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Articles by Doris M. Benbrook
Total Records ( 3 ) for Doris M. Benbrook
  Shennan Lu and Doris M. Benbrook
  Retinoid compounds induce multiple molecular effects that need to be taken into consideration in the development of theses agents as pharmaceuticals for cancer chemoprevention. Inhibition of cancer cell growth by retinoids is thought to occur through at least two mechanisms of transcriptional regulation resulting from direct binding of retinoids to nuclear retinoid receptors (RARs and RXR’s). First, the nuclear receptors induce or repress expression of specific genes by direct binding to retinoic acid response elements (RAREs) in gene promoters. Second, the nuclear receptors antagonize transactivation of activator protein-1 (AP-1) promoter elements by the AP-1 transcription factors. The objective of this study was to determine the contributions of RARE transactivation and AP-1 antagonism to the mechanism of growth inhibition in cervical cancer cell lines by: the 9-cis isomer of retinoic acid (9-cis-RA), which binds both RARs and RXRs; and a series of synthetic retinoids, called heteraoarotinoids, that possess various receptor specificities and reduced toxicity. The effects of these compounds on reporter gene expression and proliferation were measured in CC-1 and SiHa cell lines stably transfected with RARE or AP-1 reporter plasmids or a retrovirus harboring an inducibile AP-1 protein that is a dominant negative mutant of c-Jun (TAM67). In the CC-1 cell line, which exhibited high AP-1 activity, retinoid growth inhibition significantly correlated with both RARE transactivation and AP-1 repression, was antagonized by superinduction of AP-1 with TPA (12-O-tetradecanoylphorbol-13-acetate) and was enhanced by TAM67. In the SiHa cell line, which exhibited low AP-1 activity, RARE transactivation also significantly correlated with growth inhibition, but AP-1 induction, in contrast to AP-1 repression, correlated with growth inhibition. Furthermore, TPA superinduction of AP-1 did not attenuate retinoid growth inhibition activity in SiHa. In conclusion, repression of AP-1 with retinoids may only be effective against a subset of tumors with high AP-1 activity.
  Johnny Hyde and Doris M. Benbrook
  The administration and combination of a variety of chemotherapeutic agents for treatment of advanced or recurrent uterine cancer of different histologies is under current debate. Mixed Mullerian Tumors (MMTs), which contain both adenocarcinoma and sarcoma components, are the most rate histologic type and it is therefore difficult to conduct clinical trials to determine if they should be treated like endometrial adenocarinomas or like sarcomas. Flexible Heteroarotionoids (Flex-Hets) are a promising class of anti-cancer drugs with low toxicity that have demonstrated activity against a wide variety of cancer types, but their efficacy in uterine cancers is unknown. The objective of this study was to determine if cell lines established from endometrial carcinoma (HEC-1-A), uterine sarcoma (SK-UT-1) and MMT (MES-SA) cancers exhibit differential sensitivities to cisplatin, carboplatin, paclitaxel, docetaxel, doxorubicin and SHetA2, if SHetA2 can enhance sensitivity to the chemotherapeutic drugs and if SHetA2 exhibits a differential effect on uterine cancer cells in comparison to normal endometrial cells using a cytotoxicity assay. These cell lines did not differ in their sensitivities to platinum or taxel drugs. Doxorubicin was active against the sarcoma but not the adenocarcinoma or MMT cell lines. SHetA2 decreased the survival of all three cell lines, but did not enhance their sensitivities to the chemotherapeutic agents. Two of the three uterine cancer cell lines were more sensitive to SHetA2 in comparison to normal endometrial cells. In conclusion, doxorubicin appears to have a greater effect against sarcoma than other uterine histology types. SHetA2 is affective against uterine cancer cell lines, but does not enhance their sensitivities to chemotherapeutic agents.
  Suresh Guruswamy and Doris M. Benbrook
  Treatment of ovarian cancer with cisplatin-based chemotherapy is highly toxic and is often followed by cancer recurrence. Repeated treatments with cisplatin frequently result in the development of resistance to this drug. Drugs with low toxicity that could enhance the tumor cell killing effects of cisplatin could potentially reduce the toxicity and enhance the efficacy of cisplatin. The mechanism of cell kill by cisplatin is partially due to induction of apoptosis through the p53 pathway. Retinoids can regulate apoptosis through nuclear retinoic acid receptors, but the role of p53 in the mechanism varies with the individual retinoid and cell type. The objective of this study was to evaluate the potential of receptor-active and –independent retinoids as chemosensitization of ovarian cancer cell lines with different p53 status. The growth of two ovarian cancer cell lines, OVCAR-3 that has wild type p53 and Caov-3 that has mutant type, was evaluated in the presence and absence of various combinations of cisplatin, a series of retinoids and a chemical inhibitor of p53 transactivation activity (pifithrinα). Both receptor active and receptor independent retinoids chemosensitized the two cell lines to cisplatin. PFTα partially attenuated growth inhibition by cisplatin, slightly enhanced the growth inhibition of retinoids and did not affect growth inhibition when retinoids were used in combination with cisplatin. RNase protection demonstrated that PFTα did not alter retinoid effects on p53 regulated genes. In conclusion, retinoids chemosensitize both sensitive and resistant ovarian cancer cells to cisplatin through mechanisms independent of nuclear retinoid receptors and p53.
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