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Biomedical subjects

R A Bender

Publications and source records attributed to R A Bender.

100 records · Page 6Linked to original sources
PubMed1975

Genetic control of glutamine synthetase in Klebiella aerogenes.

Mutations at two sites, glnA and glnB, of the Klebsiella aerogenes chromosome result in the loss of glutamine synthetase. The locations of these sites on the chromosome were established by complementation by episomes of Escherichia coli and by determination of their linkage to other genetic sites by transduction with phage P1. The glnB gene is located at a position corresponding to 48 min on the Taylor map of the E. coli chromosome; it is linked to tryA, nadB, and GUA. The glnA gene is at a position corresponding to 77 min on the Taylor map and is linked to rha and metB; it is also closely linked to rbs, located in E. coli at 74 min, indicating a difference in this chromosomal region between E. coli and K. aerogenes. Mutations in the glnA site can also lead to nonrepressible synthesis of active glutamine synthetase. The examination of the fine genetic structure of glnA revealed that one such mutation is located between two mutations leading to the loss of enzymatic activity. This result, together with evidence that the structural gene for glutamine synthetase is at glnA, suggests that glutamine synthetase controls expression of its own structural gene by repression.

Ammonia↗
PubMed1975

Alteration of methotrexate uptake in human leukemia cells by other agents.

The uptake of methotrexate (MTX) and the effect of drugs known to either inhibit or enhance MTX transport in L1210 murine leukemia were studied in man using blast cells from patients with acute myelogenous leukemia in vitro. MTX uptake was found to proceed slowly, requiring at least 160 min for cells to reach a "steady state" when extracellular MTX concentrations were 1 muM. Efflux of MTX from preloaded cells required 80 to 120 min and the nonexchangeable or tightly bound fraction was 40% of the total intracellular drug. Utilizing doses that are estimates of achievable peak blood levels following single i.v. injection, cephalothin (21 mug/ml) and hydrocortisone (20 mug/ml) inhibited net MTX accumulation by 20 and 28%, respectively. Vincristine sulfate at 8.3 and 0.083 mug/ml enhanced MTX uptake by 54 and 33%, respectively, by inhibiting MTX efflux, thus increasing the level of intracellular drug in excess of the tightly bound fraction. The potential clinical implications of using MTX in combination with the aforementioned drugs for cancer chemotherapy are discussed.

Cephalothin↗
PubMed1974

Direct selection for P1-sensitive mutants of enteric bacteria.

A method has been developed to isolate mutants sensitive to coliphage P1 from bacterial genera normally not sensitive to this phage. P1clr100KM was used. This phage is heat inducible and confers kanamycin resistance when present as a prophage (in lysogens). P1-sensitive mutants of Klebsiella, Enterobacter, Citrobacter, and Erwinia have been found. This technique provides a well-known genetic system for the study of many bacterial genera that previously had either no such system or only a marginally useful means of genetic manipulation. It also extends the range of possible intergeneric hybrids that may be constructed and studied.

Bacteriological Techniques↗
PubMed1974

Meningeal carcinomatosis: treatment with intrathecal methotrexate.

A case of bronchogenic carcinoma with meningeal carcinomatosis is reported. Intrathecal chemotherapy with twice weekly methotrexate was effective in clearing the cerebrospinal fluid abnormalities, pathologic evidence of meningeal disease, and all of the clinical manifestations, with the exception of spinal root symptoms and signs associated with tumor infiltration of nerve roots at autopsy. The role of radiotherapy as an adjunct to chemotherapy in the treatment of this condition is discussed.

Adenocarcinoma↗
PubMedDate not supplied

Correlates of vincristine resistance in four murine tumor cell lines.

The mechanism(s) of cellular resistance to vincristine (VCR) are poorly understood. Four murine tumor cell lines with varying degrees of VCR resistance, as measured by prolonged survival of tumor-bearing mice following VCR treatment, were selected for study. These lines were P1534, P388, P388/VCR and L1210. Steady-state cellular VCR levels, bound intracellular VCR, displaceable intracellular VCR, influx velocities and efflux velocities following VCR preloading were all measured in vitro and correlated with augmentation of survival. Neither the influx velocity, efflux velocity nor the steady-state VCR level showed any apparent correlation with in vivo sensitivity. Moreover, the ratio of influx velocity to efflux velocity was highest in the most sensitive cell line (i.e. P1534) and lowest in the most resistant cell line (i.e. P388/VCR). Bound intracellular VCR correlated best with VCR sensitivity suggesting that high-affinity intracellular binding, presumably to tubulin (Ka congruent to 1 X 10(-7) M), is a critical determinant of VCR sensitivity.

Animals↗
PubMedDate not supplied

Pharmacokinetic considerations on resistance to anticancer drugs.

A model framework is discussed for a quantitative description of intercompartment drug transport in terms of individual processes involved. It permits joint consideration of blood flow, membrane transport, binding, and enzyme synthesis. Illustrations are drawn from the pharmacokinetics and pharmacodynamics of methotrexate. Special cases include flow and membrane limitation, and a simple expression is derived to estimate the time required for intracellular drug to reach the concentration of high-affinity binding sites. Transport parameters between blood and cerebrospinal fluid are inferred from new clinical data. Lumbar injection provided a reservoir effect which maintained plasma concentration for a prolonged time compared with intravenous injections.

Animals↗