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Biomedical subjects

G R Gale

Publications and source records attributed to G R Gale.

137 records · Page 8Linked to original sources
PubMedDate not supplied

Methods of reduction of cisplatin nephrotoxicity.

Cisplatin, an agent widely used in the chemotherapy of a variety of human malignancies, is often dose-limited owing to its nephrotoxicity. Some of the approaches under consideration, regarding the reduction of cisplatin nephrotoxicity, include the use of hydration and osmotic diuresis, pharmacological diuretics, chelating agents or agents which otherwise react with cisplatin or reverse cisplatin-induced deoxyribonucleic acid cross-links, and antioxidants to destroy free radicals, especially superoxide radicals, produced by cisplatin. The effects of each of these and other interventions on cisplatin-induced nephrotoxicity are delineated, along with their proposed mechanisms and effects on therapeutic efficacy. The current status of development of organoplatinum analogs yielding congeners with less nephrotoxicity and greater efficacy is discussed briefly. Finally, a possible role of endogenous and/or exogenous prostaglandins in protecting against or reversing heavy metal nephrotoxicity is suggested.

Amifostine↗
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Effects of diethyldithiocarbamate on organ distribution and excretion of cadmium.

Sodium diethyldithiocarbamate (DDTC) was evaluated for its efficacy in promoting organ mobilization and excretion of metallothionein-bound cadmium (Cd) using mice which received a single injection of CdCl2 X 2.5 H2O, 0.03 mg per mouse, along with 109CdCl2 three to six weeks earlier. After seven or 13 i.p. injections of DDTC, 500 mg per kg, over a two or four week interval, DDTC was highly effective in mobilizing Cd from kidney (Ki) and spleen (Sp), but less effective in removing it from liver (Li). Treatment with DDTC moderately enhanced Cd levels in lung (Lu), heart (He) and testes (Te), and increased brain (Br) levels to over 500 percent of control values. Relative accumulation of Cd in organs of control mice were in the order Li greater than Ki greater than Sp greater than Lu greater than He greater than Te greater than Br. The extreme values were Li = 57 percent and Br = 0.07 percent of the Cd administered. Even though a major portion of Cd mobilized was from the kidneys, excretion was apparently exclusively by the fecal route.

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Comparative effects of diethyldithiocarbamate, dimercaptosuccinate, and diethylenetriaminepentaacetate on organ distribution and excretion of cadmium.

Diethyldithiocarbamate (DDTC), dimercaptosuccinate (DMSA), and diethylenetriaminepentaacetate (DTPA) were compared for their relative efficacies at equimolar doses in promoting mobilization of metallothionein-bound cadmium (Cd) from its sites of deposition several weeks after i.p. injection of a sublethal dose of Cd containing 109Cd. Routes and rates of excretion were also determined. The most rapid and extensive reduction of renal, hepatic, and splenic Cd was obtained with DDTC. Concurrently, however, DDTC caused moderate increases in lung, testicular, and heart Cd burdens, and increased the brain burden about ten-fold. Only renal and testicular levels of Cd were reduced by DTPA, and it was much less effective than DDTC in lowering the renal levels. No reduction of Cd levels in any organ was attained with DMSA treatment. Excretion of Cd following DDTC treatment was exclusively by the fecal route; DTPA promoted both urinary and fecal excretion, but the total amount excreted by both routes was considerably less than that observed following DDTC treatment. It was concluded that the effectiveness of a chelator in promoting mobilization and excretion of metallothionein-bound Cd cannot be predicted on the basis of its effectiveness in protecting mice against a lethal dose of Cd when given immediately after Cd and prior to induction of metallothionein synthesis. The possibility is discussed that the greater effectiveness of DDTC may be due to an interaction with nascent metallothionein rather than to chelation of Cd.

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Factors influencing cadmium mobilization by diethyldithiocarbamate: chelator dose, cadmium burden, and sex.

A study was made of the effects of diethyldithiocarbamate (DDTC) on organ distribution and excretion of cadmium (Cd) as influenced by DDTC dose, Cd burden, and sex of mice. One hundred to 250 mg per kg of DDTC did not promote mobilization of hepatic Cd, but it was effective at 500 mg per kg. All doses tested were significantly effective in mobilizing renal and splenic Cd, and the response was dose-dependent, as was the increase in brain levels of Cd. Cadmium mobilization by DDTC following Cd loads over a three-fold range appeared to be first order in nature; i.e., a given regimen of DDTC treatment promoted mobilization of a virtually constant percentage of the Cd administered, rather than a constant amount of Cd. The response to DDTC was markedly sex-dependent, being more effective in females than males. In organs of control Cd-loaded mice one sex-related difference was noted; spleens of females retained a considerably greater percentage of administered Cd than those of males.

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Effects of combined treatment with diethyldithiocarbamate and diethylenetriaminepentaacetate on organ distribution and excretion of cadmium.

Diethyldithiocarbamate (DDTC) and diethylenetriaminepentaacetate (DTPA) were assessed to determine if combination treatment with these two chelators of different chemical classes would enhance mobilization and excretion of metallothionein-bound cadmium (Cd) from selected organs of mice which had earlier received 0.03 mg of CdCl2 . 2.5 H2O along with 1.0 microCi of 109Cd. In addition to measuring individual organ radioactivity after seven and after 13 injections of each compound individually as well as in combination, whole body Cd burden was measured, and the routes and rates of Cd excretion were determined. When used alone, DDTC was effective in mobilizing Cd from kidney, liver, intestine, and spleen. The DTPA when used alone was not consistently effective in reducing Cd burdens in any of the organs assessed. Coadministration of DDTC and DTPA promoted an enhancement of Cd mobilization from liver, kidney, spleen, and intestine over that which was observed with DDTC alone. When DTPA was administered with DDTC, it did not prevent accumulation of Cd in lung and brain which was observed upon treatment with DDTC alone. Combined treatment did produce a more marked depletion of total body 109Cd burden than did the administration of DDTC alone. A more rapid rate of both fecal and urinary excretion of Cd was observed when the chelators were coadministered. It was concluded that at least an additive or possibly supraadditive effect may be obtained by combining a dithiocarbamate chelator with one of the aminocarboxylate class in total body Cd decorporation.

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Mechanism of diethyldithiocarbamate, dihydroxyethyldithiocarbamate, and dicarboxymethyldithiocarbamate action of distribution and excretion of cadmium.

Diethyldithiocarbamate (DEDC), dihydroxyethyldithiocarbamate (DHDC), and dicarboxymethyldithiocarbamate (DCDC) were assessed for their relative efficacies in mobilizing metallothionein-bound cadmium (Cd) from selected organs and tissues of mice and in promoting Cd excretion. The DHDC was effective but less so than DEDC in mobilizing Cd from liver, kidney and spleen. However, while DEDC effected a redistribution of Cd which resulted in higher levels in lungs, testes, heart, and brain, DHDC after 13 injections reduced the levels of Cd in all four of these organs. The DCDC analog did not alter the Cd load of any organ. Bone Cd content was most effectively reduced by DEDC; DCDC was somewhat less active, and DCDC was without effect. Skin Cd burden was enhanced markedly after treatment with DEDC but was reduced by treatment with DHDC or DCDC. Treatment with DEDC increased the muscle Cd content about 250 percent over control values; treatment with DHDC reduced it significantly, while DCDC was without effect. Both DEDC and DHDC reduced the whole body Cd burden, but DCDC was ineffective. The initial rate of fecal excretion of Cd was much greater following DHDC treatment than after DEDC treatment, while DCDC did not promote excretion to any detectable extent. The pattern of mobilization, redistribution, and excretion of Cd following treatment with each chelator was related to the organic/aqueous partition coefficient of each dithiocarbamate-Cd complex.

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Dithiocarbamates and cadmium metabolism: further correlations of cadmium chelate partition coefficients with pharmacologic activity.

N,N-bis(beta-Hydroxyethyl)dithiocarbamate (DHDC), N-methyl-N-hydroxyethyldithiocarbamate (MHDC), and N-ethyl-N-hydroxyethyldithiocarbamate (EHDC) were compared for their relative efficacies in promoting organ mobilization and excretion of metallothionein-bound cadmium (Cd). An attempt was made to correlate certain aspects of their pharmacodynamic properties with the octanol/aqueous partition coefficient of each Cd-dithiocarbamate complex. All compounds assessed were effective in mobilizing renal, intestinal, and testicular Cd. Those analogs with slightly greater lipid than aqueous solubility were more effective in this regard (DHDC less than MHDC less than EHDC). However, those analogs with higher lipid solubility (log10P greater than 0) promoted redistribution of Cd to liver. Only DHDC, with the lowest lipid solubility (log10P = -0.3 to -0.6), promoted Cd excretion. None of the congeners effected any redistribution of Cd to brain. Methods of preparation of the sodium salts of these analogs are described in detail.

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Antitumor effects of abrin and ricin used singly and in combination with cisplatin.

Abrin, ricin, and cisplatin produced significant increases in survival times of mice inoculated with 10(6) Ehrlich ascites carcinoma or L1210 leukemia cells 24 hours prior to treatment. Combinations of abrin or ricin with cisplatin produced markedly synergistic action in prolonging survival times of mice bearing cell line A of L1210 leukemia. For example, a dosage of 1.33 micrograms per kg abrin produced a 40 percent increased length of survival (ILS) and 2.5 mg per kg of cisplatin produced a 45 percent ILS while a combination of the two agents resulted in a 229 percent ILS and produced 60-day survivors or "cures" in 20 percent of the mice treated. Similar combinations of abrin or ricin with cisplatin also produced significant additive or synergistic increases in survival times of mice bearing cell line B of L1210 leukemia or Ehrlich ascites carcinoma. Aged solutions of abrin and ricin appeared to be less toxic, but have similar antitumor effect alone or in combination with cisplatin, than freshly prepared solutions.

Abrin↗
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Chemotherapy of advanced L1210 leukemia with platinum compounds in combination with other antitumor agents.

Six antitumor platinum compounds were used in combination with cyclophosphamide (CY) plus one of five other antitumor drugs in the treatment of advanced (Day 3) L1210 leukemia in (C57BL/6 X DBA/2)F1 mice. The combination of CY with a platinum compound yielded a collective cure rate of 24%; the addition of a third drug to the dual regimen increased the collective cure rate to 55%. The most effective drugs when used in combination with platinum compounds plus CY were, in increasing order of efficacy, 5-fluorouracil, hydroxyurea, and methotrexate. No toxic deaths occurred with any regimen at the dose levels used.

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