diethyl-maleate and Carcinoma--Ehrlich-Tumor

To investigate whether [(99m)Tc]-hexamethyl propyleneamine oxime ([(99m)Tc]-HMPAO) is applicable for evaluating glutathione (GSH) localization in tumor, the difference of distribution between [(99m)Tc]-d,l- and meso-HMPAO was studied using a mouse tumor model. Biodistribution of [(99m)Tc]-d,l- or meso-HMPAO was studied in GSH-depleted and control Ehrlich tumor-bearing mice. GSH levels in tumors in GSH-depleted and control mice were measured in another set of mice. The uptake of [(99m)Tc]-d,l-HMPAO in tumor was significantly decreased by the diethyl maleate (DEM) treatment. On the other hand, the DEM treatment increased the accumulation of [(99m)Tc]-meso-HMPAO in tumor. Meanwhile, the content of GSH was lowest in tumor among the tissues tested and decreased in a manner similar to other tissues on preloading of DEM. [(99m)Tc]-d,l-HMPAO may be useful for estimating the GSH status in a certain tumor and thereby contribute to the diagnosis of anticancer therapy.

Topics: Animals; Brain; Carcinoma, Ehrlich Tumor; Glutathione; Kidney; Liver; Lung; Male; Maleates; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Organ Specificity; Radionuclide Imaging; Spleen; Stereoisomerism; Technetium Tc 99m Exametazime; Tissue Distribution

ATP-induced tumour growth inhibition is accompanied by a selective decrease in the content of the tripeptide glutathione (GSH) within the cancer cells in vivo. Depletion of cellular GSH sensitizes tumours to chemotherapy and radiation, but the usefulness of this depletion depends on whether the levels of GSH can be reduced in the tumour relative to normal tissues. We report here that administration of ATP in combination with diethylmaleate and X-rays leads to complete regression of 95% of Ehrlich ascites tumours in mice. This shows that an aggressive tumour can be eliminated by using a therapy based on modulation of GSH levels in cancer cells.

Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Buthionine Sulfoximine; Carcinoma, Ehrlich Tumor; Cell Division; Combined Modality Therapy; Enzyme Inhibitors; Glutamate-Cysteine Ligase; Glutathione; Hydrogen-Ion Concentration; Male; Maleates; Methionine Sulfoximine; Mice; Radiation-Sensitizing Agents; X-Rays

Heating of Ehrlich ascites tumour (EAT) cells and mouse fibroblast LM cells to 43 or 44 degrees C respectively, results in an increased level of reduced glutathione (GSH). The maximum elevation in GSH was to 140 per cent for LM cells and to 120 per cent for EAT cells. No increase of GSH in EAT cells was observed after heating at 44 degrees C. LM cells were treated with diethylmaleate (DEM) and the EAT cells with buthionine-sulphoximine (BSO) at non-toxic doses to deplete the levels of GSH. No effect on thermosensitivity or on the development of thermotolerance was observed when the DEM and BSO treatments were chosen such that the lowering of GSH was just down to the level of detection (about 5 per cent of control). When higher concentrations of DEM were used, thermal sensitization was observed. The activity of the pentose phosphate pathway (PPP) was also investigated because of its importance in supplying NADPH for the regeneration of GSH from GSSG and for the endogenous production of polyols. Hyperthermia was found to enhance markedly the flux of glucose through the PPP. While the DEM treatment inhibited glucose oxidation through the PPP, BSO addition to the cells resulted in a slightly increased activity of the PPP. The PPP activity of thermotolerant cells was lower (fibroblasts) or hardly affected (EAT cells) compared to control cells. The extent of PPP activation by hyperthermia was comparable for thermotolerant and control cells. For the two cell lines studied neither a high level of GSH nor an active PPP is a prerequisite for the development of thermotolerance.

Topics: Animals; Buthionine Sulfoximine; Carcinoma, Ehrlich Tumor; Cell Line; Cell Survival; Fibroblasts; Glutathione; Hot Temperature; Maleates; Methionine Sulfoximine; Mice; Pentose Phosphate Pathway; Sulfhydryl Compounds