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Biomedical subjects

B A Chabner

Publications and source records attributed to B A Chabner.

At least 19 recordsLinked to original sources
PubMed1979

Isolation and identification of a small molecular weight inhibitor of cyclic nucleotide phosphodiesterase from bovine brain.

In a search for endogenous regulators for cyclic nucleotide phosphodiesterase (3':5'-cyclic-AMP 5'-nucleotidohydrolase, EC 3.1.4.17), we found that the ultrafiltrate of bovine brain homogenate contained a cyclic nucleotide phosphodiesterase inhibitor. The inhibitor-containing fraction was further purified by ion-exchange column chromatography and gel filtration chromatography. The purified inhibitor was found to be a small molecular weight compound which had a maximum absorption at 248 nm. This compound was identified by thin-layer chromatography and high-pressure liquid chromatography as hypoxanthine. We suggest that hypoxanthine may serve as an endogenous regulator for the hydrolysis of cyclic nucleotide by cyclic nucleotide phosphodiesterase.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1979

Presence of 2,4-diamino-N10-methylpteroic acid after high-dose methotrexate.

Assay of plasma methotrexate has been established as important to its safe use. We have investigated the specificity of 2 assay procedures for methotrexate: the competitive dihydrofolate reductase binding assay (CRBA) and the radioimmunoassay (RIA). The RIA of plasma methotrexate resulted in consistently higher values than the CRBA, with greater differences at later measurement times. A compound that strongly cross-reacts in the RIA, but not the CRBA, has been identified in plasma and urine of patients on high-dose methotrexate therapy, and appears to be the carboxypeptidase cleavage product (2,4-diamino-N10-methylpteroic acid) on the basis of chromatographic and ultraviolet spectral properties. Although this compound is present as a minor contaminant in commercial methotrexate preparations, quantitative assessment of urinary excretion suggests that in man a major portion of the compound is derived from methotrexate metabolism.

Biological Assay↗
PubMed1979

Thirty-six-hour preoperative high-dose methotrexate infusion in patients with squamous carcinoma of the head and neck.

Twenty 36-hour infusions of high-dose methotrexate were given preoperatively to 10 patients with head and neck cancer. Plasma methotrexate levels of greater than 1 X 10(-5) M were maintained for 36 hours and declined with primary and secondary plasma half-lives of 1.7 and 9.2 hours following the end of the infusion. Toxicity of this infusion regimen was minimal (10% incidence of significant (WBC less than 2000/mm3) myelosuppression; no renal toxicity) and all patients underwent surgical resection within 3 weeks of therapy without obvious increase in operative complications. Four of ten patients responded to chemotherapy. Further comparison of the therapeutic efficacy of this prolonged preoperative infusion regimen with surgery alone or schedules employing conventional doses or 6-hour infusions of high-dose methotrexate appears warranted.

Aged↗
PubMed1979

The clinical features of hepatic angiosarcoma: a report of four cases and a review of the English literature.

Four cases of hepatic angiosarcoma are reported with a review of 99 other cases in the English literature. Angiosarcoma of the liver is associated with chronic exposure to thorotrast, vinyl chloride, arsenicals, radium and possibly copper and with chronic idiopathic hemochromatosis. Although 40% of patients have hepatic fibrosis or cirrhosis at autopsy, the nature of the association between chronic liver disease and hepatic angiosarcoma is unknown. The clinical presentation of hepatic angiosarcoma is nonspecific with abdominal pain, weakness and weight loss common complaints and with hepatomegaly, ascites and jaundice common findings. Liver function tests are usually abnormal but there is no one liver function test or set of tests specific for the tumor. The occurrence of thrombocytopenia and disseminated intravascular coagulation is characteristic of hepatic angiosarcoma and may be related to local consumption of clotting factors and formed blood elements in the tumor. Catastrophic intraabdominal bleeding is also characteristic and occurs in one-fourth of all cases. This complication is likely related to the high incidence of clotting abnormalities and the vascular nature of the neoplasm. Selective hepatic arteriogram and open liver biopsy are the foundations of diagnostic evaluation. Percutaneous liver biopsy should be avoided. Failure to appreciate the possibility of hepatic angiosarcoma in the proper clinical setting, leading to blind percutaneous biopsy, may result in failure to make the diagnosis at the cost of significant morbidity and mortality. Survival of patients with hepatic angiosarcoma is brief; only 3% live longer than 2 years. Treatment of the tumor to date is empirical. There are probably a few patients who might benefit from radical surgery with curative intent. For all others chemotherapy is indicated. Adriamycin is active against hepatic angiosarcoma, but optimal dose and mode of administration require further investigation. Further study is also required to delineate the cause of hepatic angiosarcoma in the 60% of cases without definite epidemiologic association.

Adult↗
PubMed1979

Potential clinical applications of a new method for quantitation of plasma levels of 5-fluorouracil and 5-fluorodeoxyuridine.

A new high-pressure liquid chromatographic method for the clinical assay of 5-fluorouracil and 5-fluoroudexyuridine has been developed. The sensitivity and specificity of the method equals that of gas chromatography/mass spectrometric methods. The practical value of the method has been demonstrated by its application in several preliminary clinical studies of 5-fluorouracil in which plasma levels of 10(-8)-10(-6)M were readily monitored.

Chromatography, High Pressure Liquid↗
PubMed1979

Phase I trial of N-(phosphonacetyl)-L-aspartate.

A Phase I clinical trial of N-(phosphonacetyl)-L-aspartate, an antimetabolite which inhibits a key enzyme in the de novo pathway of pyrimidine biosynthesis, was conducted. N-(Phosphonacetyl)-L-aspartate was given as an i.v. 15-min infusion once daily for five days; cycles of treatment were repeated every three weeks. Thirty-four patients received treatment. Dose-limiting toxicity was observed at 1500 to 2000 mg/sq m/day and was manifested by skin rash, diarrhea, and stomatitis. Rash and diarrhea usually began during the first week of treatment and persisted up to Day 17 of a cycle of therapy. No consistent hematopoietic, hepatic, or renal toxicity was observed. One partial response in a patient with colon carcinoma was seen and continues at more than eight months. Stable disease was observed in three patients with colon carcinoma, two patients with hypernephroma, one patient with pancreatic carcinoma, and one patient with melanoma. The predictability and reversibility of toxicity and the suggestion of antitumor activity in humans are observations which support the further evaluation of N-(phosphonacetyl)-L-aspartate in Phase II studies.

Adolescent↗
PubMed1979

Treatment of osteogenic sarcoma. I. Effect of adjuvant high-dose methotrexate after amputation.

Thirty-nine patients with extremity osteogenic sarcoma and no discernible metastases were treated with amputation and postoperative adjuvant high-dose methotrexate with leucovorin rescue. One half of the patients were also randomized to receive bacillus Calmette-Guérin by a multiple-puncture technique. Results have been analyzed with a minimum followup of 10 months and a median followup of 27 months. Actuarial analysis estimates that 38% of current protocol patients remain continuously free of disease for 24 months compared to only 17.4% of historical control patients (P = 0.029; one-sided generalized Kruskal-Wallis test). Bacillus Calmette-Guérin administered by a multiple-puncture technique had no effect on disease-free interval. Minor differences between current protocol and historical control patients with regard to race, age, histologic type, and site and size of primary tumors do not affect the difference in disease-free interval between these two patient groups. However, current patients had somewhat lower grade lesions and consideration of the patients with grade III and IV lesions only, lessens the difference between current and historical control patients (P = 0.11; one-sided generalized Kruskal-Wallis test). High-dose methotrexate was administered with virtually no morbidity and no deaths. The small differences observed in this study between protocol patients treated with surgery plus high-dose methotrexate and historical control patients treated with surgery alone point to the need for a prospective randomized study to establish the role of high-dose methotrexate in the adjuvant treatment of patients with osteogenic sarcoma.

Adolescent↗
PubMed1979

Ara-C metabolism: implications for drug resistance and drug interactions.

Clinical studies of resistance to cytosine arabinoside have not produced agreement as to the specific biochemical lesions responsible for altered sensitivity, although experimental and clinical work supports the concept that a decreased ability to generate ara-CTP must be the ultimate effect of this lesion. 3-deazauridine, an inhibitor of CTP synthetase, was found to enhance ara-CTP production in murine tumor cells, and in the present study, was shown to inhibit deamination of ara-C at both the nucleoside and nucleotide level. Enhanced ara-CTP formation was observed in cells lacking cytidine deaminase (L1 210 and HL60), indicating that 3-deazauridine inhibition of deoxycytidylate deaminase may be important in this drug interaction.

3-Deazauridine↗
PubMed1979

Competitive binding radioassay for 5-fluorodeoxyuridine 5'-monophosphate in tissues.

A competitive binding radioassay has been developed for 5-fluorodeoxyuridine 5'-monophosphate, based on the tight binding of this potent inhibitor to thymidylate synthetase (EC 2.1.1.45). Unbound ligand may be separated from that bound to enzyme by precipitating the intact inhibitor-enzyme complex with trichloroacetic acid. Scatchard plot analysis using a two-site model for binding yielded apparent dissociation constants of 1.2 x 10(-11) and 1.7 x 10(-10) M from a least-squares computer fit of the data. 5-Fluorodeoxyuridine 5'-monophosphate could be detected in the range of 0.02 to 2.0 pmol with no apparent interference by other substances. Assay of 5-fluorodeoxyuridine 5'-monophosphate levels in L1210 ascites tumor following 5-fluorouracil in vivo revealed peak levels occurring within the first hr with a subsequent disappearance half-life of 3.9 hr. Close agreement was found between the previously described enzyme inhibition assay and the more rapid and sensitive competitive binding method.

Animals↗
PubMed1978

Advanced ovarian adenocarcinoma. A prospective clinical trial of melphalan (L-PAM) versus combination chemotherapy.

Eighty patients with advanced ovarian adenocarcinoma were treated in a prospective, randomized trial comparing a four-drug combination--hexamethylmelamine, cyclophosphamide, methotrexate and 5-fluorouracil--with the oral alkylating agent, melphalan. Treatment with the four-drug combination was associated with a significantly increased overall response rate (75 vs. 54 per cent) (P less than 0.05), more complete remissions (33 vs. 16 per cent) and longer median survival (29 vs. 17 months) (P less than 0.02) but more severe toxicity than occurred with melphalan. Patients with minimal residual disease had a significantly higher overall response rate than patients with extensive residual disease (84 vs. 53 per cent) (P less than 0.05). Patients with advanced disease who achieved a complete remission documented by peritoneoscopy or laparotomy (or both) have a median survival that will exceed three years. The four-drug regimen is more effective than melphalan in the management of advanced ovarian adenocarcinoma.

Adenocarcinoma↗
PubMed1978

Diffuse histiocytic lymphoma involving the gastrointestinal tract.

The results of staging and treatment of 18 patients with diffuse histiocytic lymphoma involving the gastrointestinal tract are summarized. Widespread disease (Stage IV) was found in the majority (72%) of patients after rigorous staging, indicating the relative rarity of localized gastrointestinal lymphoma and the resulting need for systemic therapy in most of these patients. Chemotherapy combined with surgical resection and/or radiation therapy produced complete remissions in only 5 of 18 patients (28%). Patients failed to achieve complete remission due to 1) tumor resistance to drug therapy (46% of treatment failures), and 2) massive intestinal hemorrhage or bowel perforation secondary to tumor necrosis (38% of treatment failures). These findings indicate the need for more active chemotherapeutic regimens and for measures aimed at preventing complications such as bowel perforation or hemorrhage, possibly by combining surgical resection of bowel lesions with systemic chemotherapy.

Adult↗
PubMed1978

Patterns of relapse in advanced Hodgkin's disease treated with combination chemotherapy.

One hundred sixty-one patients with advanced Hodgkin's disease achieved complete remission after combination chemotherapy. Of these, 52 (32%) have subsequently relapsed and the patterns of relapse have been studied. The probability of relapse increases with increasing stage and particularly with the presence of systemic symptoms. Patients with Nodular Sclerosis histology are more likely to relapse than those with other histologies. Patients relapse primarily (92%) in sites of previous disease and particularly in nodal sites (75%). Nodal sites most frequently involved at relapse are the central nodal areas and the left supraclavicular area. When patients relapse in new sites they tend to be either adjacent to sites of previous disease which relapse or to be contiguous with previously involved sites of disease. In the small number of patients who received prophylactic radiation therapy to sites of nodal disease after complete remission, the pattern of relapse was not significantly altered.

Adolescent↗