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Biomedical subjects

C N Coleman

Publications and source records attributed to C N Coleman.

162 records · Page 9Linked to original sources
PubMed1977

Hematologic neoplasia in patients treated for Hodgkin's disease.

We studied 680 patients with Hodgkin's disease, treated at Stanford University Medical Center from July 1, 1968, through December 31, 1975, to determine the risk of development of hematologic neoplasia. Six cases of leukemia occurred in patients in clinical remission, one 7 1/2 years after diagnosis. Two additional cases occurred in patients with active Hodgkin's disease. No cases were seen in 320 patients treated with radiotherapy alone or in 30 treated with chemotherapy alone. A single case of subacute leukemia occurred in a patient treated initially with radiation therapy and colloidal gold. The actuarial probability of development of leukemia at five and seven years is 1.5 and 2.0 per cent for the entire group and 2.9 and 3.9 per cent for the 330 patients treated with combined radiation and chemotherapy. The medium survival after diagnosis is four months, with no patient living beyond six months.

Adult↗
PubMed1975

Deoxycytidine kinase: properties of the enzyme from human leukemic granulocytes.

Deoxycytidine kinase, which phosphorylates deoxycytidine (CdR) and its analog, cytosine arabinoside (ara-C), has been purified 71-fold from human leukemic cells. Biochemical properties of the partially purified enzyme included a molecular weight of 68,000, Kms of 7.8 muM for CdR and 25.6 muM for ara-C, and optimal activity with ATP and GTP as phosphate donors. Ara-C phosphorylation was strongly inhibited by CdR (Ki = 0.17 muM) and dCTP (Ki = 7.3 muM) and was weakly inhibited by ara-CTP (Ki = 0.13 mM). Purification by calcium phosphate gel elution and DEAE chromatography effectively separated this enzyme from cytidine deaminase, which deaminates both CdR and ara-C, and from uridine-cytidine kinase, the enzyme which phosphorylates 5-azacytidine. CdR kinase activity was found to decrease and cytidine deaminase to increase with maturation of normal and leukemic granulocytes. Myeloblasts purified by Ficoll sedimentation revealed an average kinase activity of 15.4 U/mg protein in acute myelocytic leukemia and 12.3 U/mg protein in blastic crisis of chronic myelocytic leukemia (CML). The average ratio of CdR kinase to deaminase activity in crude cell extracts varied from 0.197 in AML and 0.089 in blastic crisis to 0.0004 in normal granulocytes, reflecting the changes which take place with cellular maturation. The absolute levels of kinase and deaminase and the ratio of these two enzymes varied considerably among patients with AML, indicating that quantitative differences may be found in the metabolism of CdR and its analogs in leukemic cells.

Azacitidine↗
PubMed1974

Purification and properties of cytidine deaminase from normal and leukemic granulocytes.

Cytidine deaminase, an enzyme that catalyses the deamination of both cytidine and its nucleoside analogues including the antineoplastic agents cytosine arabinoside (ara-C) and 5-azacytidine (5-azaC), has been partially purified from normal and leukemic human granulocytes. The purification procedure included heat precipitation at 70 degrees C, ammonium sulfate precipitation, calcium phosphate gel ion exchange, and Sephadex G-150 gel filtration. The enzyme has mol wt 51,000, isoelectric pH of 4.8, and maximum activity over a broad pH range of 5-9.5. The enzyme is stabilized by the presence of the sulfhydryl reagent, dithiothreitol. Cytidine deaminase from normal human granulocytes has a greater affinity for its physiologic substrate cytidine (K(m) = 1.1 x 10(-5) M) than for ara-C (8.8 x 10(-5) M) or 5-azaC (4.3 x 10(-4) M). Halogenated analogues such as 5-fluorocytidine and 5-bromo-2'-deoxycytidine also exhibited substrate activity, with maximum velocities greater than that of the physiologic substrates cytidine and deoxycytidine. No activity was observed with nucleotides or deoxynucleotides. The relative maximum velocity of the enzyme for cytidine and its nucleoside analogues remained constant during purification, indicating that a single enzyme was responsible for deamination of these substrates. Tetrahydrouridine (THU) was found to be a strong competitive inhibitor of partially purified deaminase with a K(i) of 5.4 x 10(-8) M. The biochemical properties of partially purified preparations of cytidine deaminase from normal and leukemic cells were compared with respect to isoelectric pH, molecular weight, and substrate and inhibitor kinetic parameters, and no differences were observed. However, normal circulating granulocytes contained a significantly greater concentration of cytidine deaminase (3.52+/-1.86 x 10(3)/mg protein) than chronic myelocytic leukemia (CML) cells (1.40+/-0.70 x 10(3) U/mg protein) or acute myelocytic leukemia (AML) cells (0.19+/-0.17 x 10(3) U/mg protein). To explain these differences in enzyme levels in leukemic versus normal cells, the changes in cytidine deaminase levels associated with maturation of normal granulocytes were studied in normal human bone marrow. Myeloid precursors obtained from bone marrow aspirates were separated into mature and immature fractions by Ficoll density centrifugation. Deaminase activity in lysates of mature granulocytes was 3.55-14.2 times greater than the activity found in the lysates of immature cells. Decreased enzyme activity was also found in immature myeloid cells from a patient with CML as compared to mature granulocytes from the same patient. These observations support the conclusion that the greater specific activity of cytidine deaminase in normal mature granulocytes as compared to leukemic cells is related to the process of granulocyte maturation rather than a specific enzymatic defect in leukemic cells.

Adolescent↗
PubMedDate not supplied

Initial pharmacology and toxicology of intravenous desmethylmisonidazole.

Since January 1981, 52 patients have entered the Radiation Therapy Oncology Group Phase I trial with intravenous (i.v.) desmethylmisonidazole (DMM). DMM is less lipophilic than misonidazole (MISO) and theoretically will be less neurotoxic due to lower penetration into neural tissue and more rapid elimination. The drug is administered intravenously to achieve the maximum drug concentration in tumor for a given dose. The protocol slowly escalates the total dose of drug administered. At this time the planned dose on the three week schedule is 1g/m2 five times per week to a total of 15g/m2, and on the seven week schedule is 1.25g/m2 twice weekly to a total dose of 17.5g/m2. The preliminary plasma pharmacokinetic data demonstrates high peak plasma levels within five minutes of the end of the drug infusion. Compared to MISO the percent of DMM excreted in the urine is increased, 63% vs 10%, and the elimination half-life is decreased: DMM, i.v. 5.3h; MISO, i.v. 9.3h; MISO, oral 10 to 13h. Neurotoxicity has been observed in approximately 30% of patients given a cumulative dose of greater than 11g/m2. This is in comparison to a 50% incidence in the RTOG Phase I study with oral MISO at doses of 12g/m2. There is not sufficient data to evaluate the relationship between neurotoxicity and drug exposure. Further patient accrual on this study is required to better define the properties of DMM.

Adult↗
PubMedDate not supplied

The development of an oral prodrug, SR-2545, of the 2-nitroimidazole radiosensitizer SR-2508.

SR-2508, a 2-nitroimidazole radiosensitizer, is expected to be clinically superior to desmethylmisonidazole or misonidazole because of its lower lipophilicity with subsequent lower drug levels in neural tissue and more rapid plasma elimination. The intravenous route of administration will be optimal but oral drugs may be necessary. Since decreased lipophilicity will decrease oral absorption we have synthesized, and tested in mice, SR-2545, an acetate ester prodrug of SR-2508. In the liver there is complete first pass metabolism to parent drug with no prodrug detectable in the blood. Compared to an equal dose of oral SR-2508, the prodrug yields a more rapid, reproducible, plasma peak with twice the bioavailability, peak plasma concentration and radiosensitization. If oral preparations of SR-2508 are to be used in the clinic the prodrug, SR-2545, is likely to be superior to oral SR-2508.

Administration, Oral↗
PubMedDate not supplied

Developmental effects of intermittent prenatal exposure to 1,1,1-trichloroethane in the rat.

The effects of daily three 1-h exposures to 7000 ppm 1,1,1-trichloroethane (TCE) on physical and behavioral development were examined in Sprague-Dawley rats exposed during the last week of gestation. A sham group was exposed to filtered air. Offspring of both groups were fostered to untreated dams. No significant group differences were detected in total maternal weight gain or food and water consumption, but differences were observed in initial litter characteristics, including a longer gestation period in the TCE group, a smaller number of litters delivered in the TCE group, and fewer live pups per litter in the TCE group. At birth, the total litter weight was less in the TCE group, but there was no significant difference in average pup weight. Pups prenatally exposed to TCE did not differ from shams in day of eye opening, pinnae detachment, or incisor eruption. The TCE group weighed less the first 2 weeks of life, was impaired in its ability to perform the inverted screen, negative geotaxis, and vertical screen tests, and had less forelimb grip strength. Locomotor activity was reduced in the TCE group, and the ratio of brain to body weight was reduced in TCE-exposed offspring. These data provide evidence for neurobehavioral teratogenicity of intermittent prenatal exposure to high concentrations of TCE in rats.

Animals↗
PubMedDate not supplied

Rationale for use of local hyperthermia with radiation therapy and selected anticancer drugs in locally advanced human malignancies.

The addition of local hyperthermia to radiation therapy has significantly improved the ability of oncologists to control superficial malignancies. Large tumours, tumours which cannot be heated adequately, and those situated in areas where surrounding normal tissues have decreased radiation tolerance, however, are difficult to eradicate even with this combination treatment. We believe that properly selected and scheduled anticancer drugs will add substantially to the efficacy of local hyperthermia and radiation. A review of the literature concerning the cytotoxic interactions of various anticancer agents with hyperthermia, with radiation and with relevant physiological parameters is presented. From this review, anticancer drugs which are good candidates for trimodality therapy are identified and a general approach to trimodality scheduling is suggested.

Animals↗
PubMedDate not supplied

Pilot study of local hyperthermia, radiation therapy, etanidazole, and cisplatin for advanced superficial tumours.

Five patients (six hyperthermia sites) with advanced superficial tumours were treated with combined etanidazole, cisplatin, local hyperthermia, and radiation therapy as part of a Phase I pilot study. Treatment was given once weekly and consisted of etanidazole 3 gm/m2 IV bolus, cisplatin 50 mg/m2 IV bolus, hyperthermia for 60 min with a target temperature of 43 degrees C, and radiation therapy 500 cGy/fraction (median total dose 3000 cGy) for a total of six weeks. Blood levels of etanidazole were taken during treatment at week 1 and week 4. Etanidazole drug exposure was calculated using the trapezoidal rule and expressed as the area under the curve (AUC) of plasma concentration x time. Five of six treatment sites had received prior irradiation. Prior chemotherapy had been given in three patients and tamoxifen therapy given in the other two patients. The median follow-up time is 34 months; 3/5 patients have died of disease. The most significant toxicity was grade I or II nausea and vomiting associated with 19/32 treatments (59%) and a second degree burn in 2/6 fields. None of the five patients experienced peripheral neuropathy, skin ulceration, or needed surgical repair. In addition, there was mild renal toxicity; pharmacokinetic analysis showed a 28-75% increase in the week 1 to week 4 AUC in three patients, all of whom had a decrease in creatinine clearance over the same time of 15-47%. This pilot study suggests this combined modality therapy can be delivered without major complications and that renal function, determined by creatinine clearance, affects clearance of etanidazole and alters the AUC. Therefore, monitoring renal function is important in patients receiving etanidazole in addition to other nephrotoxic agents such as cisplatin. The impact of etanidazole on the therapeutic index of hyperthermia, radiation therapy and cisplatin may be worth of study, especially since a positive interaction between these modalities is found in laboratory models.

Adult↗
PubMedDate not supplied

A prospective study of hprt mutant and mutation frequencies in treated cancer patients.

We previously reported that some Hodgkin's disease patients had elevated hprt mutant frequencies in peripheral blood lymphocytes long after cessation of therapy. To determine if these elevations in mutant frequency represent true persistently elevated mutation frequencies, we recruited for a prospective study six previously treated Hodgkin's disease patients and five patients who had been treated for squamous cell carcinoma of the head and neck. These individuals were studied several times over a 6-7-month period. The results confirmed that a subset of patients have persistently high mutant frequencies when compared to 71 previously studied controls. The present study was designed to determine if the elevated mutant frequencies of treated patients represented independent mutations or resulted from the in vivo expansion of single mutant cells. We used the polymerase chain reaction to examine DNA single-strand conformation polymorphisms at the T-cell receptor gamma locus of individual mutant clones. This analysis showed that at any given time 20.1% of the mutants from Hodgkin's disease patients and 17.5% of the mutants from squamous cell carcinoma patients consisted of siblings, identified as having identical polymerase chain reaction/single-stranded conformation polymorphism patterns. The remaining mutants had unique polymerase chain reaction/single-stranded conformation polymorphism patterns and therefore can be presumed to have arisen from independent mutational events. Particular sibling mutants generally did not persist over time. However, one patient had one mutant clone which persisted but slowly decreased in prevalence over a 7-month sampling period. The data demonstrate that treatments for cancer result in persistently elevated mutation frequencies at the hprt locus in some, but not all, patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Alpha omega alpha election and medical school thesis publication: relationship to subsequent publication rate over a twenty-year period.

To determine the importance of academic and research success during medical school upon subsequent academic activity, a computerized literature search was performed using the names of the 79 surviving members of the Yale Medical School Class of 1970. Individuals elected to Alpha Omega Alpha (AOA) during the third year of school had significantly more publications (mean 101.7 +/- 69.6) between 1970 and 1990 than those elected during the fourth year (mean 28.3 +/- 48.0, p = 0.01). Both had significantly more publications than non-AOA members (mean 11.1 +/- 19.4, p = 0.02). Publication of the student's medical school thesis was also associated with a greater number of publications than thesis non-publication (mean 22.1 +/- 37.5 vs 14.4 +/- 30.0, p = 0.005). These studies demonstrate that, at least at the institution studied, election to AOA and publication of the results of a research project were associated with increased publication rates in the medical field over the 20-year period following medical school graduation.

Academic Dissertations as Topic↗
PubMedDate not supplied

Long-term survival in Hodgkin's disease relative impact of mortality, second tumors, infection, and cardiovascular disease.

PURPOSE: Despite dramatic improvements in the survival of patients with Hodgkin's disease attributable to advances in treatment over the past 30 years, concern for the risk of treatment-related deaths has led to a number of trials to evaluate reduction of therapy. The consequences of these trials on recurrence, development of long-term complications, and survival remain unknown. We determined the causes of death in a group of patients with pathologically staged and intensively treated Hodgkin's disease who were followed for long intervals. MATERIALS AND METHODS: Between April 1969 and December 1988, 794 patients with laparotomy-staged IA to IIIB Hodgkin's disease were treated with radiation therapy alone or combined radiation therapy and chemotherapy. There were 8700 person-years of follow-up (average, 10.95 person-years/ patient). Causes of mortality were grouped into the categories Hodgkin's disease, second malignant tumors, cardiovascular, infection, and miscellaneous. Age- and gender-specific incidence rates were multiplied by corresponding person-years of observation to obtain expected numbers of events. Observed-to-expected results were calculated by type of treatment, age at treatment, sex, and time after Hodgkin's disease. Absolute (excess) risk was expressed as number of excess cases per 10,000 person-years. RESULTS: Of 124 patients who died, 56 died of Hodgkin's disease, 36 of second malignant neoplasms, 15 of cardiac causes, 9 of infection, and 8 of miscellaneous causes. The 20-year actuarial survival rate for all patients in this study is 73%. Age 40 years or older, mixed cellularity/lymphocyte-depleted histologic type, and stage-III disease were adverse independent predictors of survival. The largest differences were seen by age. The 20-year actuarial rates of survival were 78%, 78%, and 46%, respectively, for patients aged 16 or less, 17 to 39, and 40 years or older at diagnosis. Hodgkin's disease diagnosed at age 40 or older was a significant risk factor for all causes of death. The use of combined chemotherapy/ radiotherapy was a significant risk factor for second tumor and infection-related mortality. The excess risk of death from all causes, including Hodgkin's disease, remained constant with time from treatment and was approximately 1.2% per year over the first 20 years. Deaths from Hodgkin's disease decreased with time from treatment, with no patients dying after 15 years. This decrease, combined with an increased excess mortality risk with time from other causes, especially second tumors, accounted for the constant excess mortality with time after Hodgkin's disease. CONCLUSIONS: Hodgkin's disease followed by second tumors, cardiac events, and infections remain the major causes of death after treatment of Hodgkin's disease. Our findings suggest the importance of both maintaining a high disease-free survival and reducing long-term complications in designing treatments of Hodgkin's disease.

Adolescent↗