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Biomedical subjects

B A Chabner

Publications and source records attributed to B A Chabner.

At least 55 records · Page 3Linked to original sources
PubMed1993

Biological basis for cancer treatment.

The new knowledge of the regulation of cell growth and the genetic and biochemical changes that lead to malignancy have created many new opportunities for cancer drug discovery. These new targets include oncogenes, growth factors and their receptors, signal transduction pathways, and cell differentiation signals. Attempts to identify new therapies based on these targets can complement traditional drug discovery efforts that rely on high-volume screening of candidate natural products and synthetic chemicals against human tumor cell lines and against defined molecular reactions. Through modern computer-based data analysis, drug screening data can be used to establish mechanism of drug action of new agents; these analyses shed light on patterns of cross-resistance of new compounds and their interactions with defined molecular targets as well as allow selection of chemically and biologically unique agents as candidates for clinical development.

Antineoplastic Agents↗
PubMed1993

Decreased expression of the human folate receptor mediates transport-defective methotrexate resistance in KB cells.

The human membrane-associated folate binding protein, or folate receptor (hFR), is a necessary component of folate and methotrexate (MTX) transport in some cell lines. To investigate the role of hFR in acquired MTX resistance in human cells, we characterized nine MTX-resistant clones selected from human nasopharyngeal epidermoid carcinoma (KB) cells (cells which transport folates/anti-folates via the hFR) cultured in media containing low folate concentrations. Compared with wild type KB cells, the level of resistance of the clones ranges from 2- to 80-fold higher and the resistant phenotypes of the clones are characterized as follows. 1) DHFR levels are increased (3-13-fold) in four of nine clones; 2) MTX polyglutamation is not detectably different; 3) the extents of MTX efflux are similar; 4) initial rates of MTX efflux are similar except for two clones which exhibit slightly faster efflux rates (approximately 2-fold); and 5) the Vmax for specific MTX and 5-methyltetrahydrofolate transport are decreased (2-18-fold) in all mutants. The Kt values for MTX transport of each mutant are similar to the Kt of KB cells. These results indicate that all nine MTX-resistant clones exhibit defective MTX transport and that four clones also have increased DHFR levels. Based on folic acid binding assays, the hFR is reduced by 1.8-24-fold in these clones relative to KB cell hFR expression. Western, Northern, and Southern analyses are consistent with decreased hFR expression in these clones rather than mutations, resulting in alterations in the size or ligand binding affinities of the hFR. The decrement in hFR expression correlates closely with the degree of reduction in MTX transport Vmax for each clone. Since folate and MTX influx proceed via hFR in KB cells and in these mutants, the correlation (R2 = 0.90) between hFR expression and the MTX transport Vmax of each clone indicates that hFR expression is an important determinant of acquired MTX resistance in this human tumor cell line. These studies demonstrate that defective transport (manifested by decreased Vmax) resulting from decreased expression of the hFR is frequent in KB cells cultured under these conditions and suggest that modulation of hFR may be relevant to MTX cytotoxicity or resistance in tissues or cells expressing functionally significant levels of hFR.

Biological Transport↗
PubMed1993

Age does not influence taxol dose intensity in recurrent carcinoma of the ovary.

BACKGROUND: In the treatment of advanced-stage ovarian cancer, it is common practice to treat elderly patients in a less aggressive fashion than young patients. This approach is based on the notion that age is associated with poor patient tolerance to aggressive chemotherapy. Relatively little data exist to support this contention. The most exciting new chemotherapy agent to be developed in the last 10 years is taxol, a diterpeniod derivative of the Northwestern yew Taxus brevifolia. METHODS: The ability to administer dose-intensive taxol to adult patients with recurrent ovarian cancer was assessed retrospectively, and the question was asked whether the administered dose intensity of taxol was unfavorably influenced by age. Forty-eight patients with recurrent ovarian carcinoma received taxol at an initial dose of 250 mg/m2 every 3 weeks. Age in this cohort ranged from 26 to 74 years, with a median of 55. Twenty-nine percent (14 of 48) of the patients treated were 61 years of age or greater. Criteria for administration of taxol included a creatinine clearance of > 45 ml/minute, minimal abnormalities in liver function tests, good performance status, and the absence of substantial comorbid disease. RESULTS: Elderly patients in this cohort (age > 60 years) did not differ from younger patients with respect to administered dose intensity, number of cycles of therapy administered, or the occurrence of serious or mild toxicities.

Adult↗
PubMed1993

Antimetabolites.

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Antimetabolites, Antineoplastic↗
PubMed1992

Camptothecins.

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Camptothecin↗
PubMed1992

Recent National Cancer Institute lymphoma trials of etoposide-containing combination chemotherapy.

Short-course prednisone/doxorubicin/cyclophospha- mide/etoposide-cytarabine/bleomycin/vincristine/methotrexate (ProMACE-CytaBOM) contains the same drugs as standard ProMACE-CytaBOM but is delivered weekly for 16 weeks rather than 2 weeks out of 3 for 18 weeks. This results in a significant increase in dose intensity, ranging from 27% to 65% for all drugs. A total of 46 patients have been treated with short-course ProMACE-CytaBOM. The overall complete response rate of 91% and relapse rate of 17% compares favorably with results obtained using standard ProMACE-CytaBOM (86% and 27%, respectively). Toxicity was slightly greater with short-course therapy, but in general the regimen was well tolerated. Further dose intensification is possible in eligible patients by dose escalating myelotoxic drugs. A second strategy for augmenting the dose intensity is to deliver the drugs by continuous intravenous infusion. Infusional chemotherapy with doxorubicin/etoposide/vincristine/oral prednisone/bolus cyclophosphamide (EPOCH) results in significant antitumor activity in heavily pretreated patients with chemotherapy-resistant Hodgkin's disease and non-Hodgkin's lymphomas. Complete responses or partial responses were seen in 91% of 21 evaluable patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Antimetabolites.

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Animals↗
PubMed1992

The National Cancer Institute: cancer drug discovery and development program.

The discovery and development of novel therapeutic products for the treatment of malignancy is vitally important to those physicians responsible for the management of cancer patients. A description of the ongoing efforts at the National Cancer Institute (NCI) is intended to provide insight into those complex processes necessary to accomplish this mission. An update on the NCI's revised cancer screen is accompanied by a brief summary of those new agents scheduled to be entered into clinical investigation in the near future. The tremendous potential advantages and challenges associated with the use of a molecular approach to cancer drug design are discussed. Despite the differences of opinion that may exist regarding the optimal strategies for accomplishing the mission, there is no disagreement regarding the importance of the effort to find effective new therapies for cancer patients.

Animals↗
PubMed1991

Production and characterization of monoclonal antibodies that localize human thymidylate synthase in the cytoplasm of human cells and tissue.

Thymidylate synthase (TS; EC 2.1.1.45) is an important cellular enzyme that converts dUMP to dTMP, which is essential for DNA biosynthesis. In addition, TS is an important cellular target for the fluoropyrimidine cytotoxic drugs that are widely used in the treatment of solid tumors. We have generated five monoclonal antibodies against human TS using a recombinant human TS enzyme. These antibodies react specifically with human TS and display negligible cross-reactivity with other cellular proteins found in human cells. Binding affinity studies demonstrate that all antibodies form a tight interaction with recombinant human TS enzyme (Kd range = 0.3-11.0 nM). All antibodies display reactivity on enzyme-linked immunosorbent assay and immunoprecipitation. On Western blot analysis each detects a protein of approximately 36 kDa molecular mass under denaturing conditions. In addition to their reactivity on immunoprecipitation and Western analysis, two of the antibodies, TS 106 and TS 109, are reactive on immunohistochemical staining of human colon carcinoma cell lines and tissue, producing a granular cytoplasmic staining pattern. Specificity for TS is demonstrated by the lack of staining with preimmune IgG and the disappearance of the signal when the antibodies are preabsorbed with recombinant human TS enzyme. Quantitation of TS by Western blot analysis and biochemical FdUMP binding assay in 5-fluorouracil-resistant colon carcinoma cell lines (NCI H630R10, NCI H630R1) and a sensitive colon carcinoma cell line (NCI H630) revealed a 36- and 6-fold increase in TS in the resistant cell line as measured by the biochemical assay compared to a 39- and 10.6-fold increase as measured by densitometric analysis of the Western blot. These comparative studies of immunohistochemical, Western, and biochemical analyses reveal that the immunological detection of TS in human colon cell lines is a sensitive and quantitative assay. Thus the ability of these antibodies to detect TS in human cancer cells and tissue may allow measurement of TS in human tissues by quantitative immunohistochemistry in studies of drug resistance and for determination of proliferative rates.

Antibodies, Monoclonal↗
PubMed1991

Autoregulation of human thymidylate synthase messenger RNA translation by thymidylate synthase.

Thymidylate synthase (TS; 5,10-methylenetetrahydrofolate:dUMP C-methyltransferase, EC 2.1.1.45) is essential for the de novo synthesis of thymidylate, a precursor of DNA. Previous studies have shown that the cellular level of this protein is regulated at both the transcriptional and posttranscriptional levels. The regulation of human TS mRNA translation was studied in vitro with a rabbit reticulocyte lysate system. The addition of purified human recombinant TS protein to in vitro translation reactions inhibited translation of TS mRNA. This inhibition was specific in that recombinant TS protein had no effect on the in vitro translation of mRNA for human chromogranin A, human folate receptor, preplacental lactogen, or total yeast RNA. The inclusion of dUMP, 5-fluoro-dUMP, or 5,10-methylene-tetrahydrofolate in in vitro translation reactions completely relieved the inhibition of TS mRNA translation by TS protein. Gel retardation assays confirmed a specific interaction between TS protein and its corresponding mRNA but not with unrelated mRNAs, including human placenta, human beta-actin, and yeast tRNA. These studies suggest that translation of TS mRNA is controlled by its own protein end product, TS, in an autoregulatory manner.

Animals↗