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Biomedical subjects

M D Walker

Publications and source records attributed to M D Walker.

At least 109 records · Page 6Linked to original sources
PubMed1977

DNA damage and repair in L1210 cells exposed to 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea.

The DNA of L1210 cells exposed to low concentrations of 1-(2-chloroethyl)=3-cyclohexyl-1-nitrosourea has been analyzed for the presence of single-strand breaks. DNA from 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea-treated cells both sediments more slowly than control DNA on alkaline sucrose gradients andshows a greater extent of strand separation of the DNA helix in alkali. These effects are a typical result of exposure of cellular DNA to alkylating agents or ionizing radiation. The extent of DNA damage caused by 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea has been related to the same amount of damage resulting from exposure of cells to low doses of gamma-irradiation. The rate and extent of repair of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea-induced damage is slow and incomplete, compared with the repair of gamma-irradiation damage to DNA. It is concluded that 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea behaves as a weak alkylating agent, a property that may explain its antitumor properties.

Animals↗
PubMed1976

A phase II study of intravenously- administered methyl CCNU in the treatment of advanced sarcomas.

Thirty-two patients with advanced, inoperable nonhematologic soft-tissue and osseous sarcomas were treated with Methyl CCNU administered via controlled intravenous infusion in doses of 130-170 mg/m2 every 6 weeks in a Phase II trial. All 28 evaluable patients were no longer responsive to adriamycin. Greater than 50% tumor regression was seen in one of two patients with chondrosarcoma and one of five patients with rhabdomyosarcoma. Less than 50% tumor regression occurred in one of five patients with rhabdomyosarcoma, one of two patients with malignant giant cell tumor, and one of three patients with malignant fibrous histiocytoma. Stabilization of previously advancing disease occurred in two of seven patients with leiomyosarcoma. The drug preparation was well tolerated. Nausea and vomiting occurring in three of 32 patients. Major toxicity was myelosuppression, characterized chiefly by thrombocytopenia with lesser degrees of leukopenia. This drug preparation appears to have activity in this group of tumors.

Clinical Trials as Topic↗
PubMed1976

Intrathecal N, N', N"-triethylenethiophosphoramide [thio-TEPA (NSC 6396)] in the treatment of malignant meningeal disease: phase I-II study.

N, N', N"-Triethylenethiophosphoramide [Thio-TEPA (NSC 6396)] is the third drug to be evaluated for the treatment of meningeal neoplasia. Eleven patients with meningeal leukemia, lymphoma, or ependymoma were treated with intrathecal thio-TEPA in doses from 1 to 10 mg/m2 of body surface area. There was no hematologic toxicity definitely attributable to thio-TEPA, and neurologic toxcity was limited to mild transient paresthesias of the lower extremities during lumbar sac injection in three patients. Two of those experiencing such paresthesias received concentrated drug solutions to decrease the large injected volumes associated with the higher dosages of thio-TEPA. Three patients achieved complete meningeal remission, and five others had a partial response to therapy.

Adolescent↗
PubMed1976

Methotrexate pneumonitis induced by intrathecal methotrexate therapy: a case report with pharmacokinetic data.

A patient with adenocarcinoma of the breast metastatic to the leptomeninges was treated with 10 doses of intrathecal methotrexate (MTX) administered at intervals of 2 days. Following these treatments she developed fever, hypoxemia, and bilateral pulmonary infiltrates without documented pulmonary infection. Autopsy findings were consistent with the pneumonitis that has been associated with intermittent oral, intramuscular, and intravenous MTX therapy. It is suggested that this patient's pulmonary process represented MTX pneumonitis following intrathecal MTX. Cerebrospinal fluid and serum MTX concentrations determined retrospectively on frozen samples reflect an atypically rapid transport of MTX from this patient's cerebrospinal fluid to a slowly decaying systemic pool. Because of this, serum MTX levels probably exceeded 10-8M during the entire 20-day course of therapy, thus exposing the pulmonary parenchyma to significant drug concentrations for a prolonged interval. It is suggested that these unfavorable pharmacokinetics may have contributed to this patient's susceptibility to MTX pneumonitis.

Adenocarcinoma↗
PubMed1976

Evaluation of mithramycin in the treatment of anaplastic gliomas.

A controlled, prospective, randomized study evaluated the use of mithramycin in the treatment of anaplastic glioma compared to a similar group of patients receiving best conventional care. From a total of 116 patients in the study, 96 were within the valid study group. All patients were operated on, had histological confirmation of anaplastic glioma, and received radiotherapy at the discretion of the principal investigator. Fifty-two patients received mithramycin at a dose of 25 mug/kg/day for 21 days, while 44 patients were in the control group. There was no significant difference in the median survival from time of randomization in those receiving mithramycin (21 weeks) as compared to those not receiving mithramycin (26 weeks). There was no significant difference between the two groups in relation to age distribution, sex, location, diagnosis, tumor characteristics, signs or symptoms, or radiotherapy received. Duration of symptoms correlates positively with survival and was also significantly longer in the control group than in the treated group. This, however, did not account for the failure of mithramycin to be found an effective agent. Although the study was not designed to evaluate the efficacy of radiotherapy, patients who were so treated had a significant improvement in survival. The toxic complications of mithramycin included gastrointestinal symptoms, dermatological involvement, anemia, and liver dysfunction, indicating the need for close supervision.

Adult↗
PubMed1976

Acute nonlymphocytic leukemia associated with nitrosourea chemotherapy: report of two cases.

Acute nonlymphocytic leukemia developed in two patients who were treated postoperatively with cytotoxic chemotherapy. Both patients survived more than 4 years after the diagnosis of brain tumor, and both had extended periods of myelosuppression secondary to nitrosourea chemotherapy. Nitrosourea therapy may have facilitated the development of acute leukemia in these patients.

Autopsy↗
PubMed1976

Neuropharmacological effects of methotrexate perfused through the cerebrospinal fluid system of the rhesus monkey.

Thirteen adult Rhesus monkeys were repeatedly perfused through the ventriculocisternal or ventriculolumbar spaces with Elliott's B solution containing various concentrations of methotrexate (MTX) and trace amounts of [3H]MTX and [carboxy-14C]inulin. The concentrations of MTX ranged from 4.8 to 0.15 mg/ml representing perfusion dosages of 551 mg/sq m to 16 mg/sq m. The average steady-state concentration out-concentration in (Co/Ci) value for MTX was 0.78 +/- 0.04 for the ventriculocisternal and 0.66 +/- 0.01 for the ventriculolumbar routes. MTX treatments did not significantly affect mean inulin steady-state Co/Ci values or CSF formation rate. With the exception of a monkey perfused with MTX at an inflow concentration of 4.8 mg/ml, body weight, food intake, and urine output, analyzed at weekly intervals, generally were not remarkably affected by MTX perfusions. In five monkeys perfused with MTX in concentrations of 4.8 to 0.6 mg/ml, gross neurological toxicity was observed, principally in the form of seizures and hypokinesia during perfusion series with occasional residual motor deficit. Significant cerebral damage was associated with the brains of two monkeys perfused with MTX at concentrations of 2.4 and 0.6 mg/ml and two monkeys perfused at concentrations of 1.2 and 0.3 mg/ml; there of the four animals displayed signs of gross neurotoxicity, and two animals developed permanent motor deficits. However, the extent to which neurotoxic signs could be attributed solely to MTX was difficult to judge because some changes in central nervous system morphology were associated with the mechanical aspects of the procedure. Overall behavioral performance as measured by a visual pattern discrimination reinforced by avoidance or escape from an electric shock was not significantly affected by repeated perfusions of MTX (0.6 mg/ml) in two monkeys not otherwise studied in detail.

Animals↗
PubMed1975

The chemical principles of chronotherapy as established from an in vitro model of circadian concentration rhythms.

A model reaction for investigating the effects of chemical parameters on circadian rhythms is suggested. Its main advantage is that oscillations occur on a minute scale rather than daily and so accelerate studies. Some factors were found to increase the period of amplitude of the oscillations, others decreased them. The chemical principles prevailing during such oscillations are itemized. The effects of adding poisons or drugs are also noted and a computer calculation has been used to show that desferrioxamine B treatment for serum iron removal could be 65 percent more effective if administered at the correct point in the circadian cycle.

Circadian Rhythm↗
PubMed1975

Separation of "estrogen-induced" protein from phosphoprotein phosphatase activity of immature rat uterus.

Preparations of the "induced protein" which appears in the rat uterus within 40 min of estradiol administration have recently been reported to contain phosphoprotein phosphatase (phosphoprotein phosphohydrolase, EC 3.1.3.16) activity. We found that these two proteins distribute differently on ammonium sulfate fractionation of uterine cytosol. Preparative cellulose acetate electrophoresis afforded complete (greater than 99.9%) separation of phosphoprotein phosphatase activity from the induced protein. The specific activity of phosphoprotein phosphatase in uterine cytosol was unchanged 1, 4, 12, or 24 hr after estradiol administration. These results are incompatible with the view that the induced protein mediates estrogen action by virtue of an inherent phosphoprotein phosphatase activity.

Animals↗
PubMed1975

Fat emulsion vehicle for intravenous administration of an aqueous insoluble drug.

Formulation of a sterile preparation for the parenteral administration of a water insoluble drug is described. Methyl CCNU was first dissolved in absolute alcohol and slowly added to a fat emulsion, Intralipid. The preparation was found to be stable for eight hours at room temperature and seven days under refrigeration. After administration of the preparation to approximately 100 patients, no significant side effects were attributed to the fat emulsion.

Drug Stability↗