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Biomedical subjects

S B Howell

Publications and source records attributed to S B Howell.

At least 235 records · Page 13Linked to original sources
PubMed1982

Modulation of the cellular pharmacology and clinical toxicity of 1-beta-D-arabinofuranosylcytosine.

The effect of thymidine (dThd) and hydroxyurea (HU) on the cellular metabolism of 1-beta-D-arabinofuranosylcytosine (Ara-C) was investigated in the human promyelocytic cell line HL-60. Both dThd and HU increased the cellular uptake and rate of formation of Ara-CTP. Measurement of ribo- and deoxyribonucleotide triphosphate pools implicated a reduction of the dCTP as the mechanism of this effect. dThd and HU had opposite effects on the incorporation of Ara-C into DNA per unit time, but both enhanced the incorporation of Ara-C per unit of newly synthesized DNA. In a Phase I trial Ara-C was given by continuous infusion for five days at 100 mg/m2, and HU by mouth every six hours with dose escalation from 0.375 to 1.78 g/m2 every six hours. Myelosuppression was the dose-limiting toxicity; the major nonhematologic toxicity was skin rash. To date responses have been observed in chronic myelogenous leukemia in blast crisis and diffuse histiocytic lymphoma.

Arabinofuranosylcytosine Triphosphate↗
PubMed1982

Intraperitoneal cisplatin with systemic thiosulfate protection.

Seventeen patients with intraperitoneal tumors were treated by 4-hour intraperitoneal dialysis with cisplatin alone, or in combination with an intravenous neutralizing agent, sodium thiosulfate. Cisplatin alone, 90 mg/m2 body surface area intraperitoneally, produced nephrotoxicity. When intraperitoneal cisplatin therapy was combined with intravenous thiosulfate treatment, the dose of cisplatin could be escalated to 270 mg/m2 body surface area without causing an increase in serum creatinine levels or undue myelosuppression. Even at doses up to 270 mg/m2, no local toxicity occurred. The peak peritoneal concentration of free reactive cisplatin averaged 21-fold higher than the plasma level, and the area under the peritoneal cisplatin elimination curve averaged 12-fold more than the area under the plasma curve. Neither of these ratios varied significantly with cisplatin dose. Regression of intraperitoneal tumor masses was observed in patients with far-advanced ovarian carcinoma, mesothelioma, and malignant carcinoid.

Adult↗
PubMed1982

Modulation of cytarabine metabolism in the human promyelocytic leukemia cell line HL-60 by polyhydroxy-substituted benzohydroxamic acids.

Two potent new ribonucleotide reductase inhibitors, 3,4,5-trihydroxybenzohydroxamic acid (VF 122) and 3,4-dihydroxybenzohydroxamic acid (VF 147), were investigated for their ability to modulate the cellular pharmacology of cytarabine (ara-C) in HL-60 cells. VF 122 and VF 147 increased the total cellular uptake of ara-C by a mean (+/- SE) of 8% +/- 3% and 29% +/- 3%, respectively, when measured 2 hours after the start of exposure to 0.1 microM ara-C. This effect was evident after only 10 minutes of exposure to the riboNucleotide reductase inhibitor and did not vary significantly over the concentration range of 10-100 microM for either agent. VF 122 enhanced the incorporation of ara-CTP into DNA by 3.6-fold; VF 147 produced a 5.6-fold increase. In comparison, the maximum enhancement achievable with hydroxyurea was 2.1-fold, and with thymidine was 1.8-fold. These results provide a biochemical rationale for further investigation of these agents in combination with ara-C.

Cell Line↗
PubMed1982

5-FU and allopurinol: toxicity modulation and phase II results in colon cancer.

Concurrent administration of allopurinol allows escalation of 5-FU doses in man when 5-FU is given by continuous infusion for 5 days. Forty-nine patients received 81 courses of treatment with 5-FU and allopurinol in phase I and II trials. The dose-limiting toxicity was mucositis; marrow toxicity was mild. Neurotoxicity, possibly related to 5-FU, occurred in eight patients. No responses were seen in 14 evaluable patients with colon cancer, 11 of whom had had prior 5-FU. One patient with Hodgkin's disease had a partial response; one patient with diffuse histiocytic lymphoma had transient disease regression. Although allopurinol does modify the toxicity of 5-FU, permitting dose escalation, it does not increase the therapeutic index in colon cancer. Infusional 5-FU deserves further study in lymphoma.

Allopurinol↗
PubMed1982

High-dose allopurinol modulation of 5-FU toxicity: phase I trial of an outpatient dose schedule.

In an attempt to decrease the activation of 5-FU by normal cells relative to cancer cells, 20 patients with metastatic cancer were given 72 courses of 5-FU and allopurinol (HPP) in a phase I trial. 5-FU was given daily by iv bolus injection for 5 consecutive days every 4 weeks: HPP, 300 mg orally every 8 hours for 6 consecutive days, was started 24 hours before the first injection of 5-FU. HPP appeared to modulate 5-FU toxicity by allowing higher doses (18-21 mg/kg daily for 5 days) to be given. Unexpectedly, neurotoxicity was the dose-limiting toxicity; it was slowly reversible and manifested primarily as encephalopathy, with some patients having cerebellar signs. Gastrointestinal and hematologic toxic effects were mild and infrequent. Because of the high incidence of neurotoxicity and low response rate, this program does not appear to offer any advantages over conventional dose schedules of 5-FU alone.

Adenocarcinoma↗
PubMed1981

Modulation of 5-fluorouracil toxicity by allopurinol in man.

Oxipurinol, the major metabolite of allopurinol, decreased the toxicity of 5-fluorouracil (5-FU) to human granulocyte colony-forming units in vitro by a factor of four. The ability of allopurinol to reduce 5-FU toxicity in vivo was studied in 23 advanced cancer patients during 42 courses of treatment. 5-FU was administered by continuous intravenous infusion for five days; allopurinol, 300 mg, po, every 8 hours was started 2 hours before and continued during and for 24 hours after 5-FU infusion. 5-FU was escalated from 1.5 to 2.25 g/m2/day on separate courses; the dose-limiting toxicity was mucositis which occurred at a level of 2.0 g/m2/day. At a 5-FU dose rate of greater than 2.0 g/m2/day 5-FU pharmacokinetics were nonlinear, reflecting saturation of catabolic pathways, and the steady-state 5-FU serum concentration was approximately 4 times that which was tolerable without allopurinol. At these concentrations of 5-FU oxipurinol significantly influenced the clearance of 5-FU. Thus concurrent allopurinol therapy permitted a doubling of the maximum tolerated dose of 5-FU and a four-fold increase in the tolerated concentration x time exposure to 5-FU.

Adenocarcinoma↗
PubMed1981

Significance of variation in serum thymidine concentration for the marrow toxicity of methotrexate.

Thymidine (dThd) concentrations have been measured in the sera of normal subjects and solid tumor cancer patients by means of a sensitive high-pressure liquid chromatographic assay to determine whether natural and methotrexate (MTX)-induced fluctuations were large enough to alter the toxicity of MTX to marrow. The mean concentration in normal subjects with measurable levels was 1.3 X 10(-7) M (range less than 4 X 10(-8) to 6 X 10(-7) M). In cancer patients it was 2.0 X 10(-7) M (range less than 4 X 10(-8) to 8.7 X 10(-7)), and in malignant effusions 1.2 X 10(-7) M (range less than 4 X 10(-8) to 2.2 X 10(-7) M). The wide range of variation in random samples was also found when multiple samples were obtained from the same patient during a 24-h period where dThd concentration varied from a minimum of two- to greater than six-fold. Treatment with MTX 3 mg/m2 caused an average 59% reduction in serum dThd during the first 24 h after injection during nine courses of therapy. dThd was tested for its ability to modulate the toxicity of MTX to human granulocate colony-forming units in culture across the concentration range found in vivo: changes in dThd concentration equivalent to normal fluctuations in vivo altered colony survival by 31% to greater than 72%. A reduction in culture dThd equivalent to that produced in vivo by high-dose TMX increased colony kill by 25%. The results indicate that in vivo variations in serum dThd are in an appropriate range and of a sufficient magnitude to alter the toxicity of MTX to marrow, and they demonstrate that MTX can modulate its own toxicity by reducing serum dThd.

Blood Proteins↗
PubMed1981

Synergistic interaction between 1-beta-D-arabinofuranosylcytosine, thymidine, and hydroxyurea against human B cells and leukemic blasts in vitro.

Isobologram analysis was used to examine the interaction between 1-beta-D-arabinofuranosylcytosine (Ara-C), thymidine (dThd), and hydroxyurea. All three pairs of drugs, as well as the triple combination, were synergistic against a human B cell line in vitro across a broad range of concentrations. Synergy was associated with an increase in the Ara-C nucleotide pool and Ara-C triphosphate concentration. dThd increased, and hydroxyurea decreased, the incorporation of Ara-C into trichloroacetic acid-insoluble macromolecules per unit time. Hydroxyurea was more effective than dThd at equimolar concentrations in increasing the acid-soluble Ara-C pool. Maximal stimulation of Ara-C triphosphate formation by dThd occurred at 1 mM and was associated with reduction of the deoxycytidine triphosphate pool to 31% of control. At the same concentration, hydroxyurea increased Ara-C triphosphate formation to a greater extent but increased deoxycytidine triphosphate to 116% of control. When tested at clinically achievable concentrations on blasts from patients with acute leukemia, hydroxyurea increased the Ara-C nucleotide pool in all six cases studied, whereas dThd decreased the Ara-C nucleotide pool. These results indicate that in SB cells dThd and hydroxyurea work by different mechanisms to augment the Ara-C nucleotide pool and that hydroxyurea may be more effective than dThd as a modulator of Ara-C activity in patients with acute leukemia.

Animals↗
PubMed1981

Influence of co-trimoxazole on methotrexate pharmacokinetics in children with acute lymphoblastic leukemia.

The effect of co-trimoxazole on methotrexate (MTX) pharmacokinetics was studied in seven children with ALL in remission receiving weekly maintenance therapy. Each child received MTX alone during one course, and MTX with co-trimoxazole during the next. Co-trimoxazole did not cause any significant alteration in either intestinal absorption of MTX, the degree of MTX plasma protein binding, or the average concentration X time exposure to MTX. These results indicate that low doses of co-trimoxazole do not perturb the serum pharmacokinetics of MTX. However, interaction of these drugs at the cellular level still remains a distinct possibility.

Adolescent↗
PubMed1981

Long-duration intracavitary infusion of methotrexate with systemic leucovorin protection in patients with malignant effusions.

18 patients with malignant effusions were treated with continuous intraperitoneal, intrapleural, or intrapericardial infusion of methotrexate (MTX) 30 mg/m2 per d combined with simultaneous intravenous administration of leucovorin at a dose rate calculated to yield an equimolar concentration in the serum. In the serum the geometric mean steady-state MTX concentration was 0.95 microM, whereas it was 24 microM in the peritoneal, 213 microM in the pleural, and 434 microM in the pericardial cavities. Mean clearance was 6.6 ml/min from the peritoneal cavity, 2.6 ml/min from the pleural cavity, and 0.14 ml/min from the pericardial cavity. Leucovorin provided sufficient protection to allow the duration of infusion to be escalated from 24 to 120 h before myelosuppression was encountered. Marrow thymidylate synthetase activity was inhibited by an average of 46% compared to 86% inhibition in malignant cells in the effusions. Flow cytometric analysis showed no perturbation of the cell cycle phase distribution of marrow cells. All eight of the evaluable patients have responded: three received no other form of therapy, five also received systemic hormonal or chemotherapy. This study demonstrated that tumors confined to third space body fluids can be given very high concentration x time exposures to MTX with minimal systemic toxicity.

Drug Therapy, Combination↗
PubMed1981

Cytotoxic activity, tumor accumulation, and tissue distribution of ruthenium-103-labeled bleomycin.

Bleomycin (BLM) was labeled with gamma-emitting 103Ru. Yields of 103Ru-labeled BLM as high as 50.6% were attained. 103Ru-labeled BLM was stable in vitro and the 103ru label was not displaced by large excesses of Cu (II) and Co (II) or Fe (III). Chromatography of the urine following 103Ru-labeled BLM injection indicated no in vivo decomposition. Pharmacokinetic studies in healthy inbred SD and tumor-bearing inbred BUF rats demonstrated tumor accumulations, tissue distributions, and clearance nearly identical with those reported for 3H-labeled BLM. Cytotoxicity studies on a WI-L2 human B-cell line showed that BLM labeled with nonradioactive Ru retained 100% of the activity demonstrated by native BLM. Thus BLM may be labeled with isotopes of Ru to form stable complexes by a simple, rapid reaction without loss of its chemotherapeutic properties or variations in its in vivo distribution. BLM labeled with the proper Ru isotope should prove useful as a gamma-emitting tracer for BLM or a beta-emitting compound capable of providing combination chemotherapy and radiotherapy of tumors.

Animals↗
PubMed1981

Activity of free and carrier-bound methotrexate against transport-deficient and high dihydrofolate dehydrogenase-containing methotrexate-resistant L1210 cells.

A difference in the mechanism of transmembrane transport was demonstrated for methotrexate (MTX) and MTX bound to the high molecular weight carrier bovine serum albumin (MTX-BSA) when the drug dose needed to reduce growth of cells to 50% of that of untreated cells (ID50) was compared in the sensitive L1210 leukemia and 3 L1210 sublines resistant to MTX by virtue of either deficient MTX transport or high levels of dihydrofolate dehydrogenase (DHFD). The loss of transport increased the ID50 for inhibition of growth rate by free MTX tenfold to twentyfold, whereas the elevation of DHFD levels increased the ID50 by tenfold. In contrast, deficiency of transport resulted in only a twofold increase in the ID50 for MTX-BSA, and elevation of DHFD caused a tenfold increase similar to that for free MTX. This difference was confirmed in studies of inhibition of DHFD activity by free and BSA-bound MTX. MTX-BSA but not MTX had antitumor activity against the transport-deficient L1210 line in (C57BL/6 x DBA/2)F1. These studies confirm a separate mode of cell entry for MTX-BSA and suggest a role for these complexes in overcoming resistance.

Animals↗
PubMed1981

Pharmacological and therapeutic properties of carrier bound methotrexate against tumor confined to a third space body compartment.

The pharmacokinetics and therapeutic effectiveness of methotrexate (MTX) and MTX covalently bound to bovine serum albumin (MTX-BSA) and poly-l-lysine, MW 3,000 (MTX-PLL 3K) or MW 40,000 to 60,000 (MTX-PLL 40-60K) were compared when these drugs were injected directly into the pleural cavities of BDF1 mice containing the L1210 tumor. Simultaneous measurements od drug levels in both pleural fluid and blood after a single dose demonstrated that free MTX and MTX-PLL 3K were cleared from the pleural cavity and blood within 4 hr, MTX-PLL 40K-60K was cleared within 2 hr, and MTX-BSA was still present in the tumor compartment at 48 hr. The coupling of MTX to these carriers increased its toxicity by extending the half-life of MTX-BSA within the animal and by incorporating a toxic PLL derivative as a carrier. At equitoxic doses, a single dose of MTX-BSA gave a peak increase in lifespan (ILS) of 50% (at 35 mg/kg) compared with a peak ILS of 30 to 35% for both free drug (at 95 mg/kg) and the MTX-PLL derivatives (at 1.4-6 mg/kg). Systemic administration of sufficient leucovorin to provide partial marrow protection compromised the antitumor activity of both MTX and MTX-BSA in the pleural cavity, and although leucovorin permitted higher doses to be used, this resulted in only a small increase in peak ILS for MTX-BSA on a single dose schedule.

Animals↗