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R A Lawrence

Publications and source records attributed to R A Lawrence.

149 records · Page 9Linked to original sources
PubMedDate not supplied

5,6 Dihydro-5'-azacytidine (DHAC) restores androgen responsiveness in androgen-insensitive prostate cancer cells.

INTRODUCTION: The androgen resistance of some prostate cancer patients may be due to transcriptional inactivation of the androgen receptor (AR) gene catalyzed by cytosine DNA methyltransferase. MATERIALS AND METHODS: To determine if an inhibitor of cytosine DNA methyltransferase, 5,6-dihydro-5'-azacytidine (DHAC), can restore the androgen sensitivity in androgen-insensitive human prostate carcinoma cell lines in vitro, we cultured androgen-insensitive (PC3, DU-145, and TSUPrl) and androgen-responsive (LNCaP) cells with subcytotoxic concentrations (< or = IC50) of DHAC for 14 days followed by exposure to dihydrotestosterone (DHT) or to hydroxyflutamide for 7 days. RESULTS AND CONCLUSIONS: Only DHAC-treated DU-145 cells showed growth stimulation by 10(-11) to 10(-9) M DHT and a partial inhibition by 10(-5) and 10(-6) M hydroxyflutamide. However, since DU-145 is the only cell line tested that is known to have a hypermethylated AR promoter, the observed effects may be due to a partial demethylation of the AR by DHAC. Our data provide an evidence that cytosine DNA methyltransferase inhibitors can restore androgen responsiveness in androgen-refractory tumor cells, which are then sensitive to growth inhibition by antiandrogens.

Androgens↗
PubMedDate not supplied

5,6-Dihydro-5'-azacytidine (DHAC) affects estrogen sensitivity in estrogen-refractory human breast carcinoma cell lines.

BACKGROUND: There is little effective therapy for patients with hormone-refractory breast cancer. Hormone resistance is frequently due to the transcriptional inactivation of the estrogen receptor (ER) gene. We determined the effect of DHAC, a cytosine DNA methyltransferase (CMT) inhibitor, on the estrogen sensitivity in three human breast carcinoma cell lines with intermediate to low levels of estrogen receptor (ER) expression: MCF7 (adriamycin-sensitive), MCF7M/Adr (adriamycin-resistant), and MDA-435, and one ER+ cell line, ZR75-1. MATERIALS AND METHODS: Cells maintained in culture were exposed to DHAC or vehicle continuously for 14 days, then exposed to estradiol or tamoxifen and counted on day 21. RESULTS: Exposure to DHAC did not affect estrogen sensitivity in ZR-75-1 and MCF7M/Adr cells. DHAC treatment of MCF7 and MDA-435 cells resulted in significant (p < 0.05) growth stimulation in response to estrogen at 10(-6) M, and to growth modulation by tamoxifen at 10(-5) to 10(-7) M. CONCLUSIONS: These data suggest that DHAC can restore the estrogen sensitivity in ER-breast cancer. Thus, DHAC and other novel CMT inhibitors may have a clinical application in treating estrogen-refractory breast cancer patients by restoring the estrogen sensitivity and allowing these patients to respond again to conventional therapy with estrogen antagonists.

Antineoplastic Agents↗
PubMedDate not supplied

Alterations in DNA repair and telomere maintenance mechanism affect response to porphyrins in yeast.

BACKGROUND: DNA quadruplex-interactive porphyrin TMPyP4, but not its isomer TMPyP2, inhibits telomerase activity and causes chromosome fusion in vivo, suggesting interference with telomere maintenance. MATERIALS AND METHODS: We examined effects of these porphyrins and hydroxyurea on growth rates of yeast Saccharomyces cerevisiae wild type and strains with defects in telomere maintenance and/or DNA repair pathways (mec1, tel1, rad9), telomere binding protein (cdc13), and anaphase control (pds1). RESULTS: Hydroxyurea (20 mM) decreased proliferation rates only in mec1 mutant and deletion strains. TMPyP4 (200 microM) decreased growth in all strains, especially in rad9delta and mec1delta. The growth inhibition by TMPyP4 showed low growth inhibition in strains defective in cdc13 and pds1. TMPyP2 sterically prevented from forming a planar species did not significantly inhibit growth of any strain. Overexpression of telomere binding protein Rap1 hypersensitized the mec1delta and tel1delta to TMPyP4. CONCLUSIONS: Telomere maintenance represents a viable target for anticancer agents.

Antineoplastic Agents↗
PubMedDate not supplied

Intraocular pressure effects of selective prostanoid receptor agonists involve different receptor subtypes according to radioligand binding studies.

The receptors involved in the ocular hypotensive activity of prostaglandins (PG) E2 and F2 alpha in dogs and monkeys was investigated by examining the effects of putative receptor selective agonists on intraocular pressure. A diverse variety of receptor selective agonists lowered intraocular pressure in these species. Thus, FP-receptor agonists (17-phenyl PGF2 alpha, fluprostenol), agonists with potent activity at the EP3 receptor (MB 28767, sulprostone) and a prostanoid with activity at the EP2 receptor (11-deoxy PGE1) were all potent ocular hypotensives when administered as a single dose to dogs and monkeys or b.i.d. for 5 days in monkeys. These findings were regarded as surprising and prompted us to re-examine some aspects of the current classification for prostanoid receptors. At present certain receptor subtypes, notably EP2, EP3 and FP receptors, are defined only according to the potency rank order for agonists. In these studies, we employed radioligand binding studies to determine the degree of competition between prostanoid agonists claimed to be selective on the basis of functional assays. Competition studies with a diverse variety of prostanoids at the binding site for PGE2 and sulprostone on the myometrial plasma membrane prepared from the rat uterus were consistent with the presence of an EP3 receptor. Thus, EP3-receptor agonists (MB 28767 and sulprostone) potently inhibited PGE2 and sulprostone binding, whereas FP agonists (17-phenyl PGF2 alpha, fluprostenol), a DP agonist (BW 245C), an EP1 antagonist (AH 6809), an EP2 agonist (AH 13205) and TP-receptor ligands (BM 13505, I-BOP) afforded little or no inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗