An in vitro assay system to measure the production of phosphorylated nucleotide products of 5-FU by human tumor cytosols is described. Samples from 11 patients with breast cancer treated with 5-FU-containing chemotherapy regimens were assayed. Significant differences were seen in quantitative and qualitative patterns of phosphorylation between samples from chemotherapy responding and nonresponding patients. Both the rate of 5-fluorodeoxyuridylate production and the amount of fluorinated nucleotide triphosphate produced were significantly increased (P less than 0.05) in patients responding to chemotherapy. The latter finding may be attributed to the demonstration of significantly higher nucleoside diphosphate kinase levels in the tumors of responding patients. Further study of this in vitro assay system as a potential system for prospectively predicting clinical response to fluorinated pyrimidines is indicated.

Breast Neoplasms↗

PubMed1980

Prediction of clinical response to 5-fluorouracil-containing chemotherapy: preliminary results of in vitro assay in human breast cancer.

An in vitro assay system measuring the production of phosphorylated nucleotide products of 5-FU by human tumor cytosols is described. Samples from 11 patients with breast cancer treated with 5-FU-containing chemotherapy regimens were assayed. Significant differences were seen in quantitative and qualitative patterns of phosphorylation between samples from chemotherapy responding and nonresponding patients. The rate of 5-fluorodeoxyuridylate production and the amount of nucleotide triphosphate produced were significantly P < 0.05 increased in chemotherapy-responding patients. This in vitro assay system is a simple, reproducible procedure that requires further evaluation as a potential system for prospectively predicting clinical response to fluorinated pyrimidines.

Breast Neoplasms↗

PubMed1980

Mechanisms of sensitivity and resistance of murine tumors to 5-fluorouracil.

The biochemical basis for the resistance of murine leukemia P388 to 5-fluorouracil (FUra) was systematically investigated by examining the transport and metabolism of FUra, or its anabolites, as well as the inhibition of enzymes and processes known to be affected by the drug. Of these parameters, only three were found to be altered significantly in the resistant line: (a) the enzyme required for the phosphorylation of uridine 5'-monophosphate to uridine 5'-diphosphate was present at a significantly lower specific activity in the resistant line than in its sensitive counterpart; (b) the rates of generation and persistance of 5-fluoro-2'-deoxyuridine 5'-monophosphate were significantly lower and shorter in the variant; and (c) there was a 1.6- and 3-fold decrease in the incorporation of FUra into polyadenylic acid-containing RNA and polyadenylic acid-lacking RNA, respectively, in resistant versus sensitive cells. Taken together, these findings suggest a dual mechanism for resistance to FUra in these leukemic cells, namely, a depressed capacity to generate di- and triphosphates of the riboside and deoxyriboside of the drug leading to lower pools of the proximate antimetabolite, fluorouridine 5'-triphosphate, and accelerated excretion of 5-fluoro-2'-deoxyuridine 5'-monophosphate, so that thymidylate synthetase is perturbed in a less than lethal way.

Alkaline Phosphatase↗

PubMed1978

Phase I studies on chlorozotocin.

A phase I investigation of chlorozotocin, a new-water soluble chloroethylnitrosourea, was undertaken to define its pharmacologic effects in man. Forty-three patients received single intravenous doses ranging from 5 to 175 mg/m2 every 6 wk. No signs of toxicity were observed at doses of under 120 mg/m2, but thrombocytopenia occurred at higher doses. The thrombocytopenic nadir appeared to be dose-dependent and occurred 4 wk after treatment. Platelet transfusions were required in 2 patients who had previously received intensive chemotherapy. No significant leukopenia occurred. A mild reversible and delayed elevation of hepatic transaminases was found in 25% of courses of 120 mg/m2 or more. No renal toxicity was observed and gastrointestinal toxicity was mild. Investigation of clinical pharmacology revealed a rapid triphasic plasma clearance with initial t1/2S of 3, 15, and 30 min. The concentration of N-nitroso intact drug at 1 hr was 10% of the initial peak level. Renal excretion accounted for half of the dose. No significant concentration of N-nitroso intact or radiolabeled drug was detected in the cerebrospinal fluid of 2 patients in whom it was examined. There were objective signs of therapeutic activity in 5 patients, 3 of whom had melanoma. Based on these studies, the recommended dose for phase II investigation of chlorozotocin is 120 mg/m2 every 6 wk.

Adolescent↗

PubMed1977

Carcinoma of the pancreas and periampullary region: a 41 year experience.

A retrospective review of 329 cases of adenocarcinoma of the pancreas and 31 adenocarcinomas of the ampulla and and common bile duct seen between the years 1929 and 1973 was carried out. The most common complaints for carcinoma of the pancreas were pain, weight loss, and jaundice in that order of frequency; while jaundice was the most common complaint with periampullary lesions. The most common procedure carried out was a gastric and/or biliary bypass. Thirty-five patients underwent pancreatoduodenectomy. The survival of this latter group was longer and better than those undergoing bypass and in 40% of patients with ampullary carcinoma a cure was effected. Patients undergoing bypass did not live longer than patients undergoing simple exploratory laparotomy. Duration of symptoms and location of tumor within the pancreas (excluding ampullary tumors) did not appear significantly to alter the prognosis. In view of our experience it is felt that pancreatoduodenectomy should be undertaken whenever the tumor is deemed resectable as this provides the only chance for cure and the best palliation.

Adenocarcinoma↗

PubMed1977

Responses to reading as perceived by boys with and without specific reading retardation and behavioural disorders: a repertory grid study.

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Child↗

PubMed1976

Therapeutic use of tamoxifen in advanced breast cancer: correlation with biochemical parameters.

Tamoxifen (NSC-180973; ICI-46474) can provide palliation to patients with advanced breast cancer whose tumors contain estrogen-binding proteins (EBP). The drug is most effective in patients with bone metastasis and minimal prior therapy. In the present study, 72 patients with advanced breast cancer were evaluated for their response to oral tamoxifen therapy administered at a dose of 20 mg twice daily. Twenty-eight of 72 patients (38%) demonstrated objective responses to tamoxifen therapy. For patients with a positive EBP and no prior chemotherapy, eight of 11 (74%) responded. No patient possessing a tumor negative for EBP achieved a remission. Patients with tumors that possessed normal arylsulfatase B and glucose-6-phosphate dehydrogenase enzyme activities responded most favorably to tamoxifen therapy. These results demonstrate that tamoxifen is effective in the treatment of patients with advanced breast cancer, and EBP and specific enzymes might be useful in selecting the patients for hormone manipulation.

Adult↗

PubMed1974