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Biomedical subjects

P V Woolley

Publications and source records attributed to P V Woolley.

At least 55 records · Page 3Linked to original sources
PubMed1982

Distribution and binding of the carcinogens 1-methyl-1-nitrosourea and 1-methyl-3-nitro-1-nitrosoguanidine in the guinea pig after oral administration.

Guinea pigs were given radioisotopic 1-methyl-1-nitrosourea (MNU) or 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) as a single oral dose of 0.1 mmol/kg and uptake into TCA-precipitable material, whole tissue protein and 7-methyl-guanine and O6-methylguanine were determined in brain, kidney, liver, pancreas, small intestine and stomach after 2, 4 and 24 h. The labeling of TCA-precipitable material and the formation of methylated bases by methyl-labelled MNU clearly exceeded that by MNNG in extra-intestinal tissues such as brain, liver, kidney and pancreas. In the stomach, there was greater DNA methylation by MNNG than by MNU. Labelling of TCA-precipitable material and whole tissue protein by the carbonyl group of MNU was greater than that by the guanidino group of MNNG in brain, liver, kidney and pancreas, while MNNG exceeded MNU in the stomach. These data are consistent with the concept that orally administered MNU would be an effective carcinogen in extra-intestinal tissues, while MNNG would be a locally acting gastric carcinogen.

Administration, Oral↗
PubMed1981

Binding of N-nitroso carcinogens in pancreatic tissue.

Carcinoma of the pancreas can be produced in guinea pigs by the oral administration of 1-methyl-1-nitrosourea (MNU). Our present studies have examined the distribution of this compound in these animals following parenteral and oral administration and also its specific sites of binding within the pancreatic cell. Emphasis has been placed upon the comparison of the uptake and binding of MNU with the related compound 1-methyl-3-nitro-1-nitrosoguanidine (MNNG), which does not seem to be carcinogenic to the pancreas after oral administration. The distribution data indicate uptake into pancreas that is comparable to that of other organs. Binding data show both MNU and MNNG to extensively modify subcellular organelles and the DNA and proteins of chromatin, but that MNU does this to a somewhat greater extent than MNNG.

Animals↗
PubMed1981

Phase I trial and clinical pharmacology of 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea.

1-(2-Chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea (NSC 95466) is a lipid-soluble nitrosourea that is presently undergoing clinical evaluation. In this Phase I study, the toxicity of this drug was examined after administration of the drug to cancer patients on 3 successive days every 6 to 8 weeks. Clinical pharmacology was studied using 1-[chloroethyl-14C](2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea. The dose-limiting toxicity was myelosuppression. The maximal tolerated dose was 105 mg/sq m, which produced a median platelet nadir of 40,000/microliter on Day 32 and a median white blood cell count nadir of 2200/microliter on Day 42. Progressive anemia was also observed. There was no evidence of acute or chronic hepatic, renal, or pulmonary damage. One patient with a metastatic hypernephroma exhibited a partial clinical remission. Plasma disappearance of the drug following bolus administration was biphasic, with an initial half-life of 18 to 25 min and a second half-life of 9 hr. Clearance of intact drug coincided largely with the initial disappearance phase of total radioactivity. Entry of radioactivity into the cerebrospinal fluid was observed. Approximately 35% of plasma radioactivity was protein bound, the major binder being albumin. Drug excretion was predominantly renal, and biliary elimination was only minor.

Anemia↗
PubMed1981

Phase II trial of methyl-G (methylglyoxal bis-guanylhydrazone) in patients with metastatic renal cell carcinoma.

Fourteen patients with metastatic renal cell carcinoma received methyl-G weekly at a starting dose of 600 mg/m2 (five patients) and 500 mg/m2 (nine patients) intravenously. All 14 patients are evaluable for response and toxicity. No antitumor responses were observed. Six patients achieved stabilization of disease for 8 to 42 weeks. Toxicity was nonhematologic and included nausea or vomiting (35%), fever with shaking chills (28%), diarrhea (21%), myalgia (63%), paresthesia (49%), and bilateral foot drop (7%). Methyl-G does not appear to have activity against renal cell carcinoma.

Adenocarcinoma↗
PubMed1980

5-fluorouracil, Adriamycin, and mitomycin-C (FAM) chemotherapy for advanced adenocarcinoma of the pancreas.

Thirty-nine patients with advanced metastatic adenocarcinoma of the pancreas were treated with a combination of 5-fluorouracil, Adriamycin, and mitomycin-C (FAM). Twenty-seven of these patients had measurable disease, and ten (37%) achieved a partial response. An additional three patients had evidence of disease stabilization. The median survival period of responding patients was 12 months, compared with 3.5 months for nonresponders (P < 0.01). The median survival period for all patients was 6 months. Moderate myelosuppression constituted the treatment-limiting toxicity. The FAM combination is an active and well-tolerated regimen for pancreatic cancer and may have an application in the management of patients with less advanced disease.

Adenocarcinoma↗
PubMed1980

A phase II study of chlorozotocin in metastatic malignant melanoma.

Thirty-five patients with metastatic malignant melanoma underwent treatment with chlorozotocin administered as a single dose of 120 mg/m2 by means of rapid intravenous infusion every six weeks. There were 1 complete and 4 partial remissions with an overall response rate of 14%. The median duration of response was 18 weeks; the patient in complete remission continues disease-free in excess of 42 weeks. The sites of response included: lung, 2; subcutaneous, 2; and lymph node, 1. There was minimal myelotoxicity: for the first cycle, the median white blood cell count nadir was 5400/mm3, and the platelet nadir was 210,000/mm3. No evidence of cumulative platelet toxicity was observed. Chlorozotocin is active against metastatic melanoma to the same degree as other chloroethylnitrosoureas in clinical use, but without causing bone marrow toxicity. These data suggest that chlorozotocin should be evaluated in combination with other agents active against melanoma.

Adult↗
PubMed1980

Clinical strategies in the chemotherapy of gastrointestinal cancer.

Clinical strategy in chemotherapy of gastrointestinal cancer depends on availability of drugs with single-agent activity. If active drugs are available, combination chemotherapy trials can be developed. In gastric cancer, combinations of 5-fluorouracil with chloroethyl nitrosoureas or adriamycin and mitomycin C are capable of producing responses in 40-50% of patients. Such active combinations may now be evaluated in patients with less advanced gastric carcinoma. The role of combination chemotherapy is now being defined in patients with locally unresectable cancer and in the surgical adjuvant situation. In pancreatic and colorectal cancer, combination chemotherapy regimens have been of marginal effectiveness. The major thrust of clinical investigation must be directed toward phase II evaluations of single agents in these diseases.

Antineoplastic Agents↗
PubMed1980

Pharmacokinetics and protein binding of cis-dichlorodiammine platinum (II) administered as a one hour or as a twenty hour infusion.

The pharmacokinetics of cis-dichlorodiam-minoplatinum (II) (cisplatin) have been studied in seven patients, of whom four received the drug as a one hour infusion and three received it as a 20 h infusion. The patients receiving the drug over one hour exhibited biphasic clearance of total platinum with a rapid initial phase (8.7-22.5 min) and a prolonged second phase (30.5-106 h). Free (ultrafilterable) cisplatin was readily detectable in this group and was rapidly cleared (half-life about 22 min). The volume of distribution of the drug was 50.3-65.6 liters and it was 26.6-50% excreted in the urine in 48 h. In the patients receiving the 20 h infusion, a more complex plasma elimination curve was seen, with the appearance of a secondary peak. Free drug was not detectable in these patients and they showed less urinary excretion (21.4-25.9% at 48 h) than the one hour group. Cisplatin was bound to several plasma proteins, including albumin, transferrin, and gamma-globulin. The data indicate that cisplatin is retained in the body more extensively after a 20 h infusion than after a one hour infusion.

Biological Availability↗
PubMed1980

Uptake and binding of 1-methyl-1-nitrosourea (MNU) and 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) by the isolated guinea pig pancreas.

1-Methyl-1-nitrosourea (MNU) and 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) are carcinogens which methylate nucleic acids and proteins and covalently modify proteins by carbamoylation (MNU) or guanidination (MNNG). Using MNU and MNNG labeled with carbon-14 in the individual carbon positions, the above reactions were quantitated in the isolated guinea pig pancreas, an organ susceptible to tumorigenesis by MNU. Freshly prepared pancreatic lobules were incubated with the labeled drugs (0.03, 0.3 and 1.0 mM) for one hour at 37 degrees C. Alkylated purines from hydrolyzed DNA were separated on Sephadex G10 and acid-soluble nuclear proteins were extracted and separated on polyacrylamide gels. Total uptake of all four labels into lobules was linear with concentration. Acid insoluble radioactivity also increased linearly except for MNNG methylation which plateaued between 0.3 and 1.0 mM. 7-Methylguanine formation by both compounds was approximately ten fold greater than 06-methylation. However, DNA modification by MNU exceeded that by MNNG, especially at the higher drug concentrations. No carbamoylation or guanidination of DNA was detected. Total binding (methylation plus carbamoylation/guanidination) to acid-extractable chromatin proteins was equivalent to DNA modification on a molar basis (approximately 0.35 and 0.08 pmol/microg for exposure to 1.0 mM MNU and MNNG, respectively). All histones were labeled by all drug preparations, with H2A being the principal site of methylation and H2B, H3 and H1 being the major targets of carbamoylation and guanidination. H4 was the least modified histone. Drug binding to cytoplasmic organelles also occurred. These results show a broad spectrum of nuclear and cytoplasmic modification of pancreatic cells by MNU and, to a smaller extent, MNNG.

Animals↗
PubMed1980

5-Fluorouracil, doxorubicin, and mitomycin (FAM) combination chemotherapy for advanced gastric cancer.

Sixty-two patients with advanced measurable gastric cancer were treated with a combination chemotherapy program of 5-fluorouracil, doxorubicin, and mitomycin (FAM). Forty-two percent of patients achieved an objective partial response. The median duration of remission was 9 months and the median survival for responding patients, 12.5 months. The median survival for nonresponding patients was 3.5 months; all patients were dead by 8 months after initiation of therapy. The median survival of all 62 patients treated with FAM was 5.5 months. An analysis of possible prognostic variables including initial performance status, resectability of the primary gastric tumor, and histologic differentiation of the neoplasm failed to account for differences in patient response and survival. The FAM regimen was well tolerated, producing only moderate bone marrow suppression. These results show that patients with metastatic gastric cancer can be effectively palliated with FAM chemotherapy. The efficacy of this regimen should now be tested in patients with less advanced stages of this disease.

Adenocarcinoma↗
PubMed1979

5-Fluorouracil, adriamycin, and mitomycin-C (FAM) chemotherapy for adenocarcinoma of the lung.

Twenty-five patients with advanced measurable adenocarcinoma of the lung were treated with combination chemotherapy consisting of 5-fluorouracil, adriamycin, and mitomycin-C (FAM). Objective response (1CR, 8PR) was obtained in 36% of patients. The median duration of response was 7.0 months and the median survival for responders is greater than 8.5 months. Five responders are alive 5.5 to 23.5 months after starting therapy. Three of four patients evidencing stabilization of disease are alive at 10-23 months. Non-responding patients had a median survival of 2.5 months and none lived beyond seven months. Tumor response and survival suggested correlation with initial performance status and limited disease. The FAM regimen was tolerated well, with moderate bone marrow suppression and gastrointestinal symptoms being the only clinically significant toxicities. These results indicate that patients with advanced pulmonary adenocarcinoma can obtain objective tumor regression with FAM chemotherapy.

Adenocarcinoma↗
PubMed1979

5-fluorouracil, adriamycin, and mitomycin-C (FAM) combination chemotherapy in the treatment of advanced gastric cancer.

Thirty-six patients with advanced measurable gastric cancer were treated with a new combination chemotherapy program consisting of 5-fluorouracil, Adriamycin and mitomycin-C (FAM). Fifty percent of patients achieved an objective partial response. The median duration of remission was 9.5 months and the median survival for responding patients was 13.5 months, with 2 remaining alive at 14 and 26 months. The median survival for nonresponding patients was 3.0 months and all were dead by 6 months after initiation of therapy. The median survival of all 36 patients treated with FAM was 5.5 months. An analysis of possible prognostic variables including initial performance status, resectability of the primary gastric tumor and histologic differentiation of the neoplasm failed to account for differences in patient response and survival. The FAM regimen was well tolerated, and produced only moderate bone marrow suppression. These results demonstrate that some patients with advanced gastric cancer can be effectively palliated with FAM chemotherapy. Phase III trials are warranted to assess the effect of the FAM regimen on the survival of patients with advanced gastric cancer.

Adenocarcinoma↗
PubMed1979

Delayed radiation necrosis of brainstem related to fast neutron beam irradiation: case report and literature review.

A 42-year-old man developed necrosis of the brainstem 10 months following fast neutron irradiation of a recurrent adenocystic carcinoma of the right submandibular salivary gland. The neoplasm had been diagnosed 15 years earlier. Neck dissection and several local excisions failed to control local extension, so that 7000 rad 4.8 MeV x-rays were administered. The right mandible and part of the tongue and palate were resected for recurrence and chemotherapy and transfer factor were given. Because of cranial neuropathy and erosion of the skull base, fast neutron radiation (2.080 rads) was administered five and one-half years after the x-ray therapy, but to a nonoverlapping field. Ten months later, rapidly progressive symptoms and signs of multiple cranial nerve palsies on the right side and left hemihypesthesia and hemiplegia appeared. Clinical manifestations of brainstem necrosis lasted 4 months. Postmortem examination demonstrated radionecrosis of pons and upper medulla, predominantly on the right side. This case illustrates the efficacy of neutron radiation in eradicating local carcinoma and also the serious complications of this therapeutic modality.

Adult↗