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Biomedical subjects

W Plunkett

Publications and source records attributed to W Plunkett.

At least 181 records · Page 10Linked to original sources
PubMed1984

High-dose cytosine arabinoside in multiple myeloma.

In 14 patients with advanced refractory multiple myeloma, the effect of high-dose cytosine arabinoside (ara-C) administration was evaluated. There was one partial remission among 13 evaluable patients who received 2 g/m2 intravenously over 2 hr every 12 hr, for a total of 2-8 g/m2 per course, repeated every 3-4 weeks. Myelosuppression constituted the dose-limiting toxicity, causing two treatment-related deaths from infection and bleeding. Prior extensive therapy, a low percentage of cells in S phase and low levels of intracellular ara-CTP accumulation in the bone marrow could explain the resistance of myeloma to this treatment.

Aged↗
PubMed1983

2-fluoro-ATP: a toxic metabolite of 9-beta-D-arabinosyl-2-fluoroadenine.

Murine P388 cells incubated in vitro with the anticancer drug arabinosyl 2-fluoroadenine accumulate its 5'-triphosphate, F-araATP, as the major phosphorylated metabolite. A new chromatographically separate metabolite that accumulated to levels 10% of that of F-araATP was identified as 2-fluoro-ATP, by the following criteria. 1. The metabolite coeluted with the authentic compound on anion-exchange HPLC. 2. Dephosphorylation of the metabolite yielded a compound that was chromatographically identical to 2-fluoroadenosine. 3. The compound was sensitive to NaIO4 oxidation. Cellular incubation experiments indicated that 2-fluoroadenine, but not arabinosyl 2-fluorohypoxanthine, was the likely intermediate in the formation of 2-fluoro-ATP.

Adenine↗
PubMed1983

Metabolism of 9-beta-D-arabinosyl-2-fluoroadenine-5'-phosphate by mice bearing P388 leukemia.

The metabolism of 9-beta-D-arabinofuranosyl-2-fluoroadenine-5'-phosphate (F-araAMP), a soluble nucleoside analog with promising antitumor activity, has been studied in mice bearing P388 leukemia. Upon i.p. injection of an LD10 dose (1485 mg/kg) in tumor-bearing mice, F-araAMP disappeared from the ascitic fluid with a T1/2 of 1.2 h. This was accompanied by the appearance of 9-beta-D-arabinofuranosyl-2-fluoroadenine and lesser amounts of 9-beta-D-arabinofuranosyl-2-fluorohypoxanthine in both the ascitic fluid and plasma. The principal active metabolite, 9-beta-D-arabinofuranosyl-2-fluoroadenine-5'-triphosphate, accumulated to approximately 1 mM in P388 cells, a concentration nearly 20-fold greater than that of the bone marrow or intestinal mucosa. DNA synthesis was inhibited to a similar extent in tumor and host tissues, but the duration of maximum inhibition was twice as long in P388 cells. 2-Fluoro-ATP, a second toxic metabolite, accumulated to 27 microM in P388 cells and was eliminated with a T1/2 of 3.7 h. The contributions of both 9-beta-D-arabinofuranosyl-2-fluoroadenine-5'-triphosphate and 2-fluoro-ATP to the cytotoxicity and therapeutic action of F-araAMP should be considered in evaluations of the biochemical bases for these activities.

Adenosine Triphosphate↗
PubMed1983

High-dose cytosine arabinoside in non-Hodgkin's lymphoma.

Thirty-two patients with refractory non-Hodgkin's lymphoma were treated with high-dose cytosine arabinoside (ara-C) given at 2 g/m2 IV over three hours every 12 hours for 4-8 g/m2/course repeated at three to four week intervals. There were eight partial responses (29%) and two minor responses among 28 evaluable patients. The median response duration was 10 weeks (range, 6-33 weeks). The median survival was significantly prolonged in responders compared to nonresponders (28 versus 15 weeks; p = 0.03). Two additional patients treated with 12 g/m2/course died of sepsis and myelosuppression. The dose-limiting toxicity was myelosuppression, which was more pronounced in patients with prior extensive radiation therapy and bone marrow involvement. In vivo measurements of intracellular concentrations of ara-CTP, the active metabolite of ara-C, showed significantly higher values in bone marrows with lymphomatous involvement compared to normal bone marrows (210 versus 95 microM; p = 0.05), probably indicating a preferential formation and retention of ara-CTP in malignant cells compared to normal hemopoietic cells. In addition, higher ara-CTP levels were found in bone marrows that had higher percentages of cells in S phase.

Adult↗
PubMed1982

Aspartate carbamoyltransferase activity, drug concentrations, and pyrimidine nucleotides in tissue from patients treated with N-(phosphonacetyl)-L-aspartate.

Biopsy specimens were obtained from patients treated with N-(phosphonacetyl)-L-aspartate (PALA) in a phase I clinical trial. Activities of aspartate carbamoyltransferase (ACTase), the target enzyme, in ten specimens before treatment varied from 0.4 to 1.7 units/mg. PALA was measured in protein-free extracts of thirteen specimens by inhibition of rat ACTase. At 1.5 to 145 hr after doses of 1 to 6 g/m2, PALA concentrations were 0.9 to 89 micrograms/g; at 4 hr or later the tissue concentrations were similar to those in plasma (five samples). The observed inhibition of ACTase (17-87%) correlated with the PALA concentrations. Pyrimidine nucleotides were decreased (relative to purine nucleotides) in nine to ten specimens, by 16-72%. ACTase partially purified from human spleen had a Km for carbamoyl phosphate of 20.6 microM and the Ki for PALA was 0.011 microM. The results suggest that inhibition of ACTase by PALA affects the concentration of pyrimidine nucleotides in human tumors in a dose-dependent manner.

Antimetabolites, Antineoplastic↗
PubMed1982

Modulation of 9-beta-D-arabinofuranosyladenine 5'-triphosphate and deoxyadenosine triphosphate in leukemic cells by 2'-deoxycoformycin during therapy with 9-beta-D-arabinofuranosyladenine.

The effect of the adenosine deaminase inhibitor, 2'-deoxycoformycin, on cellular nucleotides during therapy with continuous infusion of 9-beta-D-arabinofuranosyladenine (ara-A) has been investigated. In three courses of treatment using increasing doses, the active 5'-triphosphate of ara-A, 9-beta-D-arabinofuranosyladenine 5'-triphosphate (ara-ATP) accumulated in leukemic cells and erythrocytes from a patient treated for acute lymphocytic leukemia in proportion to the dose of ara-A. The cellular ara-ATP concentration increased more than 5-fold after the injection of a single, nontoxic, but pharmacologically active dose of 2'-deoxycoformycin 24 hr after initiation of ara-A infusion. However, this response was associated with a concomitant increase in the cellular deoxyadenosine triphosphate concentrations to levels equal to or greater than those of ara-ATP throughout the three treatment courses studied. Consistent with previous results using cell-free systems, it was demonstrated that a competitive relationship exists between deoxyadenosine triphosphate and ara-ATP for the inhibition of DNA synthesis in cultured human lymphoblastoid cells and that the ratio of the cellular concentrations of these nucleotides could predict the extent of inhibition of DNA synthesis. Application of this rationale to the nucleotides in the leukemic cells of the patient suggested that administration of 2'-deoxycoformycin may create a cellular biochemical milieu that could be antagonistic to the inhibition of DNA synthesis by ara-ATP.

Adult↗
PubMed1982

Correlation of cytotoxicity with total intracellular exposure to 9-beta-D-arabinofuranosyladenine 5'-triphosphate.

The mechanism by which 9-beta-D-arabinofuranosyladenine produces cell death has been studied extensively, but the details remain controversial. The results presented here describe an evaluation of 9-beta-D-arabinofuranosyladenine-induced cytotoxicity in terms of the product of the total amount of the active 5'-triphosphate metabolite, 9-beta-D-arabinofuranosyladenine 5'-triphosphate (ara-ATP), which accumulated in the cells, and the duration of the exposure expressed in units of ara-ATP microM-hr. It was demonstrated that a strong correlation exists between these parameters which was not affected by the rate of accumulation of ara-ATP. In addition, inhibition of 9-beta-D-arabinofuranosyladenine deamination by 2'-deoxycoformycin did not alter the relationship between cell death and total intracellular exposure to ara-ATP. The consistency of this relationship both within and between experiments indicates that the quantitation of the total cellular exposure to ara-ATP is useful in predicting cytotoxicity.

Animals↗
PubMed1982

Metabolism and therapeutic efficacy of 9-beta-D-arabinofuranosyl-2-fluoroadenine against murine leukemia P388.

The biochemical basis for the differential therapeutic activity of equally toxic doses of 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) administered on two schedules to tumor-bearing mice has been studied. A single dose (234 mg/kg) of F-ara-A in solution decreased the number of P388 leukemia cells by greater than 10(3), whereas a multiple-dose regimen (41 mg/kg every day for 5 days) of equal toxicity to the host was ineffective at reducing the tumor burden. No antitumor activity was seen when an equal dose of the relatively insoluble F-ara-A was injected as a suspension. The 5'-triphosphate of F-ara-A accumulated in P388 cells in levels proportional to the dose of the nucleoside and disappeared from these cells at an exponential rate with a half-life of 2.9 hr, which was independent of the cellular concentration of the nucleotide. The extent and duration of the inhibition of DNA synthesis of P388 cells was dependent on the dose of F-ara-A, but the rates of recovery were similar and in proportion to the cellular concentration of the analog triphosphate. The extent of the inhibition of DNA synthesis in host bone marrow and intestinal mucosa was also related to the dose of F-ara-A, but the recovery of these tissues proceeded to similar, incomplete levels (less than 60% of initial) 24 hr after F-ara-A injection of either 41 or 234 mg/kg. These results suggest that the equal toxicity of the two regimens of F-ara-A may be attributed to the similar extent of inhibition of host-tissue DNA synthesis evoked by each. In contrast, the greater extent and longer duration of inhibition of P388 cell DNA synthesis caused by the single dose of F-ara-A was responsible for its superior therapeutic activity. Measurements of F-ara-A triphosphate concentrations and the DNA-synthetic capacity of tumor and host tissues are determinants of the action of F-ara-A and may be used to predict optimal therapeutic dose schedules.

Animals↗
PubMed1980

Quantitation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate in the leukemic cells from bone marrow and peripheral blood of patients receiving 1-beta-D-arabinofuranosylcytosine therapy.

A method for the detection and quantitation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP), the active metabolite cells and leukemic cells of the peripheral blood from patients receiving ara-C therapy is described. ara-CTP is separated from normal cellular nucleotides by high-pressure liquid chromatography and is quantitated by its absorbance of ultraviolet light at 280 nm with a lower limit of sensitivity of 25 pmol/2 x 10(7) cell equivalents. During separate courses of continuous infusion of different therapeutic doses of ara-C, ara-CTP accumulated in the leukemic bone marrow cells of a patient with acute myelogenous leukemia in proportion to the dose of ara-C. Continuous infusion of ara-C (90 mg/sq m/day) resulted in plateau levels of ara-CPT in peripheral blast cells after 24 hr (115 pmol/1 x 10(7) cell equivalents). A priming dose of ara-C(125 to 250 mg/sq m) followed by a 1-hr infusion of an equal dose of ara-C to patients with acute myelogenous leukemia facilitated the determination of ara-CTP retention in bone marrow and peripheral blood leukemic cells in vivo. This procedure should be useful for extended studies of the biochemical pharmacology of ara-CTP in vivo.

Arabinofuranosylcytosine Triphosphate↗