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Biomedical subjects

D G Poplack

Publications and source records attributed to D G Poplack.

At least 145 records · Page 8Linked to original sources
PubMed1985

Prevention of methotrexate cytotoxicity by asparaginase inhibition of methotrexate polyglutamate formation.

Escherichia coli asparaginase (Asnase) pretreatment of Asnase-sensitive L5178Y cells in vitro is thought to antagonize methotrexate (MTX) cytotoxicity through nonspecific inhibition of protein synthesis and MTX uptake. We have reexamined the mechanism of this interaction in view of recent data demonstrating the importance of MTX metabolism to polyglutamate derivatives (MTXPGs) in the cytotoxic effects of the antifolate. After a 3-hr exposure to 0.5 microM MTX, 67% of intracellular drug was in the form of MTXPGs containing a total of 2 to 5 glutamyl residues (MTX-Glu2-5), and cloning efficiency in drug-free medium was only 7% of untreated control. After a 3-hr pretreatment with E. coli Asnase (0.1 unit/ml), [3H]thymidine incorporation dropped by 29%, MTXPG formation during subsequent MTX exposure decreased by more than one-half (MTX-Glu2 unchanged; MTX-Glu3 and 4 decreased to 51.7 and 18.5% of levels achieved in cells not pretreated with Asnase; no MTX-Glu5 formed), and cloning efficiency increased to 71% of untreated control. This effect was not due to decreased MTX uptake into L5178Y cells or to decreased intracellular free L-glutamate or L-glutamine levels. A 3-hr exposure of L5178Y cells to media lacking L-isoleucine, an essential amino acid for cell growth, prior to MTX exposure inhibited [3H]thymidine incorporation by 37%, decreased subsequent MTXPG formation by 62%, and increased subsequent cloning in drug-free medium to control levels. Decreased MTXPG formation was responsible for the prevention of MTX cytotoxicity seen after both pretreatments. Unmetabolized MTX rapidly left L5178Y cells after removal of extracellular MTX. Consequently, lower levels of unbound intracellular drug, a prerequisite of drug activity, were maintained in pretreated than in control cells after passage in drug-free medium. Asnase pretreatment protects L5178Y cells from the cytotoxic effects of MTX, possibly through inhibition of cell growth which nonspecifically decreases MTXPG formation.

Animals↗
PubMed1985

Pharmacokinetics of tiazofurin in the plasma and cerebrospinal fluid of rhesus monkeys.

The pharmacokinetic disposition of tiazofurin in plasma and cerebrospinal fluid was examined in rhesus monkeys. Tiazofurin was readily detectable in both plasma and cerebrospinal fluid within 20 min of commencement and for 24 h after a short i.v. infusion of the drug. The mean clearance of tiazofurin from plasma was 70 +/- 23 (SD) ml/min/sq m after a dose of 100 mg/kg and 106 +/- 38 ml/min/sq m after a dose of 500 mg/kg with no evidence of dose dependency. The data for plasma elimination of tiazofurin were fit to a triexponential equation for comparison with data from other species. The t 1/2 alpha was 0.23 h, t 1/2 beta was 1.9 to 2.0 h, and t 1/2 gamma was 6.8 to 7.1 h. The ratio of area under the cerebrospinal fluid drug concentration-time curve to the area under the plasma drug concentration-time curve was 0.28, which suggests significant penetration of the blood-brain barrier. These results demonstrate the propensity of tiazofurin to enter the cerebrospinal fluid and, probably, the brain, and suggest a potential role for this agent in the treatment of central nervous system cancer.

Animals↗
PubMed1984

Acute megakaryoblastic leukemia in childhood.

Routine morphologic and cytochemical study of the leukemic cells of a 13-month-old child did not permit definitive determination of either a lymphoid or a myeloid cell origin. However, ultrastructural cytochemical analysis revealed platelet peroxidase (PPO) reactivity. The malignant cells expressed PPO in both unfixed and fixed preparations. PPO was observed in the perinuclear space and reticulum but not in the Golgi saccules. In a 1% glutaraldehyde, 1% formaldehyde solution known to inhibit PPO but not myeloperoxidase, no reaction product was observed. The demonstration of PPO activity in these undifferentiated cells established their megakaryoblastic lineage. Further studies including DNA flow cytometry confirmed that these cells were megakaryoblasts. This study demonstrates that megakaryoblastic malignancy may occur as an acute leukemia of childhood and emphasizes the value of ultrastructural cytochemistry in cases of acute leukemia which defy routine classification. Abnormalities of chromosome 21 were present in our patient as in four previous cases of megakaryoblastic leukemia in childhood. The nonrandomness of chromosome 21 involvement in this disease should therefore be considered.

Acute Disease↗
PubMed1984

Reduced pulsatile growth hormone secretion in children after therapy for acute lymphoblastic leukemia.

Basal growth hormone levels were measured every 20 minutes over 24 hours in eight long-term survivors of acute lymphoblastic leukemia and in 13 age- and pubertal stage-matched normal children. Among the patients, the median total basal growth hormone output (AUC) was 43 units, compared with 341 units in the normal control group (P less than 0.001). In the patients, mean pulse amplitude (6.9 ng/ml) and frequency (4.6) over 24 hours also were reduced, compared with the control values (32 ng/ml and 8.5, P less than 0.001 and P less than 0.05, respectively). In addition, normal children secreted more GH at night (median AUC 280) than during the day (113, P less than 0.001). However, this diurnal pattern was absent in three of the patients studied. These data suggest that perturbations of spontaneous pulsatile GH secretion are common after standard therapy for ALL and may be a sensitive means of detecting therapy-related neuroendocrine damage. Blunting of spontaneous pulsatile GH secretion may contribute to the abnormalities in growth seen in children with ALL.

Adolescent↗
PubMed1984

Cytosine arabinoside cerebrospinal fluid kinetics.

To better characterize the disposition of cytosine arabinoside (Ara-C) in cerebrospinal fluid (CSF), its kinetics were studied in seven patients with meningeal leukemia in complete remission. After intraventricular injection of 30 mg Ara-C, CSF and plasma samples were obtained over a 24-hr period. Ara-C levels were measured by a reverse-phase HPLC assay (with a sensitivity of 0.5 microM in CSF and 1.0 microM in plasma) that readily separated Ara-C from its major metabolite uracil arabinoside (Ara-U). Elimination of Ara-C from CSF followed a biphasic pattern, with an initial t1/2 of 1 hr and a terminal t1/2 of 3.4 hr. Ara-C clearance from CSF was 0.42 ml/min, suggesting that drug elimination was primarily by CSF bulk flow. The ratio of the AUC of Ara-U to the AUC of Ara-C was 0.08, indicating only minor metabolism of Ara-C to Ara-U in CSF, in contrast to that after systemic Ara-C. Despite initial CSF Ara-C concentrations exceeding 2 mM, Ara-C was not detectable in plasma in any patient. Intraventricular Ara-C results in very high levels in CSF, but systemic tissues are relatively spared from exposure to Ara-C.

Adolescent↗
PubMed1984

Effect of intravenous dose and schedule on cerebrospinal fluid pharmacokinetics of 5-fluorouracil in the monkey.

There is little information regarding the pharmacology of 5-fluorouracil (5-FUra) in the central nervous system (CNS), despite its role in the treatment of diseases with CNS metastases and recent reports of neurotoxicity. In this study, the plasma and cerebrospinal fluid (CSF) pharmacokinetics of 5-FUra were examined in a primate model. Following a bolus dose, the area under the concentration versus time curves for 5-FUra in CSF was 48% of the plasma area under the concentration versus time curves. For continuous infusion of 5-FUra, the area under the concentration versus time curves ratio for CSF:plasma was 20 or 11%, depending upon the infusion rate. The mechanism for variations in CSF exposure based upon the pattern of plasma delivery is consistent with local metabolism of 5-FUra in the CNS. These findings should be considered in the evaluation of delivery schedules which are intended to maximize drug delivery to the CNS and/or minimize neurotoxicity.

Animals↗
PubMed1984

Cerebrospinal fluid pharmacokinetics of intraventricular and intravenous aziridinylbenzoquinone.

The cerebrospinal fluid (CSF) pharmacokinetics of aziridinylbenzoquinone (AZQ) was studied following i.v. and intraventricular drug administration. Initial studies were performed in six rhesus monkeys with chronic indwelling Ommaya reservoirs. Following intraventricular administration of 0.2 mg of AZQ, elimination was monoexponential with half-lives of 32 and 39 min in ventricular and lumbar CSF, respectively. AZQ clearance (0.2 ml/min) was 5-fold greater than estimated CSF bulk flow, indicating that transcapillary passage and/or metabolism may be important clearance mechanisms for this drug. In spite of its rapid clearance from ventricular CSF, a substantial peak AZQ concentration was achieved in lumbar CSF (12 microM), which was 7 times higher than the peak ventricular CSF level (1.7 microM) achieved following i.v. AZQ administration (16 mg/sq m). Moreover, the mean area under the CSF concentration-time curve in ventricular CSF was 20-fold greater following intraventricular versus i.v. AZQ dosing, despite an 80-fold-lower dose. AZQ was not detectable in plasma (less than 0.06 microM) following intraventricular administration. No animals demonstrated clinical evidence of acute neurotoxicity. Subsequently, intraventricular AZQ was administered to a patient with refractory meningeal leukemia. Intraventricular AZQ (0.5 mg) resulted in a peak ventricular (56 microM) CSF level which was 80-fold higher than ventricular CSF levels achieved following systemic AZQ administration of a dose of 24 mg/sq m in humans. Moreover, intraventricular AZQ yielded substantial CSF levels without detectable plasma concentrations. These data suggest that intraventricular administration of AZQ is feasible and may have pharmacological advantages over systemic administration for the treatment of meningeal neoplasia.

Animals↗
PubMed1984

Probenecid inhibition of methotrexate cytotoxicity in mouse L1210 leukemia cells.

The effect of probenecid on methotrexate cytotoxicity has been measured using mouse L1210 leukemia cells in vitro. Cytotoxic effects were measured using a soft agar cloning technique. Cell exposure to varying concentrations of methotrexate at fixed concentrations of probenecid resulted in increased cell survival when compared with exposure to methotrexate alone. Cell exposure to a fixed concentration of methotrexate and varying concentrations of probenecid showed this effect to be dependent on the concentration of probenecid. Intracellular methotrexate concentrations were unchanged by the presence of probenecid. However, there was an effect of probenecid on progression of cells through the cell cycle which would tend to decrease the number of cells susceptible to the cytotoxic effects of methotrexate.

Animals↗
PubMed1983

Inhibition of first-pass metabolism in cancer chemotherapy: interaction of 6-mercaptopurine and allopurinol.

Earlier studies suggested that the dose of 6-mercaptopurine (6-MP) can be reduced substantially when the drug is given with allopurinol. We studied the effect of allopurinol on the kinetics of oral and intravenous 6-MP. Studies conducted initially in rhesus monkeys and subsequently in man with 6-MP doses of 100 mg/m2 and 75 mg/m2, demonstrated that allopurinol pretreatment resulted in a nearly 400% increase in peak plasma concentration of oral 6-MP in monkeys (from a mean of 0.54 microM to a mean of 2.1 microM) and a 500% increase in man (0.74 microM to 3.7 microM). Allopurinol pretreatment also led to a 300% increase in plasma AUC in monkeys after oral 6-MP (from a mean of 121 microM/min to a mean of 391 microM/min) and a 500% increase in AUC in man (from a mean of 142 microM/min to a mean of 716 microM/min). In contrast, allopurinol pretreatment had no effect on the kinetics of intravenous 6-MP. This difference was found to be due to inhibition of first-pass metabolism of oral 6-MP as the result of the action of allopurinol on liver or intestinal xanthine oxidase. Our results indicate that, although dose reduction of oral 6-MP given in conjunction with allopurinol is appropriate, it is not necessary when 6-MP is injected intravenously.

Administration, Oral↗
PubMed1983

Immunoglobulin gene rearrangement and cell surface antigen expression in acute lymphocytic leukemias of T cell and B cell precursor origins.

We have explored the relationship among immunoglobulin gene rearrangement, cytoplasmic immunoglobulin production, and cell surface antigen expression within 37 cases of acute lymphocytic leukemia. All 12 cases of the T cell type had germ-line kappa and lambda genes and 11 of 12 had germ-line heavy chain genes. In contrast, all 25 cases of the "non-T, non-B" classification, which lacked both definitive T cell markers and surface immunoglobulin, had rearranged immunoglobulin genes, indicating that they represent precursor cells already committed to the B cell lineage at the gene level. 14 had rearranged heavy chain genes, yet retained germ-line light chain genes, whereas 11 cases had both heavy and light chain gene reorganizations. All patterns of immunoglobulin gene rearrangement predicted by a model that proceeds from heavy chain gene recombination to light chain genes were observed. Despite the uniform presence of rearranged immunoglobulin genes, only five cases produced cytoplasmic mu-chain, one exceptional case produced gamma-chain, and another produced only lambda-chain. The cases of B cell precursor type that do not produce immunoglobulin may represent cells that frequently possess ineffectively rearranged immunoglobulin genes. Included in this group may be a set of cells trapped within the B cell precursor series because their ineffective rearrangements have eliminated certain gene subsegments necessary for the assemblage of an effective heavy chain gene. All seven cases of the non-T, non-B subgroup that bore HLA-DR but lacked CALLA (the common acute lymphocytic leukemia-associated antigen) represented the earliest recognizable stage of B cell precursors with rearranged heavy chain genes but germ-line light chain genes. Correlations here suggest that cells entering B cell development express HLA-DR and rearrange heavy chain genes before the expression of a B cell-associated antigen recognized by the antibody BA-1, the antigen CALLA, and any subsequent light chain gene rearrangements.

B-Lymphocytes↗
PubMed1983

Heterogeneity of acute lymphocytic leukemia cell surface markers as detected by monoclonal antibodies.

Monoclonal antibodies 3A1, 4F2, 5E9, OKT3, OKT6, and OKT8 were tested by flow microfluorometry for reactivity with cells from patients with T-cell or null cell acute lymphocytic leukemia (ALL). The 3A1 antibody reacted with a greater percentage of cells from 1 group of patients that could be classified as T-cell leukemia patients as compared to its reaction in the group classifiable as null cell leukemia patients. Reactivity patterns of other monoclonal antibodies with lymphocytes from patients with ALL did not clearly define groups of ALL patients. All cells from individual leukemia patients reacted differently with the seven monoclonal reagents. On the basis of patterns of reactivity, T-cell leukemias could not be classified as malignant clones of cells from the previously described stages of thymus cell maturation. The results demonstrated that the cells undergoing malignant change express a variety of combinations of antigens not found on normal lymphocytes.

Antibodies, Monoclonal↗
PubMed1982

Transplantation of leukemic bone marrow treated with cytotoxic antileukemic antibodies and complement.

The ability of antiserum against murine L1210 leukemia to remove residual leukemia cells from murine bone marrow was investigated. Leukemic marrow was treated in vitro with antiserum and complement and used to hematologically reconstitute mice that had been irradiated with doses lethal to bone marrow. Following infusion of treated leukemic marrow, normal marrow returned without evidence of leukemia. More than 90 percent of the animals have survived for 11 months without untoward effects, suggesting that the technique may be of use in the treatment of acute leukemia in humans.

Animals↗
PubMed1982

Phase II study of 5-azacytidine in sarcomas of bone.

Eight patients with osteogenic sarcoma and seven patients with Ewing's sarcoma, all with advanced metastatic disease refractory to conventional therapy, were treated with 5-azacytidine (NSC-102816) intravenously at a dosage of 150 mg/m2 in three divided doses daily X 5 days. The courses were repeated q 4 weeks and the dosage was escalated to 200 mg/m2/day, as tolerated. Fourteen patients were evaluable for response. Major toxicities wee hematologic and gastrointestinal. 5-azacytidine had no demonstrable antitumor activity.

Adolescent↗