polonium and Carcinoma--Squamous-Cell

In the present study, we examined the antitumoral effects caused by the release of alpha emitting radioisotopes into solid squamous cell carcinoma (SCC) tumors. Using a novel method termed DART (Diffusing Alpha-emitters Radiation Therapy), we assessed the efficacy of short-lived daughters of (224)Ra releasing alpha particles, dispersing in the malignant tissue, to cause tumor growth retardation and destruction. It was carried out using specially designed wires loaded with (224)Ra activities in the range of 7-42 kBq in a set of experiments performed on BALB/c and nude mice bearing metastatic SCC tumors derived from either mouse SQ2 or human CAL27 cell lines. The insertion of a DART wire to the center of 6-7 mm primary tumors, retarded tumor growth, reduced lung metastatic load, prolonged life expectancy and in some cases caused tumor eradication. These effects were enhanced either when treating smaller tumors or treating identical tumors with 2 DART wires. Similar experiments on human-derived SCC tumors in nude mice were consistent with the outcomes of the murine model. Histological assessments revealed the tissue damage pattern, and indicated a role for the tumor vasculature in the dispersion of the atoms and the propagation of the damage. Our findings indicate that Diffusing Alpha-emitting Radiation Therapy is effective in a model system using SCC primary tumors. The in situ destruction of primary solid tumors by DART is evidently a necessary step toward curing cancer and might be augmented by chemotherapy and other modalities such as immunotherapy or antigrowth factors agents.

Topics: Alpha Particles; Animals; Brachytherapy; Carcinoma, Squamous Cell; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms, Experimental; Polonium; Radioisotopes; Radium; Radon; Treatment Outcome

The efficacy of radioimmunotherapy of tumours with radiolabelled monoclonal antibodies (MAbs) depends on the amount of antibody taken up by the tumour and on its intratumoral distribution. In the case of MAbs directed against intracellular antigens, increasing the permeability of the cytoplasmic membrane may augment the bioavailability of the antigen for the antibody. This raises the question whether the induction of tumour necrosis by chemotherapy can enhance the tumour uptake of radiolabelled monoclonal antibodies. In this work, the effect of doxorubicin on the biodistribution of Po66, an MAb directed against an intracellular antigen, was studied in nude mice grafted with the human non-small-cell lung carcinoma cell line SK-MES-1. After injection on day 0 of 125I-labelled Po66, tumour radioactivity increased up to days 3-5, and then remained unchanged to day 14. The combined administration of 125I-labelled Po66 with 8 mg kg-1 doxorubicin, in two doses separated by 7 days, doubled the radioactivity retained by the tumour. Histological and historadiographic analysis showed, however, that the drug induced cellular damage. In the absence of doxorubicin, the accumulation of Po66 was restricted to some necrotic areas, whereas with doxorubicin the necrosis was more extensive and the antibody more evenly distributed. These results suggest that chemotherapy and immunoradiotherapy combined would enhance tumour uptake of radioisotope and promote more homogenous distribution of the radiolabelled MAb. This would promote eradication of the remaining drug-resistant cells in tumours.

Topics: Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Neoplasm; Antigens, Neoplasm; Carcinoma, Squamous Cell; Combined Modality Therapy; Doxorubicin; Drug Administration Schedule; Female; Humans; Immunoconjugates; Immunoglobulin G; Intracellular Fluid; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Polonium; Radioimmunotherapy; Tissue Distribution

Results are reported of epidemiological studies in six groups of miners, who work in U mines, Fe mines and shale clay mines. A significant excess of lung cancer was proved in exposure categories below 50 WLM, the first significant excess of lung cancer rate was found in the sixth year following the start of exposure, and a significant difference between the observed and expected rate was found in miners even before the fortieth year of age. The mean attributable annual cancer risk after about 30 y of observation in the whole study was approximately 20.0 and in persons starting exposure after 30 y of age the risk was approximately 30.0 per year per 1 WLM per 10(6) persons. The dose-effect relationship and the attributable lung cancer risk per 1 WLM were significantly influenced by the age at the first exposure by total accumulated exposure and by the character of the accumulation of exposure. The observed effects of smoking and exposure to alpha radiation from Rn daughters were nearly additive. The lung cancer risk per 1 WLM at low levels of exposure (not including the contribution from natural sources in the living environment) in U as well as Fe mines indicated a certain elevation compared with the risk at higher accumulated exposure.

Topics: Adult; Aged; Bismuth; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Czechoslovakia; Humans; Iron; Lead; Longitudinal Studies; Lung Neoplasms; Middle Aged; Mining; Neoplasms, Radiation-Induced; Polonium; Prospective Studies; Radon Daughters; Uranium

This paper presents clinical, experimental, and epidemiologic evidence to help explain the rapidly increasing incidence of primary lung cancer, with recently observed reversal in leading cell type from squamous cell to adenocarcinoma. It postulates that this may be due to changes in modern cigarettes, with or without filters, which allow inhalation of increased amounts of radioactive lead and polonium and decreased amounts of benzopyrene. This hypothesis is based upon measurements of increased concentrations of radioactive polonium in the lungs of cigarette smokers, in modern tobaccos grown since 1950, and in high-phosphate fertilizers used for tobacco farming in industrialized countries. Critical support for this thesis is based upon experimental animal studies in which lung cancers that resemble adenocarcinomas are induced with as little as 15 rads of radioactive polonium, equal to one fifth the dosage inhaled by cigarette smokers who average two packs a day during a 25-year period.

Topics: Adenocarcinoma; Alpha Particles; Animals; Benzopyrenes; Carcinoma, Squamous Cell; Cricetinae; Female; Fertilizers; Humans; Lead; Lung; Lung Neoplasms; Male; Neoplasms, Radiation-Induced; Nicotiana; Plants, Toxic; Polonium; Smoking; Tobacco Smoke Pollution

The present series of experiments was carried out in order to see what role pre-existing localized fibrosis plays in carcinogenesis of the lung. Hemorrhagic infarction was produced in the lung of 180 male Wistar rats by injecting 0.05 ml of hexachlorotetrafluorobutane into the tail vein. This resulted in localized fibrosis in the lung 3 months later. One hundred and fiften rats were alive 3 months after administration of the chemical. Of these animals, 30 were given no further treatment (control). The remaining 85 rats were given intratracheal instillation of 0.2 microCi of polonium-210 once a week, a total of 15 times. It was subsequently found that lung carcinoma was induced in close proximity to the localized pulmonary fibrosis in 3 of 26 rats (11.5%) during the period from completion of the 15 weekly administrations of polonium-210 until the end of this experiment (21 months after the 1st instillation of polonium-210). Polonium-210 was found to be deposited in the fibrous thickening of the alveolus around the subpleural fibrotic lesion, bronchial epithelium, and peribronchial lymph apparati at the initial period of administration of polonium-210, but during the period of pulmonary carcinogenesis, it was deposited in the localized fibrotic lesion in the lung and in a few cancer cells. This suggests that polonium-210 deposited in the pulmonary fibrotic lesion remains there over a long period of time, indicating a reduced clearance ability at this site.

Topics: Adenocarcinoma; Adenocarcinoma, Papillary; Animals; Carcinoma, Squamous Cell; Hyperplasia; Lung Neoplasms; Male; Neoplasms, Experimental; Neoplasms, Radiation-Induced; Polonium; Pulmonary Fibrosis; Rats

The pathogenesis of 210Po-induced tumors in the peripheral lung of Syrian golden hamsters has been studied in a serial sacrifice experiment utilizing both plastic (glycol methacrylate) and routine paraffin embedding procedures for lung sections. A rapid progression from hyperplasia of bronchiolar-type cells that appear in the alveolar region to malignant tumors was documented. Tumors began appearing as early as 15 weeks after the first intratracheal instillation of 210Po.

Topics: Adenocarcinoma; Animals; Carcinoma, Squamous Cell; Cricetinae; Hyperplasia; Lung Neoplasms; Male; Mesocricetus; Neoplasms, Experimental; Neoplasms, Radiation-Induced; Polonium; Precancerous Conditions; Time Factors

Benzo(a)pyrene and 210Po were administered both simultaneously and sequentially by intratracheal instillations to Syrian golden hamsters in experiments designed to identify any synergistic interactions between these carcinogens. Their effects were additive after simultaneous administration. A significant synergistic interaction between the two agents appeared to occur when benzo(a)pyrene exposure followed 4 months after 210Po exposure. Most of this effect could be ascribed, however, to a potentiating effect of subsequent 0.9% NaCl solution instillations on 210Po carcinogenesis. These results emphasize the fact that seemingly innocuous stimuli may significantly potentiate lung carcinogenesis. The implications of these findings in terms of the interactions between alpha-radiation and cigarette smoke in human populations are discussed.

Topics: Adenocarcinoma; Alpha Particles; Animals; Benzopyrenes; Carcinoma, Squamous Cell; Cocarcinogenesis; Cricetinae; Humans; Lung Neoplasms; Male; Mesocricetus; Neoplasms, Experimental; Neoplasms, Radiation-Induced; Polonium; Smoking; Sodium Chloride; Solutions

Topics: Alpha Particles; Animals; Carcinoma; Carcinoma, Squamous Cell; Cricetinae; Disease Models, Animal; Female; Lung Neoplasms; Lymphoma; Mesocricetus; Neoplasm Metastasis; Neoplasms, Radiation-Induced; Polonium; Tracheal Neoplasms

Lung cancers have been induced in 9 to 53 percent of hamsters given multiple intratracheal instillations of polonium-210 in amounts yielding lifetime exposures of 15 to 300 rads to the lungs. Cigarette smokers have previously been estimated to receive 20 rads to areas of the bronchial epithelium from deposited polonium-210. This finding thus supports the hypothesis that alpha radiation resulting from the polonium-210 or lead-210 present in cigarette smoke may be a significant causative factor in human lung cancer.

Topics: Adenocarcinoma; Alpha Particles; Animals; Carcinoma, Squamous Cell; Cricetinae; Disease Models, Animal; Humans; Lead; Lung Neoplasms; Neoplasms, Experimental; Neoplasms, Radiation-Induced; Nicotiana; Plants, Toxic; Plutonium; Polonium; Radiation Dosage; Radioisotopes; Smoke; Smoking

Topics: Adenocarcinoma; Animals; Benzopyrenes; Bronchial Neoplasms; Carcinogens; Carcinoma; Carcinoma, Squamous Cell; Cricetinae; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Female; Hyperplasia; Intubation, Intratracheal; Lung Neoplasms; Male; Neoplasms, Experimental; Neoplasms, Radiation-Induced; Papilloma; Polonium; Respiratory Tract Neoplasms; Time Factors; Tracheal Neoplasms

Topics: Adenocarcinoma; Animals; Autoradiography; Benzopyrenes; Carcinoma, Squamous Cell; Cricetinae; Freeze Drying; Intubation, Intratracheal; Iron; Lung; Lung Neoplasms; Male; Microscopy, Fluorescence; Microscopy, Ultraviolet; Neoplasms, Experimental; Neoplasms, Radiation-Induced; Polonium; Time Factors

Topics: Adenocarcinoma; Adenoma; Adrenal Gland Neoplasms; Animals; Carcinoma, Squamous Cell; Dogs; Female; Kidney Neoplasms; Liver Neoplasms; Mammary Neoplasms, Experimental; Neoplasms, Radiation-Induced; Neutrons; Ovarian Neoplasms; Pancreatic Neoplasms; Parathyroid Neoplasms; Polonium; Skin Neoplasms; Thyroid Neoplasms; Urinary Bladder Neoplasms