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Biomedical subjects

R A Bender

Publications and source records attributed to R A Bender.

At least 73 records · Page 4Linked to original sources
PubMed1980

Pharmacokinetics of vincristine in the cerebrospinal fluid of subhuman primates.

Adult rhesus monkeys were given 2-mg/sq m i.v. bolus injections of radiochemically pure tritiated vincristine (VCR). Simultaneous specimens of blood and cerebrospinal fluid (CSF) were sampled from 5 min to 72 hr following injection. CSF was obtained from Ommaya reservoirs which had been implanted s.c. in each monkey. VCR and its metabolic and/or decomposition products rapidly entered the CSF producing low concentrations in this fluid; 5 min following injection, the concentration of VCR was 2.3 nM, whereas approximately a 100-fold greater concentration (203.8 nM) was attained in the plasma. Throughout a 3-day period of observation, constant, low levels of VCR and its metabolic and/or decomposition products (2.3 to 5.7 nM) were maintained in the CSF. The principal form of VCR present in the CSF 1 hr or more after i.v. injection was a water-soluble metabolite and/or decomposition product(s). Although the levels achieved in the CSF are unlikely to be lethal to tumor cells, the finding of persistent low concentrations of VCR and its metabolic and/or decomposition products in the CSF indicates prolonged exposure of neural tissue which might result in neurotoxicity, particularly cumulative neurotoxicity following multiple doses of VCR.

Animals↗
PubMed1979

Role of peritoneoscopy in the postoperative evaluation and treatment of adenocarcinoma of the exocrine pancreas.

Our experience with peritoneoscopy in the postoperative staging and evaluation of ten patients with locally unresectable adenocarcinoma of the exocrine pancreas is presented. In contrast to the German experience with previously unexplored patients, the pancreas was visualized only 30% of the time and biopsy was not possible for technical reasons. Based on our experience in these ten patients, postoperative peritoneoscopy for staging or for following the effectiveness of treatment is of limited value in carcinoma of the pancreas. Preoperative evaluation of this technique deserves greater attention.

Adenocarcinoma↗
PubMed1979

Glutamine synthetase regulation, adenylylation state, and strain specificity analyzed by polyacrylamide gel electrophoresis.

We used polyacrylamide gel electrophoresis to examine the regulation and adenylylation states of glutamine synthetases (GSs) from Escherichia coli (GS(E)) and Klebsiella aerogenes (GS(K)). In gels containing sodium dodecyl sulfate (SDS), we found that GS(K) had a mobility which differed significantly from that of GS(E). In addition, for both GS(K) and GS(E), adenylylated subunits (GS(K)-adenosine 5'-monophosphate [AMP] and GS(E)-AMP) had lesser mobilities in SDS gels than did the corresponding non-adenylylated subunits. The order of mobilities was GS(K)-AMP < GS(K) < GS(E)-AMP < GS(E). We were able to detect these mobility differences with purified and partially purified preparations of GS, crude cell extracts, and whole cell lysates. SDS gel electrophoresis thus provided a means of estimating the adenylylation state and the quantity of GS present independent of enzymatic activity measurements and of determining the strain origin. Using SDS gels, we showed that: (i) the constitutively produced GS in strains carrying the glnA4 allele was mostly adenylylated, (ii) the GS-like polypeptide produced by strains carrying the glnA51 allele was indistinguishable from wild-type GS(K), and (iii) strains carrying the glnA10 allele contained no polypeptide having the mobility of GS(K) or GS(K)-AMP. Using native polyacrylamide gels, we detected the increased amount of dodecameric GS present in cells grown under nitrogen limitation compared with cells grown under conditions of nitrogen excess. In native gels there was neither a significant difference in the mobilities of adenylylated and non-adenylylated GSs nor a GS-like protein in cells carrying the glnA10 allele.

Adenosine Monophosphate↗
PubMed1979

Caulobacter cresentus mutant defective in membrane phospholipid synthesis.

To study the relationship between phospholipid synthesis and organelle biogenesis in the dimorphic bacterium Caulobacter crescentus, auxotrophs have been isolated which require exogenous glycerol or glycerol 3-phosphate for growth when glucose is used as the carbon source. Upon glycerol deprivation, net phospholipid synthesis ceased immediately in a glycerol 3-phosphate auxotroph which was shown to have levels of biosynthetic sn-glycerol 3-phosphate dehydrogenase (E.C. 1.1.1.8) activity 10 times lower than that of the wild type. In the absence of glycerol, the optical density of the culture continued to increase for the equivalent of one generation, although the cells did not divide. After the equivalent of one generation time, rapid cell death occurred. Cell death also occurred when phospholipid synthesis was inhibited by cerulenin. Although ribonucleic acid and protein syntheses continued at a reduced rate for the equivalent of one generation in mutant strains, a substantial decrease in the rate of deoxyribonucleic acid synthesis occurred immediately upon glycerol deprivation. Revertant strains had wild-type levels of glycerol 3-phosphate dehydrogenase activity and normal rates of phospholipid and macromolecular synthesis.

Bacteria↗
PubMed1979

Cytotoxic thresholds of vincristine in a murine and a human leukemia cell line in vitro.

L1210 murine leukemia and CEM human lymphoblastoid leukemia cells were exposed to vincristine sulfate in vitro. The response of these cell lines to this agent was measured by the colony-forming ability of L1210 cells in soft agar and inhibition of growth of CEM in suspension culture. Incremental increases of vincristine concentrations in excess of 2 x 10(-9) M produced a progressive reduction of survival of L1210 cells and suppression of CEM growth under the condition of constant drug exposure. A maximum cytotoxic effect was reached with drug concentrations between 10(-8) and 10(-7) M. When L1210 cells were exposed to vincristine for a variable length of time ranging from 0.5 to 24 hr, 10(-7) M produced a noticeable cytotoxic effect following an incubation of only 30 min. A 50% cell kill of L1210 cells and a 50% reduction of CEM cell growth were produced by 10(-7) M following a 1- to 3-hr period of exposure; 6 to 12 hr were required to produce a similar effect at a vincristine concentration of 10(-8) M. Therefore, the antitumor effect of vincristine is critically dependent on both concentration and duration of exposure. These data suggest the possibility that the effectiveness of vincristine as an antitumor agent could be enhanced if methods are developed to prolong exposure of neoplastic tissues for longer periods of time than currently produced by conventional methods of administration.

Animals↗
PubMed1978

Advanced ovarian adenocarcinoma. A prospective clinical trial of melphalan (L-PAM) versus combination chemotherapy.

Eighty patients with advanced ovarian adenocarcinoma were treated in a prospective, randomized trial comparing a four-drug combination--hexamethylmelamine, cyclophosphamide, methotrexate and 5-fluorouracil--with the oral alkylating agent, melphalan. Treatment with the four-drug combination was associated with a significantly increased overall response rate (75 vs. 54 per cent) (P less than 0.05), more complete remissions (33 vs. 16 per cent) and longer median survival (29 vs. 17 months) (P less than 0.02) but more severe toxicity than occurred with melphalan. Patients with minimal residual disease had a significantly higher overall response rate than patients with extensive residual disease (84 vs. 53 per cent) (P less than 0.05). Patients with advanced disease who achieved a complete remission documented by peritoneoscopy or laparotomy (or both) have a median survival that will exceed three years. The four-drug regimen is more effective than melphalan in the management of advanced ovarian adenocarcinoma.

Adenocarcinoma↗
PubMed1978

Hexamethylmelamine in alkylating agent-resistant ovarian carcinoma.

Twenty-one patients with advanced ovarian cancer proven resistant to standard alkylating chemotherapy were evaluated in a prospective study of Hexamethylmelamine. All but three patients received 8 mg/kg daily with dose modifications appropriate to the degree of toxicity; the latter three patients were treated on an intermittent 14 day course of 8 mg/kg daily. Six patients (28%) experienced an objective response with a median duration of 2.5 months (range 1--5 months). The toxic effects requiring dose modification were gastrointestinal in 57%, hematologic in 62%, and neurologic in 28.5%. An average of 60.5% of the total projected dose was tolerated for a median of 44 days (range 7--113). Twelve patients (57%) experienced severe toxicity requiring discontinuation of therapy. It is apparent from this study that Hexamethylmelamine is an active agent in ovarian cancer and is not invariably cross-resistant to conventional alkylating agent therapy. These two characteristics make it an attractive agent for use in combination. Its toxicity in previously treated patients in the schedules used here, however, is substantial.

Adenocarcinoma↗
PubMed1978

Activity of the epipodophyllotoxin VP-16 in the treatment of combination chemotherapy-resistant non-Hodgkin lymphoma.

Twenty patients with several histologic subtypes of non-Hodgkin lymphoma who had become resistant to combination chemotherapy were treated with a five-day course of the epipodophyllotixin VP-16. Of 19 evaluable patients, 8 (42%) responded to treatment with 1 complete response and 7 partial responses. The median duration of response was 5.5 months. Seven of the responders had a diffuse lymphoma and 1 had a nodular lymphoma. Of the responders who had diffuse histiocytic lymphoma (DHL), diffuse mixed lymphoma (DML), and diffuse undifferentiated lymphoma (DUL)--the more aggressive histologies in the Rappaport classification--6 of 13 (46%) evaluable patients responded to therapy. Responses were seen in node-dominant, skin-dominant, and marrow-dominant disease. Toxicity was mainly hematopoietic, 53% of patients experiencing leukopenia ( less than 2,000 cells per cu mm) and 68% of patients experiencing thrombocytopenian 2,000 cells per cu mm) and 68% of patients experiencing thrombocytopenia ( less than 100,000 platelets per cu mm). There were two deaths attributable to profound leukopenia with sepsis. The activity of VP-16 in patients who have previously been extensively treated with multiple drugs including vincristine supports its activity in the lymphomas and suggests its lack of cross-resistance with vincristine. The inclusion of VP-16 in primary treatment protocols in the diffuse lymphomas should be considered.

Blood Cell Count↗
PubMed1978

Biliary excretion of vincristine.

A patient with pancreatic carcinoma and a choledochal T tube was given tritiated vincristine sulfate ([3H]-VCR) intravenously. Peak biliary excretion occurred in 2 to 4 hr and this sample contained 9.7% of the injected radioactivity. The first 24-hr bile sample contained 21.7% of the dose and 76.4% of the cumulative 72-hr biliary excretion. During a 3-day period of observation, 4.2%, 45.6%, and 49.6% of the excreted radiolabel was present in the feces, urine, and bile, respectively. Products of VCR metabolism and decomposition appeared in the bile rapidly; only 46.5% of the drug was present in the parent form in the 2-hr collection. Since significant amounts of these products were also identified in control specimens of bile, blood, plasma, and buffer alone after brief periods of incubation, the origin and nature of the species appearing in the bile remain unclear. Observing the fecal route to be the major source of elimination of radiolabel following intravenous injection of [3H]-VCR in our patients previously, we now conclude the biliary system to be the principal route of excretion of VCR and its products. Hepatic dysfunction might therefore alter elimination kinetics and increase the exposure to VCR and its products which might augment toxicity and require dose modification.

Bile↗
PubMed1978

The role of percutaneous liver biopsy in the pretreatment evaluation of pancreatic adenocarcinoma.

Percutaneous liver biopsies were performed on twenty-two patients with locally unresectable adenocarcinoma of the exocrine pancreas within a median of six weeks of laparotomy. Three patients (13 per cent) had positive biopsies obtained either blindly or at peritoneoscopy. Of these three patients, two had elevations in either alkaline phosphatase, direct bilirubin, or hepatic transaminase levels, and one of these two patients had an abnormal liver-spleen scintigram. Liver biopsies are recommended for all patients being evaluated for pancreatic resection either pre- or intraoperatively.

Adenocarcinoma↗
PubMed1978

Effect of interaction between methotrexate and dihydrofolate reductase on DNA synthesis in L1210 cells in vitro.

L1210 leukaemia cells were preloaded with [(3)H methotrexate] (MTX) to saturate high-affinity intracellular sites, and were then incubated with [(3)H]MTX to determine the steady-state intracellular MTX concentrations at extracellular concentrations ranging from 10 μM to zero. In addition, incubations to generate incomplete saturation of high-affinity intracellular MTX-binding sites were also carried out. Following determination of the total intracellular MTX, cells were pulsed with deoxyuridine (UdR) and its incorporation into DNA examined to assess the role of exchangeable and bound intracellular MTX on DNA synthesis. Further, cell pellets were disrupted and dihydrofolate reductase (DHFR) activity determined under each experimental condition. Extracellular MTX concentrations in excess of 1 μM depressed UdR incorporation to <2% of control, but incorporation rapidly recovered to 62% of control at the point of MTX-DHFR equivalence, and exceeded control values when all high-affinity sites were not saturated. DHFR activity was undetectable at extracellular MTX concentrations >0.50 μM, and never exceeded 6.09% of control at the "equivalence point" where all high-affinity sites were saturated. When less than 10% of potential inhibitor sites were occupied, enzyme activity increased rapidly, but never reached control. However, 5% of the DHFR activity was sufficient to permit UdR incorporation to continue at 50% of control levels, and UdR incorporation returned to control levels at 20% of the DHFR activity. The relationship between cellular MTX content and DNA synthesis or DHFR activity is sigmoid, suggesting a reversible interaction between enzyme and inhibitor. This lends support to the notion that "free" intracellular MTX is necessary for a maximal antitumour effect, and may explain its role in "high-dose" MTX therapy in man.

Animals↗
PubMed1978

Ammonia assimilation and glutamate formation in Caulobacter crescentus.

In the dimorphic bacterium Caulobacter crescentus, ammonia assimilation occurs only via the combined action of the enzymes glutamine synthetase and glutamate synthase. Mutants auxotrophic for glutamate lacked glutamate synthase activity, and the mutations leading to the glutamate auxotrophy appeared to lie at two distinct genetic loci. Both glutamate synthase and glutamine synthetase activities were subject to regulation by repression. Glutamate synthase activity was highest in cultures grown in minimal medium with ammonia as sole nitrogen source and was about fivefold lower in rich broth. Glutamine synthetase activity was highest in cells grown with growth-rate-limiting amounts of ammonia as nitrogen source and was about fourfold lower in rich broth. In addition, glutamine synthetase activity appeared to be regulated by an adenylylation system like that described for Escherichia coli.

Ammonia↗