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Biomedical subjects

E Cadman

Publications and source records attributed to E Cadman.

At least 19 recordsLinked to original sources
PubMed1992

Synthesis and in vitro characterization of novel amino terminally modified oxotremorine derivatives for brain muscarinic receptors.

A series of novel 2-substituted acetylenic pyrrolidines and piperidines related to oxotremorine (1) were prepared and evaluated in vitro as muscarinic cholinergic agents at brain M1 and M2 receptors. One analogue, 3-(2-oxo-1-pyrrolidinyl)-1-[2(R)-pyrrolidinyl]-1-propyne hydrogen oxalate (6a), was found to be a partial agonist producing a PI hydrolysis response at cortical M1 receptors approximately 3-fold larger than that produced by 1. The intrinsic activity profile of 6a at brain muscarinic receptors is similar to those of azetidine oxo analogue 2 and dimethylamino oxo analogue. All three compounds are partial M1 agonists and full M2 agonists; however, the profile of 6a in binding studies is significantly different. While 2 and 3 exhibit large M2 selectivities ranging between 8-fold to several hundred-fold, the binding profile of 6a shows almost no subtype selectivity.

Animals↗
PubMed1987

High-dose pulse chlorambucil in advanced, low-grade non-Hodgkin's lymphoma.

High-dose pulse chlorambucil was given orally at a dose of 16 mg/m2 daily for 5 consecutive days each month, as reported by Cadman et al. It was used to treat 33 patients with advanced, low-grade non-Hodgkin's lymphoma. With median follow-up of 4.2+ years, 70% of the patients achieved objective response. Eleven of 24 patients with follicular small cleaved cell lymphoma (FSCL) had pathological complete response; nine of 24 with FSCL and three of seven with small lymphocytic lymphoma had partial response. Median disease-free survival was 28 months. Actuarial survival for all patients was 60% at 5 years from initiation of therapy. Treatment toxicity was minimal. Pulse chlorambucil is an effective and minimally toxic palliative therapy for advanced FSCL.

Administration, Oral↗
PubMed1986

Modulation of fluoropyrimidine metabolism by chlorpromazine.

Chlorpromazine is a potent inhibitor of calmodulin and can alter the accumulation, metabolism, and incorporation into RNA of several fluoropyrimidine drugs. Using S-180 murine sarcoma cells, the accumulation of the base Fluorouracil and its metabolism to ribonucleotides is enhanced by chlorpromazine treatment, as measured by HPLC. In contrast, the accumulation and metabolism of the nucleoside Fluorouridine was suppressed by chlorpromazine. Cytotoxicity studies revealed that non-toxic concentrations of chlorpromazine were synergistic with Fluorouracil, but were antagonistic with Fluorouridine. These findings suggest that modulation by chlorpromazine of specific nucleoside kinase involved in Fluorouracil metabolism can result in increased therapeutic utility.

Animals↗
PubMed1986

An analysis of 1539 patients with cancer of unknown primary site.

A retrospective review of 1539 patients with cancer of unknown primary site seen at Yale-New Haven Hospital from 1922 to 1981 was performed. Information was obtained from the Tumor Registry. The method of diagnosis, patient characteristics, year of diagnosis, histologic features, treatment received, and survival were analyzed. The most common cell type was adenocarcinoma. Survival overall was poor, with a median survival of 5 months for the entire group. Age and year of diagnosis did not appear to significantly influence survival. Closer examination of a small subset of those patients with squamous cell carcinoma revealed a very high male:female ratio, possibly related to tobacco and alcohol abuse. Nearly 9% of these patients were found to have a history of one or more unrelated malignancies.

Adenocarcinoma↗
PubMed1986

Levels of thymidylate synthetase during normal culture growth of L1210 cells.

The binding of 5-fluoro-2'-deoxyuridylate generated from 5-fluoro-2'-deoxyuridine in intact cells was used to measure changes in the level of thymidylate synthetase during the course of population growth of murine leukemia L 1210 cells. By the use of elutriation techniques and flow cytometric analysis, the amount and activity of thymidylate synthetase associated with the various phases of the cell cycle were determined for the L 1210 cells during unperturbed in vitro culture growth. Fluctuations of thymidylate synthetase levels were associated with the cell cycle; there was a positive correlation (P less than 0.001) between the percentage of the total cell population in S phase and the concentration of thymidylate synthetase, although there was an increase in the level of this enzyme in association with an increase in G2-M cells, this did not achieve statistical significance. A negative correlation between G1 cells and the concentration of thymidylate synthetase was also observed. The maximum amount of thymidylate synthetase was nearly 900 fmol/10(6) cells and occurred in cell populations during logarithmic growth when the percentage of the population in S phase and G2-M phase was greater than 50 and 20%, respectively. In late culture growth (plateau) when only 25% of the cell population was in S phase and nearly 75% of the population was in G1 phase, the level of enzyme was reduced to 200 fmol/10(6) cells.

Animals↗
PubMed1985

Pulmonary metastases in ovarian cancer. Analysis of 357 patients.

The pattern of pulmonary involvement from ovarian cancer was evaluated in 357 patients who were seen at the Yale-New Haven Hospital from 1966 to 1975. Thoracic involvement by tumor was found in 169 patients (44.5%), a figure considerably higher than in previous reports. Pleural effusions were present in nearly 75% of patients who had thoracic involvement. Only 73% of the effusions contained identifiable malignant cells. Solid metastases to the pulmonary parenchyma were present in 12.3% of the patients; lymphangitic and nodal spread was observed in only 1% of the patients. The incidence of metastases did not correlate with tumor histologic features. Five-year survival figures were 29% for the control group; 5.6% of the patients who had evidence of thoracic involvement were alive after 5 years compared with a 49% 5-year survival of those patients with no evidence of thoracic involvement. Right-sided lesions produced thoracic metastases more frequently than left-sided lesions. No significant differences with respect to age, race, menopause, smoking history, or autopsy rate were found between those patients with and without pulmonary metastasis. Chest x-ray was found to be of great value in determining pulmonary metastasis; only 6% of patients who were proven by autopsy to have spread of cancer to the thoracic cavity had a chest x-ray that did not show malignancy. The majority of these ten patients had lymphangitic or microvascular disease. No cases of second primary occurring in the lung were noted in this review, although two case reports have appeared in the literature. Only three patients with pulmonary involvement by tumor had no other evidence of Stage IV disease.

Adenocarcinoma↗
PubMed1985

Lack of enhanced cytotoxicity of cultured L1210 cells using folinic acid in combination with sequential methotrexate and fluorouracil.

Previous studies from this laboratory have demonstrated that treatment of cultured cells with sequential methotrexate (MTX) and fluorouracil (FUra) leads to synergistic cell killing in several murine and human neoplasms in vitro. In this study leucovorin (folinic acid, LCV) was added to the MTX/FUra combination with the intention of generating elevated levels of methylenetetrahydrofolate to promote the formation of a stable fluorodeoxyuridylate-thymidylate synthetase ternary complex, thereby augmenting the cytotoxicity of the MTX-FUra sequence. The addition of 10 or 100 microM LCV concurrently with or after 10 microM FUra following MTX (1 microM) pretreatment did not augment the inhibition of L1210 cell growth or the clonigenicity compared with MTX prior to FUra without LCV. The effects of LCV scheduling on the sequential MTX and FUra-induced inhibition of thymidylate synthesis were measured by examining the rate of [6-3H] dUrd incorporation into the acid-precipitable cell fraction and by direct quantitation of the thymidylate synthetase ternary complex. Combination of 100 microM LCV with 10 microM FUra after 1 microM MTX resulted in significantly more ternary complex formation than did 1 microM MTX before 10 microM FUra alone. The inhibitory effects of FUra on thymidylate synthetase in the presence of MTX, however, could not be augmented by LCV as determined by [6-3H] incorporation into acid-precipitable material, nor did the addition of LCV result in increased cytotoxicity. Factors other than the inhibition of DNA synthesis may be critical to the cytotoxicity of sequential MTX and FUra in L1210 cells.

Animals↗
PubMed1985

Sequential infusions of methotrexate and 5-fluorouracil in advanced cancer: pharmacology, toxicity, and response.

Preclinical studies have suggested that synergistic antitumor toxicity occurs when methotrexate (MTX) is administered prior to 5-fluorouracil (FUra). A protocol of sequenced, overlapping infusions of MTX and FUra was designed to achieve 5 microM MTX serum levels lasting 36 h and 1 to 5 microM FUra levels lasting 24 h, with leucovorin started at the end of the MTX infusion. Thirty-nine patients with metastatic neoplasms received a total of 127 treatment courses; two-thirds of the patients had received prior treatment with radiation therapy or chemotherapy; most of the latter treatment regimens included MTX or FUra. In three patients, the duration of FUra infusion was prolonged up to 72 h to determine the toxic limits of therapy. Blood samples were collected during treatment courses to estimate the half-lives and total-body clearances of MTX and FUra. The initial serum half-lives and total-body clearances of both MTX and FUra appeared within the range of reported normal values. The terminal half-life of MTX appeared less than previously reported values, and there appeared to be a substantial delay in achieving a FUra steady-state concentration; these two differences may have resulted from either the prolonged intervals of drug infusion or from metabolic interaction between the two drugs. During the 127 courses of treatment, nearly one-half of the patients experienced mild toxicity occurring after at least one treatment, but this toxicity was predominantly Grade I mucositis and/or diarrhea. Of the three patients who received extended intervals of FUra infusion, none was able to tolerate more than 48 h of FUra without developing mucositis. Thirty-four patients were evaluable for response; no one experienced a complete response, but 11 (32%) patients had either a partial or minimal response. Adenocarcinomas as a group, arising from the lung, gut, breast, and unknown site, appeared to respond best. Sequenced MTX-FUra infusion by this schedule is a generally well-tolerated regimen that deserves further clinical assessment.

Adult↗
PubMed1984

Malignant histiocytosis. Response to VP-16-213 and cytosine arabinoside.

A patient with malignant histiocytosis who relapsed after receiving an Adriamycin (doxorubicin)-containing combination and radiation therapy subsequently had a complete remission on VP-16-213 and cytosine arabinoside. She remains free of disease 32 months after achieving a complete remission. VP-16-213 and cytosine arabinoside (Ara-C) deserve further evaluation in the treatment of this neoplasm.

Aged↗
PubMed1984

Thymidine enhancement of methotrexate and 5-fluorouracil toxicity in cultured human colon carcinoma.

Cultures of human colon carcinoma, HCT-8, were treated with millimolar concentrations of thymidine by different schedules designed to cytokinetically and biochemically modulate methotrexate (MTX) and 5-fluorouracil (FUra) toxicity. Thymidine (dThd)-synchronized HCT-8 cells monitored by flow cytofluorometry showed increased sensitivity to MTX and synergistic cytotoxicity to the combination MTX-FUra. FUra toxicity in synchronized cells showed no significant phase specificity overall, but a pattern of relative G2/M resistance was correlated with decreased intracellular FUra accumulation, incorporation into RNA, and formation of FdUMP. In asynchronous cultures dThd reduced MTX toxicity when given within the first 12 h of a 24-h MTX exposure, and also appeared to reduce the MTX-induced synergistic enhancement of FUra toxicity. When dThd was administered with FUra alone in asynchronous cultures, progressive, and synergistic enhancement of FUra toxicity was observed only after 6 h dThd pretreatment. Unlike MTX-FUra synergy, this schedule-dependent synergism between dThd and FUra did not correlate with intracellular FUra accumulation or specific incorporation into total cellular RNA. These results suggest that less well studied mechanisms of dThd modulation, other than enhanced deoxynucleotide formation or total RNA incorporation, may biochemically enhance FUra toxicity in HCT-8 cells.

Cells, Cultured↗
PubMed1984

A follow-up of a randomized study comparing two chemotherapy treatments for advanced diffuse histiocytic lymphoma.

In 1976 we began a randomized study for the treatment of patients with stage III and IV diffuse histiocytic lymphoma. The therapy was either ACOMLA (doxorubicin, cyclophosphamide, vincristine [oncovin], methotrexate with leucovorin rescue, and cytarabine) or CHOP-B (cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [oncovin], prednisone, and bleomycin). A complete response (CR) was achieved in 13 (65%) of 20 patients treated with ACOMLA and in 20 (71%) of the 28 patients treated with CHOP-B. Four patients achieving CR with ACOMLA and three patients treated with CHOP-B have relapsed for an overall relapse rate of 21%. Partial response (PR) was obtained in four patients treated with ACOMLA and five patients treated with CHOP-B. Median follow-up time is 36 months for the combined treatment groups. Multiple regression analysis demonstrated that those patients who were classified by the Lukes-Collins criteria as having histiocytic lymphoma not of follicular center-cell origin (combined T- and B-cell immunoblastic sarcoma) had a significantly worse survival as compared to patients classified with follicular center-cell origin lymphoma (large cell noncleaved, large cell cleaved, and large cell unclassified) with a 40% five-year survival versus an 80% five-year survival (P = .011). The CR rate however for these two large categories of patients was 63% v 73% respectively, and the relapse rates were equivalent. The increased survival in the follicular center-cell origin lymphomas may be related to a longer survival of PRs and relapsed patients as compared to the patients with nonfollicular center-cell lymphomas.

Adolescent↗
PubMed1983

Mechanism of cytotoxic activity of 5'-deoxy-5-fluorouridine.

The purpose of these studies was to characterize the effect of the new fluoropyrimidine nucleoside 5'-deoxy-5-fluorouridine (5'dFUrd) on macromolecular processes in correlation with its cytotoxicity in Ehrlich ascites tumor cells. Following a 2-h exposure, 5'-dFUrd exhibited an LD50 (as determined by clonogenicity) of 48 microM. In cells supplemented with 10 microM dThd, the LD50 for 5'-dFUrd increased to 660 microM. DNA synthesis was markedly and rapidly suppressed by all cytotoxic concentrations of 5'-dFUrd. There was no apparent direct measurable effect of 5'-dFUrd on either RNA or protein synthesis, although both were suppressed 24 h after the drug exposure. Thymidylate synthetase activity was completely inhibited by all cytotoxic concentrations of 5'-dFUrd. FUra incorporation into RNA was also measured and appeared to correlate with the dThd-nonreversible toxicity of 5'-dFUrd. These studies indicate that the mechanism of 5'-dFUrd cytotoxicity is directly analogous to that reported for 5-fluorouracil. The inhibition of thymidylate synthetase leading to an inhibition of DNA synthesis was the most potent cytotoxic mechanism (i.e., dThd-reversible) for 5'-dFUrd, and was found to be highly time-dependent. Higher concentrations of 5'-dFUrd resulted in dThd-nonreversible toxicity, which appeared to be related to the incorporation of FUra into RNA.

Animals↗