[en] Treatment of micrometastases of HX34 human melanoma grown as xenografts in nude mice represents an advanced stage of preclinical investigations concerning targeted radiotherapy of this neoplasm using 3,7-(dimethylamino)phenazathionium chloride methylene blue (MTB) labeled with astatine-211 (211At) (alpha-particle emitter). The therapeutic effectiveness of 211At-MTB administered i.v. was determined by a lung colony assay combined with a search for metastases to organs other than the lungs. A single dose of 211At-MTB lowered the HX34 cell surviving fraction in lungs to below 10% almost independently of the time interval between cell inoculation and radioisotope injection and of 211At-MTB radioactivity within its investigated range. Radiation dose and the time of its administration did, however, influence the size of lung colonies. In contrast, the efficacy of 211At-MTB treatment as assessed by both surviving fraction and colony size was significantly dependent on a number of HX34 cells inoculated initially into mice. These results are explained by a short range of alpha-particles emitted by 211At and a mechanism of growth of lung colonies from tumor cells circulating with blood and blocking lung capillaries. Metastases in organs other than lungs and characteristic of control animals were not found in mice treated with 211At-MTB. The high therapeutic efficacy achieved proved that 211At-MTB is a very efficient scavenger of single melanoma cells distributed through blood and micrometastases with sizes below the limit of clinical detection

[en] The paper presents a method for manufacturing 6-²¹¹At-astato-MNDP. Its efficacy was tested using i.p. injections in mice which had received a previous injection of a suspension of CCL-CMT-93 adenocarcinoma cells into their flanks several weeks ago. Tumour sizes were measured daily. Survival rate revealed to be significantly increased in mice treated with 6-²¹¹At-astato-MNDP as against controls. Possible complications of treatment using this drug are discussed briefly. (MG)

[en] The α-emitting radionuclide ²¹¹At possesses many of the desired nuclear, chemical and radiobiological properties which make it eminently suitable for cancer therapy. The syntheses of high activity ²¹¹At and high specific activity tumour-directed astatinated substrates, 6-[²¹¹At]-astato-MNDP and 4-[²¹¹At]-astato-MTB, have been outlined. The respective investigation of these compounds has been discussed within their context as possible high-LET endo-radiotherapeutic agents for thyroid, onco-phosphatase positive and melanotic neoplasms. (orig.)

[en] 6-[²¹¹At]astato-MNDP is currently being investigated as a potential high LET endoradiotherapeutic drug. Biodistribution and whole-body radiation retention studies have been carried out with 6-[²¹¹At]astato-MNDP and ²¹¹At^- in a murine rectal tumour model; results indicate that the ²¹¹At-C bond in the compound is metabolically stable for at least 6 h. The Mean Biological Concentration of 6-[²¹¹At]astato-MNDP in tumour tissue ranged from 170-253% over an initial 12 h period; this was higher than that observed for the [²¹¹At]astatide anion. Conversely, the uptake of compound into radiobiologically critical organs was significantly lower. (author)

[en] Therapeutic studies with high specific activity 6-[¹²⁵I]-iodo-MNDP (0.925-22.2 MBq) have demonstrated that this Auger-emitting drug is effective in treating mice with a transplanted CMT-93 rectal adenocarcinoma without incurring early or late radiation-associated sequelae. Its efficacy has been attributed to the selective intranuclear localization of 6-[¹²⁵I]-iodo-MNDP metabolite and consequent high-LET quality toxicity in heterogeneously distributed tumour cells that exhibit specific onco-alkaline phosphatase isoenzyme activity. Quasi-microdosimetric estimations of the radiobiologically equivalent low-LET single fraction absorbed tumour dose are of an order of magnitude that might be associated with the permanent control of this tumour. (author)

[en] Since 1953, attempts have been made to develop radioactive drugs. Preparations of tritiated menadiol sodium diphosphate (T-MNDP) of high specific activity showed a definite, though limited, but sometimes useful effect in the treatment of certain patients with advanced tumors, especially adenocarcinoma of the colon and of the pancreas and malignant melanoma of the skin. The next step was to use a much more effective isotope. 6-¹²⁵I-iodo-2-methyl-1,4-naphthoquinol bis (diammonium phosphate) - abbreviated 6-¹²⁵I-iodo-MNDP - has been synthesized, and in laboratory studies appears more promising. ¹²⁵I provides radiations which behave predominately like high LET radiation, despite the accompanying X and gamma radiations. The astatine analogue, 6-²¹¹At-astato-2-methyl-1,4-naphthoquinol bis (disodium phosphate) has also been synthesized. Confirming and greatly extending the earlier findings with T-MNDP, in vitro experiments showed that 6-¹²⁵I-iodo-MNDP is concentrated selectively in the cells of some human malignant tumors by a factor of about 15 to 20 or more in relation to the cells of normal origin that were studied. Macrodosimetric considerations and comparison with clinical treatments with T-MNDP suggest practical dosage. A typical treatment for a patient of body weight 70 kg with localized inoperable carcinoma of the colon could be 8 intravenous injections each of approximately 120mCi of 6-¹²⁵I-iodo-MNDP to a toal of 0.97 Ci in 25 days. Risks of late carcinogenesis and leukemogenesis are calculated to be less than 1%. Clinical indications are discussed briefly. Animal experiments are in progress and further preclinical studies are required

[en] Several radio-iodinated and [²¹¹At]-astatinated derivatives of methylene blue have been prepared with a view to their respective investigation as potential imaging and therapeutic agents for malignant melanoma. (author)

[en] The investigations concerning a targeted radiotherapy for pigmented melanoma with a radiolabeled phenothiazine derivative, 3,7-(dimethylamino)phenazathionium chloride [methylene blue (MTB)], were continued using melanotic and amelanotic sublines of B16 melanoma. Two radionuclides, 125I and 211At, emitting Auger electrons and alpha particles, respectively, replaced 35S previously studied since their biological effectiveness is significantly higher. In vitro autoradiography revealed a selective accumulation of methylene blue labeled with either of the radioisotopes in pigmented melanoma cells but its absence in nonpigmented cells. Treatments with [125I]MTB and [211At]MTB were performed both in vitro and in vivo, with their effectiveness determined by lung clonogenic assay. [125I]MTB proved to be relatively ineffective when incorporated into melanosomes distributed in the cytoplasm, i.e., too far away from the genome. Conspicuous therapeutic effects were achieved with [211At]MTB for pigmented melanoma only. 211At itself did not affect either of the investigated sublines of B16 melanoma confirming once again the high affinity of methylene blue to melanin. Calculations of cumulative radiation doses from [211At]MTB deposited in melanotic melanoma tumors and pigmented normal organs which would be at a particular risk led to the conclusion that [211At]MTB could be used for a highly selective and very efficient targeted radiotherapy of pigmented melanomas without damaging normal tissues

[en] Published in summary form only

[en] Uptake studies of the potential endoradiotherapeutic agent, 6-¹²⁵I-iodo-2-methyl-1,4-naphthoquinol bis(diammonium phosphate) have been carried out in vitro on a wide range of normal and malignant human cells. In general, for a standardized dose of 0.1 μCi/ml, the uptake of the compound into normal cells was 0.0015-0.135 pCi/cell. Uptake into malignant cells was significantly higher than normal cells; uptakes of 0.89-11.3 pCi/cell were noted for melanoma, teratoma of testis, osteosarcoma and adenocarcinoma of colon and pancreas. Comparative uptake ratios for melanoma:Chang liver cells and testicular teratoma:normal testis were 29 and 23, respectively. Larger uptake ratios are usually observed with higher doses