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PubMed1985

Murine transfer factor. II. Transfer of delayed hypersensitivity to synthetic antigens.

Synthetic polyaminoacid antigens were used to examine the specificity of transfer of delayed-type hypersensitivity with spleen cell dialysates in mice. Dialysates from GAT10-sensitized donors sensitized recipients to GAT10, but not GLA5 or cytochrome c. Dialysates from GLA5-sensitized donors sensitized recipients to GLA5, but not GAT10 or cytochrome c. We interpret these findings as consistent with the concept that passive transfer of delayed hypersensitivity with dialyzable materials is an immunologically specific event.

Animals↗
PubMed1985

Enhanced polyglutamylation of aminopterin relative to methotrexate in the Ehrlich ascites tumor cell in vitro.

The polyglutamylation of aminopterin and methotrexate (N10-methylaminopterin) was compared in the Ehrlich ascites tumor in vitro. Three poly-gamma-glutamyl conjugates of methotrexate and aminopterin were detected, although at an equal (1 microM) extracellular drug concentration, the net accumulation of aminopterin polyglutamates exceeded that for the methotrexate polyglutamyl derivatives by a factor of 9. When compensation was made for transport differences between these compounds by adjusting the extracellular drug concentrations to achieve equivalent intracellular monoglutamyl substrate levels, the polyglutamylation of aminopterin was still 2.8-fold greater than that for methotrexate, suggesting that aminopterin is a better substrate for the folylpolyglutamate synthetase as well as the transport carrier. An additional metabolite of aminopterin was detected within seconds following drug exposure. This derivative did not bind tightly to dihydrofolate reductase, yet it was rapidly converted to a polyglutamate. The formation of both aminopterin polyglutamates and these novel derivatives was enhanced by increases in the free intracellular level of aminopterin. Aminopterin polyglutamates were bound tightly to dihydrofolate reductase and were retained intracellularly relative to unaltered aminopterin when Ehrlich cells containing these forms were suspended in drug-free medium. These findings support a role for the polyglutamylation of aminopterin as a critical element in drug action and as a factor in addition to membrane transport in the disparate antifolate potencies of aminopterin and methotrexate.

Aminopterin↗
PubMed1979

Formation of methotrexate polyglutamates in rat hepatocytes.

Polyglutamate derivatives of [3H]methotrexate (MTX) were detected in freshly isolated rat hepatocytes in suspension within 15 min after exposure to the folate analog. The rate of polyglutamate synthesis remained constant for at least one hr, and the polyglutamate derivatives accounted for an increasing proportion of the intracellular radiolabel with time. After initial exposure to 1 micron [3H]MTX, polyglutamate derivatives of Mtx continued to be synthesized even after the extracellular [3H]-MTX concentration had been reduced 20-fold. Prolonged exposure of hepatocytes in primary culture to 1 micron [3H]MTX resulted in the formation of longer-chain polyglutamate derivatives of MTX. The present studies demonstrate another important biosynthetic capacity of the freshly isolated hepatocyte and suggest the usefulness of this system for studying the mechanism of, and controlling factors in, the synthesis of polyglutamate derivatives of MTX. The ramifications of the formation of MTX polyglutamates on drug cytotoxicity in general and hepatotoxicity in particular are considered.

Animals↗
PubMed1980

Trypsin adsorption by Hymenolepis diminuta (Cestoda).

Significant amounts of radioactivity were associated with Hymenolepis diminuta following incubation in 3H-trypsin. Autoradiography of worms incubated in 3H-trypsin for 30 min demonstrated that all radioactivity was associated with the worm's surface (tegument). The amount of 3H-trypsin adsorbed by the worms was not sufficient to account for the inactivation of this enzyme in the presence of intact worms. Unlabeled trypsin and poly-L-glutamate (but not poly-L-lysine) inhibited adsorption of 3H-trypsin, but were without effect on trypsin inactivation by H. diminuta. Therefore, trypsin was adsorbed by intact H. diminuta, but the process of adsorption apparently did not play any role in inactivation of the enzyme.

Adsorption↗
PubMed1980

Synthesis of methotrexate polyglutamates by bone marrow cells from patients with leukemia and lymphoma.

Bone marrow cells from children with lymphoblastic leukemia, myeloblastic leukemia and non-Hodgkin's lymphoma were incubated with tritium-labelled methotrexate in short-term cultures. Cells obtained both during disease activity as well as during remission synthesized large quantities of methotrexate polyglutamates. Synthesis was time- and dose-dependent and occurred with concentrations of methotrexate regularly achieved during conventional treatment with this drug.

Bone Marrow↗
PubMed1981

Differential synthesis of methotrexate polyglutamates in normal proliferative and neoplastic mouse tissues in vivo.

Synthesis of poly-gamma-glutamyl metabolites of methotrexate was demonstrated in mouse small intestine, liver, and bone marrow and in L1210 leukemia, Sarcoma 180, and Ehrlich tumor cells after s.c. injections of [3H]methotrexate to tumor-bearing mice. Ion-exchange chromatography of tissue extracts resolved six peaks of radioactivity believed to represent methotrexate and metabolites with up to five additional glutamyl residues. Polyglutamate formation in L1210 cells and small intestine was shown to be independent of dose at least to 400 mg/kg as long as intracellular levels of drug in excess of the dihydrofolate reductase-binding capacity (exchangeable) were maintained. Both the total amount of polyglutamates and the average length of the polyglutamyl chain increased with time as long as exchangeable level of drug was present intracellularly. The results also showed differences in the extent of metabolism of methotrexate polyglutamates among the tissues examined. Although these differences were at times very large, there was no consistent correlation between these differences and other pharmacological parameters or cytotoxicity. Tumor cells appeared to synthesize more polyglutamates than did the normal tissues examined. However, differences in total drug persistence and sensitivity to drug among tumor cells and among normal tissues did not reflect the relative extent of polyglutamate synthesis in each group. It is concluded that the extent of polyglutamate synthesis per se may not be a determinant of drug sensitivity in murine tissues. However, the accumulation of these metabolites may contribute in some way to overall therapeutic response or relative cytotoxicity.

Animals↗
PubMed1982

Augmentation of the intracellular levels of polyglutamyl derivatives of methotrexate by vincristine and probenecid in Ehrlich ascites tumor cells.

The intracellular accumulation of poly-gamma-glutamyl derivatives of methotrexate was evaluated in the presence of vincristine or probenecid (agents which raise the intracellular level of free methotrexate) in Ehrlich ascites tumor cells. The results show that both intracellular methotrexate and its metabolites are increased by these agents and that, in the presence of L-glutamine, polyglutamate derivatives are increased by a higher percentage than is methotrexate. From 1 to 50 microM vincristine increased the levels of polyglutamate derivatives from 25 to over 300%, whereas methotrexate was raised from 25 to 80%. Similarly, 50 to 200 microM probenecid increased methotrexate polyglutamate derivatives from 31 to 88%, whereas methotrexate was raised from 0 to 30%. A determination of the bound fraction of drug indicated that the proportion of dihydrofolate reductase bound with methotrexate polyglutamates increased in the presence of these agents. Efflux studies showed that over 90% of the large pools of intracellular methotrexate polyglutamates produced by these agents was retained for at least 1 hr in the absence of extracellular methotrexate, whereas the majority of intracellular methotrexate exited the cell. These studies (a) indicate that vincristine and probenecid may be potentially useful for selectively increasing methotrexate polyglutamates in tumor cells and (b) introduce another basis for synergism observed between alkaloids and methotrexate.

Animals↗
PubMed1981

Some considerations in the experimental approach to distinguishing between membrane transport and intracellular disposition of antineoplastic agents, with specific reference to fluorodeoxyuridine, actinomycin D, and methotrexate.

Analysis of the interaction between an anticancer agent and the intact cell can provide important clues to cytotoxic determinants and mechanisms of drug selectivity and resistance. This can be very useful in optimally evaluating single and multidrug regimens in test systems, designing new agents, and evaluating drug metabolism and binding to cellular target sites. This cellular pharmacokinetic approach requires very meticulous attention to experimental design, especially the time dimension chosen for study, and an appropriate framework for data analysis. This paper reviews cellular pharmacokinetic principles and experimental approaches that can be applied in "uptake studies" with cytotoxic agents, focusing, as examples, on studies from this laboratory with fluorodeoxyuridine, actinomycin D, and methotrexate.

Animals↗