled with alpha-particle emitter astatine-211 (211At) selectively accumulates in melanoma cells due to an exceptionally high affinity of MTB to melanin, and proves to be a very effective agent in targeting radiotherapy for pigmented human melanoma grown in mice. This study aimed at a selection of the most advantageous [211At]MTB dose fractionation leading to irreversible regression of the treated lesions. Nude mice bearing subcutaneous human melanoma xenografts of either highly pigmented HX118 or poorly pigmented HX34 human melanoma were treated with [211At]MTB administered intravenously. The treatment was performed using three different schedules of [211At]MTB fractionation: a single large dose, five fractions delivered sequentially every 48 h and two to five fractions given with a mean frequency of one per week. The effectiveness of [211At]MTB treatment was assessed by determination of the growth rate of cutaneous tumours and length of time between tumour implantation and killing of moribund mice. [211At]MTB applied with a mean frequency of one fraction per week appeared to be the most efficient treatment for highly pigmented HX118 melanomas. Its effectiveness was dependent on [211At]MTB activity used per fraction and the size of the cutaneous tumours at the beginning of the treatment. A total dose of [211At]MTB seemed of less importance. An irreversible regression of the lesions was achieved. Poorly pigmented cutaneous melanoma xenografts were affected most significantly by [211At]MTB applied as five fractions given every 48 h. The treatment caused a temporary inhibition of tumour growth after which the lesions regained the control growth rate. These and previous results suggest that [211At]MTB could successfully control the growth of already formed lesions of pigmented melanoma, as well as prevent metastatic spread of the tumour, provided an appropriate fractionation régime of the radiolabelled compound is employed.

Topics: Animals; Astatine; Drug Carriers; Female; Humans; Melanoma; Methylene Blue; Mice; Mice, Nude; Neoplasm Transplantation; Pigmentation; Skin Neoplasms; Time Factors; Transplantation, Heterologous

Topics: Animals; Astatine; Humans; Iodine Radioisotopes; Melanoma; Methylene Blue; Radionuclide Imaging; Skin Neoplasms

The present stage of our preclinical investigations of targeted radiotherapy for melanoma with 3,7-(dimethylamino)phenazathionium chloride [methylene blue (MTB)] labelled with astatine-211 (211At), an alpha-particle emitter, concerns toxicity of the treatment, as well as macro- and microscopic evaluation of its efficacy. Fragments of two human melanoma xenografts, pigmented HX118 and non-pigmented HX34 (used as a control), were implanted s.c. into nude mice subsequently treated with two doses of 211At-MTB injected i.v. Alterations in tumour growth rate were related to microscopic damage caused by 211At-MTB to the lesions, as determined by light microscopy using histopathological techniques. 211At-MTB-dependent growth inhibition of pigmented melanoma occurred either instantly or as a gradual reduction in the tumour growth rate. At a later stage, lesions that ceased to grow immediately consisted of quiescent, heavily pigmented tumour cells, as well as advanced fibrosis, and were extensively infiltrated by melanin-laden phagocytes. Large, unresorbed and often calcified necrotic deposits characterised the tumours responding gradually to the treatment. 211At-MTB remained non-toxic in normal organs. Only a relative number of small lymphocytes in the groin lymph nodes in a minority of animals was temporarily reduced, most often in conjunction with the treatment of pigmented tumours. The data demonstrated a high therapeutic effectiveness of 211At-MTB towards pigmented melanoma at the expense of negligible injury to normal tissues, and revealed that the macroscopic determination of tumour growth rate often underestimated an efficacy of the applied treatment.

Topics: Animals; Astatine; Drug Carriers; Female; Humans; Lymph Nodes; Melanoma; Methylene Blue; Mice; Mice, Nude; Neoplasm Transplantation; Radiation Injuries; Radiotherapy; Skin Neoplasms; Thyroid Gland; Transplantation, Heterologous

The next stage of our preclinical investigations of targeted radiotherapy for melanoma with 3,7-(dimethylamino)phenazathionium chloride [methylene blue (MTB)] labeled with 211At (alpha particle emitter) concerns the treatment of cutaneous tumors and their metastases. Fragments of two human melanoma xenografts, highly pigmented HX118 and poorly pigmented HX34, implanted s.c. into nude mice, were treated with four doses of 211At-MTB injected i.v. The growth rate of cutaneous tumors and the appearance and size of their lymph node metastases served as criteria of treatment effectiveness. 211At-MTB inhibited the growth of cutaneous tumors in a manner dependent on their pigmentation and initial size. Highly pigmented smaller melanomas were affected by 211At-MTB to a greater extent than poorly pigmented and larger ones. Growth of the smallest HX118 lesions investigated was completely inhibited for 65 days, whereas the growth inhibition of HX34 tumors of the same size lasted 7 days only. 211At-MTB exhibited similar pigmentation-dependent effects toward lymph node metastases. The size of metastatic lesions derived from HX118 xenografts never reached that in control animals during the period of observation, whereas those grown from HX34 xenografts attained control values after a 50-day delay. The results demonstrated the capacity of 211At-MTB to control the growth of cutaneous melanomas and their metastases.

Topics: Animals; Astatine; Drug Screening Assays, Antitumor; Female; Humans; Lymphatic Metastasis; Melanoma; Methylene Blue; Mice; Mice, Nude; Neoplasm Transplantation; Skin Neoplasms; Transplantation, Heterologous; Tumor Cells, Cultured