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T J Robbins

Publications and source records attributed to T J Robbins.

18 recordsLinked to original sources
PubMed1989

Interaction of 5'-deoxy-5-fluorouridine and methotrexate. A basis for reduced methotrexate toxicity.

Methotrexate (MTX) toxicity is reduced significantly by a non-toxic dose of 5'-deoxy-5-fluorouridine (5'dFUr). Changes in the hematopoietic system (platelets, erythrocytes, leukocytes, and hematocrit), ileal tissue, and body weight were used as parameters to assess toxicity. MTX treatment alone resulted in: (a) a reduction of body weight; (b) significantly morphological changes in ileal tissue; and (c) a marked decrease in the hematopoietic parameters. Sequential treatment with MTX followed by 5'dFUr resulted in reversal of MTX depression of animal body weight and ileal tissue necrosis, and partial reversal in MTX toxicity to the hematopoietic system. Also, for all parameters studied, there were no significant differences between scheduling of MTX after a priming dose of 5'dFUr, 5'dFUr alone, and control. Hence, this study suggests that 5'dFUr is a pharmacological antidote for MTX toxicity, and, therefore, 5'dFUr in combination with MTX may provide a basis whereby more intense and effective MTX therapy may be given.

Animals↗
PubMed1986

Modulation of high-dose methotrexate toxicity by a non-toxic level of 5-fluorouracil.

High-dose methotrexate (MTX) toxicity is reduced by a non-toxic dose of 5-fluorouracil (FU) when these agents are used in combination. Changes in the hematopoietic system (platelets, erythrocytes, leukocytes, hemoglobin, and hematocrit), ileal tissue, body weight, and mean survival were used as parameters to assess toxicity. For all parameters studied, there were no significant differences between the scheduling of MTX (245 mg/kg) after a priming dose of FU (25 mg/kg), simultaneous MTX and FU, FU alone, and control. However, sequential treatment with MTX followed by FU, and MTX alone resulted in: a marked decrease in the hematopoietic parameters; significant morphological changes in ileal tissue; a reduction of body weight; and increased mortality of animals. Hence, this study suggests that FU, a cytotoxic agent, may protect against MTX toxicity and improve its therapeutic index when FU administration precedes MTX or when these agents are given simultaneously.

Animals↗
PubMed1986

Tiazofurin metabolism in human lymphoblastoid cells: evidence for phosphorylation by adenosine kinase and 5'-nucleotidase.

The exact route of metabolism of tiazofurin, a novel nucleoside with antitumor activity, is controversial. Using human cell lines severely deficient in salvage nucleotide enzymes, we were able to identify the route of activation in tiazofurin metabolism. With loss of adenosine kinase activity by mutation in two lymphoblastoid cell lines, CCRF-CEM and WI-L2, the growth sensitivity to tiazofurin decreased by 6- and 3-fold, respectively. In contrast, the mutant lines were about 3000- to 1500- and 16- to 4-fold more resistant to the structurally similar tiazofurin analogues pyrazofurin and ribavirin, respectively. Other mutants with defective deoxycytidine or uridine kinase activity showed normal sensitivity to all three analogues. Both cell lines with defective adenosine kinase activity accumulated about 50% wild-type levels of tiazofurin-5'-monophosphate and thiazole-4-carboxamide adenine dinucleotide analogue of tiazofurin at cytotoxic concentrations of the drug. Extracts of wild-type lymphoblasts catalyzed the phosphorylation of tiazofurin in the presence of adenosine 5'-triphosphate and Mg2+. Loss of adenosine kinase activity in the mutant extract eliminated this phosphorylating activity for tiazofurin consistent with the notion that adenosine kinase catalyzes phosphorylation of tiazofurin. However, an enzyme activity that catalyzed the phosphorylation of tiazofurin in the presence of inosine-5'-monophosphate as donor and Mg2+ was detected in the extracts of both wild-type cells and adenosine kinase-deficient mutants. The monophosphate donor specificity, divalent metal, high salt requirement, and nucleoside acceptor specificity of this enzyme activity paralleled that of a 5'-nucleotidase (EC 3.1.3.5) which catalyzes inosine phosphorylation. In addition, tiazofurin phosphorylation was competitively inhibited by inosine and the apparent Ki value was similar to the apparent Km value for inosine phosphorylation. These results indicate that two enzymes, adenosine kinase and a cytoplasmic 5'-nucleotidase, are functionally important anabolizing enzymes for tiazofurin in human cells.

5'-Nucleotidase↗
PubMed1979

Effect of chronic exposure to cadmium on hepatic drug metabolism.

In an attempt to examine the chronic effect of low levels of cadmium on hepatic drug-metabolizing enzyme system, an experiment was carried out in which growing male rats were given 0, 5, 10, and 20 ppm of cadmium in drinking water for a period of 8 weeks. An ip administration of a hypnotic dose of pentobarbital to the cadmium-treated and the control rats 24 hr following the termination of the experiment exhibited that there was no significant difference in the drug metabolism in control and any of the treated groups. Next, liver microsomes were isolated from animals in all groups to study their ability to metabolize drugs in vitro. The results indicated that the activity of benzphetamine N-demethylase and aniline hydroxylase, and the concentration of microsomal cytochrome P-450 were almost identical in the control and treated groups. On the other hand, a single ip dose of cadmium (2 mg/kg) caused significant decrease in the vivo and in vitro microsomal drug metabolism. These results suggest that although a single ip dose of cadmium (2 mg/kg) causes significant inhibition of drug metabolism, chronic exposure to cadmium up to 20 ppm in drinking water over a period of 8 weeks is unlikely to affect hepatic drug metabolism.

Animals↗
PubMedDate not supplied

Thiram-induced toxic liver injury in male Sprague-Dawley rats.

A single i.p. dose (120 mg/kg) of thiram given to male Sprague-Dawley rats caused a significant increase in the activity of SGOT and SGPT 24 hr post-treatment indicating liver damage. A considerable diminution in the serum cholinesterase activity was also noted in the treated rats as against the control animals. Additional evidence for thiram-induced liver toxicity is provided by the observation that there was approximately 50% inhibition of the activity of hepatic microsomal benzphetamine N-demethylase with a concomitant decrease in the concentration of cytochrome P-450, an important component of the mixed-function oxidase system. Although not significant, hepatic glutathione levels were also depleted by thiram, probably making the liver susceptible to toxic injury.

Acetylcholinesterase↗
PubMedDate not supplied

Toxicity, pathological effects, and antineoplastic activity of a non-toxic dose of 5-fluorouracil in combination with methotrexate.

The survival time of CF-1 mice bearing Ehrlich ascites tumor cells was increased significantly by i.p. administration of a non-toxic dose of 5-fluorouracil (25 mg/kg) followed by methotrexate (40 mg/kg). The effects of 5-fluorouracil (FU) and methotrexate (MTX), singly and in combination, were examined on the hematopoietic system (platelets, erythrocytes, leukocytes, and hematocrit), body weight, and the crypt of Liberkühn to assess toxicity, and on survival of tumor-bearing animals to assess antineoplastic activity. Sequential treatment with a non-toxic dose of FU followed by MTX for 3 consecutive days produced no significant adverse effect. MTX alone and the scheduling of FU after a priming dose of MTX resulted in: (a) a marked decrease in the hematopoietic parameters; (b) significant morphological changes in ileal tissue; and (c) a reduction in body weight. The survival of tumor-bearing animals treated with FU alone and FU 2 hours before MTX was 124% and 139% greater than control, respectively. The survival rate of animals treated with MTX alone was less than that of untreated tumor animals. This study suggests the feasibility of designing FU and MTX regimens that will have little or no systemic toxicity while maintaining antineoplastic activity.

Animals↗