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Biomedical subjects

O M Colvin

Publications and source records attributed to O M Colvin.

125 records · Page 7Linked to original sources
PubMed1987

Variability in 4-hydroperoxycyclophosphamide activity during clinical purging for autologous bone marrow transplantation.

We examined the effects of varying incubation conditions on the in vitro activity of 4-hydroperoxycyclophosphamide (4HC). 4HC activity against CFU-GM and against the K562 tumor cell line decreased with increasing the RBC concentration of the incubation mixture. Increasing the concentration of nucleated bone marrow cells in the incubation mixture also decreased the 4HC activity. Evaluation of 53 consecutive patients undergoing autologous bone marrow transplantation (BMT) revealed that the incubation RBC concentration during clinical purging showed a similar effect on CFU-GM recovery. Aldehyde dehydrogenase content of RBCs and nucleated marrow cells appears to be the cause of the inhibition of 4HC activity. Although there was no difference in individual CFU-GM sensitivity to 4HC among normals, previously treated patients undergoing autologous BMT showed significant variability in CFU-GM sensitivity to 4HC. The combined effects of incubation RBC concentration and individual patient 4HC sensitivity appear to account for most of the variability in CFU-GM recovery and speed of hematologic recovery after clinical purging with 4HC.

Bone Marrow↗
PubMed1986

Autologous bone marrow transplantation in patients with acute nonlymphocytic leukemia, using ex vivo marrow treatment with 4-hydroperoxycyclophosphamide.

We studied 25 patients with acute nonlymphocytic leukemia in second remission (20 patients) or third remission (5 patients) in whom autologous bone marrow transplantation was performed with use of marrow incubated ex vivo with the alkylating agent 4-hydroperoxycyclophosphamide. Patients received intensive cytoreductive therapy with busulfan and cyclophosphamide or cyclophosphamide and total body irradiation, followed by an infusion of marrow that had been collected in remission, treated with 4-hydroperoxycyclophosphamide, and cryopreserved. Four patients died from bacterial or fungal sepsis within the first month after transplantation, and one patient with persistent marrow hypoplasia died from gram-negative sepsis 155 days after infusion with autologous marrow. In the remaining patients, peripheral-blood levels of neutrophils in excess of 0.5 X 10(9) per liter and platelet counts over 50 X 10(9) per liter were attained at median intervals of 29 and 57 days after transplantation, respectively. Nine patients had leukemic relapses at 73 to 316 days (median, 182 days) after infusion of autologous marrow, for an actuarial relapse rate of 46 percent. Eleven patients (eight in second remission and three in third) remained in remission at a median of more than 400 days (range, greater than 230 to greater than 1653 days) after transplantation. The observed disease-free survival after transplantation with autologous marrow treated with 4-hydroperoxycyclophosphamide compares favorably with the results of syngeneic or allogeneic transplantation in similar groups of patients.

Acute Disease↗
PubMed1986

Interactions between cyclophosphamide and doxorubicin metabolism in rats. II. Effect of cyclophosphamide on the aldoketoreductase system.

Under anaerobic conditions, in comparison to liver microsomes obtained from normal controls, liver microsomes obtained from rats pretreated with cyclophosphamide formed significantly less 7-deoxydoxorubicinol aglycone (P less than or equal to .05), whereas the disappearance of doxorubicin and the formation of 7-deoxydoxorubicin aglycone were unaffected. When directly investigated, the reduction of 7-deoxydoxorubicin aglycone to 7-deoxydoxorubicinol aglycone by microsomes was inhibited by cyclophosphamide pretreatment. Liver cytosols from controls and cyclophosphamide-treated rats reduced daunorubicin to daunorubicinol and 7-deoxydoxorubicin aglycone to 7-deoxydoxorubicinol aglycone at the same rate, which indicates the lack of effect of cyclophosphamide pretreatment on the cytosolic aldoketoreductase. The results suggest the existence of a microsomal carbonyl reduction system for anthracycline antibiotics and indicate that cyclophosphamide does affect the metabolism of doxorubicin; in rats, this interaction results only in an alteration of the relative concentrations of presumably inactive metabolites, the 7-deoxyaglycones. The importance of these findings for the pharmacological interaction between doxorubicin and cyclophosphamide in humans remains to be investigated.

Alcohol Oxidoreductases↗
PubMed1986

Experimental chemotherapy of human medulloblastoma with classical alkylators.

Seven classical alkylators were tested for activity against the continuous human medulloblastoma cell line TE-671 grown in vitro and as s.c. and intracranial xenografts in athymic mice. Drugs tested included melphalan, cyclophosphamide (4-hydroperoxycyclophosphamide in vitro), iphosphamide (4-hydroperoxyiphosphamide in vitro), phenylketocyclo-phosphamide, phenylketoiphosphamide, Asta Z 7557, and thiotriethyl-enephosphoramide. All agents were active, with melphalan demonstrating the most activity in vitro and in vivo. Comparative studies of cyclophosphamide and phenylketocyclophosphamide revealed partition coefficients (log P) of 0.73 and greater than 1.69, respectively, and cyclophosphamide exhibited greater cytotoxic activity in post- (equitoxic) drug administration murine plasma. Hematological toxicity was limited to leukopenia/neutropenia for both of these agents. These studies suggest that the classical alkylators may have a role in the treatment of medulloblastoma and provide a means to further analyze their therapeutic potential.

Alkylating Agents↗
PubMed1985

Human multilineage progenitor cell sensitivity to 4-hydroperoxycyclophosphamide.

This institution has documented consistent reconstitution of hematopoiesis in patients treated with marrow lethal chemoradiotherapy who are "rescued" by reinfusion of autologous cryopreserved marrow cells incubated with 4-hydroperoxycyclophosphamide (4-HC) for in vitro purging of occult tumor cells. After 4-HC incubation, the reinfusion marrow cells showed marked reduction in committed progenitor cell (BFU-E, CFU-GM) frequency, and often total absence of detectable progenitors, without significant loss of marrow reconstituting ability. Since BFU-E and CFU-GM assays did not predict marrow reconstituting ability after 4-HC incubation, we sought to determine whether multilineage progenitor cells (CFU-GEMM) might be more resistant to 4-HC incubation and therefore a more reliable predictive assay in this setting. We found that BFU-E, CFU-GM, and CFU-GEMM all show similar dose-related sensitivity to in vitro incubation with 4-HC and do not appear representative of the cell(s) responsible for marrow reconstitution.

Cells, Cultured↗
PubMed1984

Interactions between cyclophosphamide and adriamycin metabolism in rats.

Rat liver microsomes under anaerobic conditions metabolize adriamycin (ADM) to 7-deoxyadriamycinol aglycone and 7-deoxyadriamycin aglycone. The metabolism of ADM and the concentration of cytochrome P-450 were not affected by preincubation with 2.76 mM cyclophosphamide. After preincubation of microsomes with 0.2 mM 4-hydroperoxycyclophosphamide, a prodrug of 4-hydroxycyclophosphamide, there was complete denaturation of the cytochrome P-450, and 22.8% inhibition of NADPH-cytochrome P-450 reductase. Under these conditions, the degradation of ADM was delayed (area under the concentration vs. time curve in micromolar X minutes: 15.6 +/- 2.4 for the controls, and 59.8 +/- 7.3 in the presence of 4-hydroperoxycyclophosphamide, P less than or equal to .005), 7-deoxyadriamycin aglycone increased progressively to reach a plateau at 20 min instead of showing a peak at 2 min and the formation of 7-deoxyadriamycinol aglycone was reduced. Microsomes from animals pretreated with cyclophosphamide (180 mg/kg i.p. once 4 days before sacrifice) showed a 24.0% reduction of NADPH-cytochrome P-450 reductase activity (P less than or equal to .02). This was accompanied by a decreased formation of 7-deoxyadriamycinol aglycone during the first 20 min of incubation (area under the concentration vs. time curve in micromolar X minutes: 68.0 +/- 15.7 in the controls, and 25.6 +/- 3.1 in the treated animals, P less than or equal to .005), whereas the formation of 7-deoxyadriamycin animals, P less than or equal to .005), whereas the formation of 7-deoxyadriamycin aglycone was not affected. These data indicate an interaction between the metabolism of cyclophosphamide and ADM in rats.

Alkylation↗
PubMed1982

Improved rabbit brain tumor model amenable to diagnostic radiographic procedures.

The VX2 carcinoma was used to create a rabbit brain tumor model. VX2 tumors were chemically dissociated and suspended in liquid medium. Twenty-five microliters of the tumor suspension containing 3 X 10(3), 3 X 10(4), or 3 X 10(5) viable tumor cells were injected through cranial burr holes 6 mm into the right frontoparietal lobes of 17 rabbits. Fifteen of these developed histologically documented nodular intraparenchymal tumors. Tumors were demonstrable with cerebral computed tomographic scans and by cerebral angiography. The feasibility of surgical resection of lesions using the fluorescein staining technique was also demonstrated. This animal brain tumor model is suitable for neuro-oncology research focusing on imaging and therapeutic techniques.

Animals↗
PubMedDate not supplied

Initial observations on the effects of delta 9-tetrahydrocannabinol on the plasma pharmacokinetics of cyclophosphamide and doxorubicin.

We studied the effect of THC upon the pharmacokinetics of cyclophosphamide (CTX) and doxorubicin (ADR). Plasma THC was determined by RIA. Plasma concentrations of CTX and ADR were measured by GLC and fluorescence, respectively. RIA confirmed plasma levels of THC greater than 20 ng/ml for patients who received THC. CTX half-life was not significantly changed with use of THC (7.7 +/- 3.6 hours without versus 5.25 +/- 2.6 hours with THC). ADR half-life with THC was greater than without THC (175 +/- 197 hours versus 92 +/- 92 hours, respectively). Total drug exposure as determined by areas under the curves were similar (12.4 +/- 6 microM . hr without versus 13.8 +/- 4 microM . hr with THC). These preliminary data suggest that RIA is reliable for assessing THC plasma concentrations. THC induces no apparent alterations of CTX or ADR pharmacokinetics.

Cyclophosphamide↗
PubMedDate not supplied

Plasma pharmacokinetics and urinary excretion of thalidomide after oral dosing in healthy male volunteers.

The plasma pharmacokinetics and urinary excretion of thalidomide have been evaluated in eight healthy male volunteers receiving a single oral dose of 200 mg. Concentrations of thalidomide were determined by a new HPLC assay. Plasma concentration vs. time data were well fit by a one-compartment model. The mean (+/- SD) peak concentration, 1.15 +/- 0.2 microgram/ml, was achieved at 4.39 +/- 1.27 hr. Absorption and elimination half-lives were 1.70 +/- 1.05 hr and 8.70 +/- 4.11 hr, respectively, with a lag time of 0.41 +/- 0.17 hr observed in six subjects. The apparent volume of distribution and total body clearance rate, based on assumed complete bioavailability, were 120.69 +/- 45.36 liters and 10.41 +/- 2.04 liters/hr. The urinary excretion of thalidomide accounted for only 0.6 +/- 0.22% of the total dose administered over 24 hr, and the renal clearance rate was 0.08 +/- 0.03 liter/hr. This suggests that the major route of elimination of thalidomide is nonrenal.

Administration, Oral↗
PubMedDate not supplied

Iminocyclophosphamide as a chemically reactive metabolite of cyclophosphamide.

Iminocyclophosphamide has been identified among the metabolites produced by incubation of cyclophosphamide with cytochrome P-450 mono-oxygenase immobilized on beaded Sepharose. The reactive imine was trapped by addition of hydrogen cyanide, and the product, 4-cyanocyclophosphamide, was identified by comparison of its chromatographic and mass-spectral properties with those of a synthetic standard. Iminocyclophosphamide was also generated chemically from 4-hydroperoxycyclophosphamide and characterized both by addition of hydrogen cyanide and by reduction with sodium borodeuteride. The synthesis of authentic 4-cyanocyclophosphamide is also reported.

Animals↗
PubMedDate not supplied

Kinetic analysis of the reaction of melphalan with water, phosphate, and glutathione.

The reaction kinetics of the hydrolysis, phosphatolysis, glutathionyl conjugation, and alpha-glutathione-S-transferase (GST)-catalyzed glutathione conjugation of [3H-ring]melphalan were investigated at pH 6.5 and 7.4. The distribution of products relative to the initial parent compound radioactivity over time was measured by HPLC and analyzed by nonlinear regression techniques using a system of rate and distribution equations that describe the complete precursor-product pathways applicable to each reaction condition. The kinetic parameters calculated in the analysis were the first- and second-order rate constants of formation and the product ratios of the aziridinium intermediates. The second-order rate constants were normalized to those obtained for the hydroxylation reactions to yield relative rate constants. The first-order rate constants of aziridinium ion formation from melphalan and from all the monosubstituted melphalan species, except chloro, hydroxyl melphalan, were similar under all reaction conditions. The relative second-order rate constant for nonenzymatic glutathionylation of the aziridinium intermediate was 7 times larger at pH 7.4 than at pH 6.5. GST was found to react only with the aziridinium intermediate formed from melphalan and to dissociate slowly from the resultant GST-product complex (dissociation half-life, 1 hr at pH 7.4 and 3.5 hr at pH 6.5). The kinetic parameter estimates found in this study can be used to make preliminary calculations of the impact that cellular phosphate, glutathione, and GST concentrations will have on the intracellular detoxication of melphalan.

Glutathione↗