Colitis and docetaxel-based chemotherapy.
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Antineoplastic Agents, Phytogenic↗
Biomedical subjects
W Kreis
Publications and source records attributed to W Kreis.
Structure-specificity relationship of cardiac glycosides as a substrate for glucohydrolase II.
Cardenolide glucohydrolase II (CGH II) is a cardenolide-specific glucohydrolase obtained from Digitalis lanata leaves. We investigated the structure-specificity relationship of several cardenolide disaccharides as a substrate for CGH II. Conformation analysis of the substrates was performed using molecular mechanics calculations. The sugar chain conformation of two inert glycosides was significantly different from that of the other glycosides. The other two glycosides, which were weak substrates of CGH II, were suggested to have an intramolecular hydrogen bond between the sugar groups. It was deduced that this hydrogen bond restricts the conformational change of the sugar chain and prevents the glycosides from enzymatic recognition.
Carbohydrates↗
Synergistic effect of estramustine and [3'-keto-Bmtl]-[Val2]-cyclosporine (PSC 833) on the inhibition of androgen receptor phosphorylation in LNCaP cells.
Estramustine phosphate has been used frequently alone or in combination with other drugs for the treatment of hormone-refractory prostate cancer. Estramustine is one of the major active metabolites of estramustine phosphate in vivo. We recently demonstrated that estramustine acts as an androgen antagonist, and the combination of estramustine with [3'-keto-Bmtl]-[Val2]-cyclosporine (PSC 833) results in synergistic cytotoxicity. Unlike other regulators of microtubules, such as paclitaxel, the present study demonstrated that estramustine alone or in combination with PSC 833 did not induce bcl-2 phosphorylation in LNCaP cells. No synergism between estramustine and PSC 833 in the induction of bcl-2 phosphorylation was obtained in MCF-7 cells exposed for 16 hr to estramustine (5-15 microM) and PSC 833 (5 microM). A significant synergistic antiandrogenic effect as measured by the inhibition of dihydrotestosterone-induced reporter gene luciferase expression in both wild-type and mutated androgen receptor (AR) cDNA-transfected HeLa cells was observed when the cells were exposed to estramustine and PSC 833. Treatment of LNCaP cells with estramustine alone (5-15 microM) resulted in a decrease of AR expression and phosphorylation. This effect was enhanced markedly by PSC 833. A strong correlation between AR phosphorylation and expression of the AR target gene PSA was obtained in dihydrotestosterone-stimulated LNCaP cells. The up-regulated PSA expression is a function of the level of the phosphorylated AR (r = 0.9814), but not the dephosphorylated form of the receptor protein (r = 0.4808). Thus, our studies suggest that the synergism between estramustine and PSC 833 in LNCaP cells is a consequence of inhibition of AR expression and phosphorylation, thus leading to interruption of AR-mediated gene expression.
Antineoplastic Agents, Hormonal↗
Phosphorylation/dephosphorylation of androgen receptor as a determinant of androgen agonistic or antagonistic activity.
Protein phosphorylation/dephosphorylation is an important posttranslational modification that plays a critical role in signal transduction. The androgen receptor (AR) is under such control. We demonstrate that androgen receptor phosphorylation determines whether or not AR ligands perform as agonists or antagonists in LNCaP cells. Androgen receptor ligands (such as dihydrotestosterone and beta-estradiol) stimulate receptor expression and phosphorylation and, as a result, they act as agonists or partial agonists. In contrast, agents such as bicalutamide and estramustine inhibit the receptor phosphorylation and act as antagonists. This model is supported by gene expression and transactivation assays. Significant increases in levels of both mRNA and protein of prostate-specific antigen (PSA), a natural AR target gene, occur following the treatment of LNCaP cells with DHT, beta-estradiol, or hydroxyflutamide. In contrast, exposure of LNCaP cells to bicalutamide or estramustine results in a sharp decrease of PSA expression. Agonistic or antagonistic effect of these compounds on PSA expression parallels the level of phosphorylated, but not dephosphorylated androgen receptors. These agonistic or antagonistic effects are also observed in HeLa cells transfected with wild-type AR expression plasmid (pAR0) and AR-driven luciferase expression plasmid GRE-tk-LUC in the presence of different groups of AR blockers. Our data indicate that the functional status of androgen receptors is strongly correlated with the phosphorylation status of the receptors, and that the phosphorylated androgen receptor is the form of the receptor transcriptionally active in regulation. Thus the androgen receptor phosphorylation/dephosphorylation may serve as a new molecular target for screening androgen antagonists for the treatment of prostate cancer.
Androgen Antagonists↗
The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review.
PURPOSE: Microtubules are important cytoskeletal components involved in many cellular events. Antimicrotubule agents including polymerizing agents (paclitaxel and docetaxel) and depolymerizing drugs (vincristine, vinorelbine, and estramustine phosphate) are widely used either alone or in combination with other anticancer drugs. These antimicrotubule agents are promoters of apoptosis in cancer cells. In this review, we discuss the role of bcl-2 family genes in the regulation of apoptosis, and summarize effects of microtubule targeting agents on apoptotic signal transduction pathways. CONCLUSION: Disruption of microtubule structure by antimicrotubule drugs results in induction of tumor suppressor gene p53 and inhibitor of cyclin-dependent kinases, p21WAF1/CIP1 (p21), and activation/inactivation of several protein kinases including Ras/Raf, PKC/PKA I/II, MAP kinases, and p34cdc2. These protein kinases are associated directly or indirectly with phosphorylation of bcl-2. Phosphorylation of bcl-2 and the elevations of p53 and p21 lead to apoptosis. New pathways of antitumor agents could be directed at this p53, p21 and bcl-2/bax function, and may enhance the effect of existing agents.
Animals↗
Phase I trial of the combination of daily estramustine phosphate and intermittent docetaxel in patients with metastatic hormone refractory prostate carcinoma.
BACKGROUND: To apply our preclinical findings of cytotoxic synergy with the combination of estramustine phosphate (EP) and docetaxel as the basis of treatment of hormone refractory metastatic prostate cancer in man. To determine the optimal dosage and the toxicities of these two agents for future trials. PATIENTS AND METHODS: Seventeen patients with hormone refractory metastatic prostate cancer who were ambulatory with performance status < or = 2, normal marrow, renal and hepatic function were entered. Prior exposure to EP or a taxane were exclusion factors. EP was given orally at a dose of 14 mg/kg of body weight daily with concurrent docetaxel administered every 21 days as an intravenous infusion over 1 hour with dexamethasone 8 mg. PO BID for five days. EP dosages were kept static; docetaxel dosages were explored in a minimum of three patients per level for dosages of 40, 60, 70, and 80 mg/m2. Patients were evaluated weekly. Prostate specific antigen (PSA) was measured every three weeks. RESULTS: Five patients were entered at a docetaxel dose of 40 mg/m2, three at 60 mg/m2, six at 70 mg/m2, and three at 80 mg/m2. Only one patient had received prior chemotherapy. Grades 1 or 2 hypocalcemia and hypophosphatemia were seen at all dosage levels. Other grade 2 or less toxicities not related to dosage included alopecia, anorexia, stomatitis, diarrhea, and epigastric pain. Dose limiting toxicities (DLT) as grade 4 leukopenia and grade 4 fatigue were seen at 80 mg/m2. The phase II dose was defined at 70 mg/m2 with rapidly reversible leukopenia and minor liver function abnormalities. At this dosing level, dose intensity was 88% and 86% over consecutive cycles for docetaxel and EP, respectively. Two vascular events occurred at this dose level (70 mg/m2): one arterial and the other venous. PSA decreases greater than 50% from baseline were seen in 14 of 17 patients at all dosage levels. Four of the 17 patients demonstrated a complete biochemical response (PSA < or = 4 ng/ml). One patient had a partial response with measurable lung and liver lesions. CONCLUSION: EP given continuously with every three-week docetaxel at a dose of 70 mg/m2 is tolerable with evidence of antitumor activity based upon significant declines in PSA in the majority of patients and improvement of lung metastasis in one patient. Larger phase II studies of this combination in a homogenous population are warranted.
Aged↗
Daily oral estramustine and intermittent intravenous docetaxel (Taxotere) as chemotherapeutic treatment for metastatic, hormone-refractory prostate cancer.
As part of an extensive search of synergistic combinations of agents that demonstrate cytotoxic activity in tissue culture against prostate cancer cell lines, we have identified estramustine phosphate and docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) as active. Patients with hormone-refractory metastatic prostate cancer with good performance status were entered onto a phase I trial of this combination. Estramustine phosphate was given on a daily oral dosing schedule of 14 mg/kg; docetaxel was administered intravenously over 1 hour every 3 weeks. Prophylactic corticosteroids were administered to minimize taxane side effects. Four dose levels of docetaxel were studied: 40, 60, 70, and 80 mg/m2. Actual weight was used for dosing calculations. An intermittent docetaxel dose of 70 mg/m2 with estramustine phosphate at 12 mg/kg was determined to be a phase II dose and to allow repetitive dosing. Eight additional patients were entered at this dose level of docetaxel. In all patients, the limiting side effects were fatigue and leukopenia. Thromboembolic events also were seen in 16% of patients. In the first 17 patients treated in the phase I aspect of the study, the biochemical response rate was 82%, demonstrating greater than a 50% decline in prostate-specific antigen. Twenty-four percent had normalization of prostate-specific antigen. These early studies indicate that the combination of estramustine and docetaxel has activity in this population of patients.
Antineoplastic Combined Chemotherapy Protocols↗
A phase II study of docetaxel (Taxotere), estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: preliminary results of cancer and leukemia group B Trial 9780.
Combinations of estramustine with other antimitotic agents, such as docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA), are synergistic in vitro and show significant clinical activity in hormone-refractory prostate cancer (HRPC). We have studied intravenous docetaxel 70 mg/m2, oral estramustine, and low-dose daily hydrocortisone in men with HRPC who demonstrated progression after initial hormone therapy. Of the 47 men who were enrolled, 40 are evaluable for response and/or toxicity. One patient (3%) has had a complete response and eight (20%) have had a partial response, yielding a total objective response rate of 23%. Of 39 patients with elevated pretreatment prostate-specific antigen levels who have had at least one posttreatment prostate-specific antigen measurement, 27 (69%) have had > or =50% decreases and 21 (54%) have had > or =75% decreases in prostate-specific antigen levels. Toxicity is modest but manageable. This therapy is efficacious and well tolerated in HRPC and should be compared in phase III trials with other drugs active in HRPC, such as mitoxantrone and hydrocortisone.
Adenocarcinoma↗
Androgen antagonistic effect of estramustine phosphate (EMP) metabolites on wild-type and mutated androgen receptor.
Estramustine phosphate is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer. Estramustine phosphate is metabolically activated in vivo, and its metabolites, estramustine, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules [for review see: Kreis W, In: Concepts, Mechanisms, and New Targets for Chemotherapy (Ed. Muggia FM), pp. 163-184. Kluwer Academic Publishers, Boston, 1995]. We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of estramustine phosphate and its metabolites, estramustine, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, bicalutamide, and hydroxyflutamide, to the mutated androgen receptor (m-AR) in LNCaP cells and to the wild-type androgen receptor in wild-type AR cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells. Analogous to the antiandrogens, bicalutamide and hydroxyflutamide, binding of estramustine phosphate metabolites to the androgen receptor was observed. The EC50 values (in microM) were: estramustine phosphate, > 10; estramustine, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; bicalutamide, 4.920 +/- 0.361; and hydroxyflutamide, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to bicalutamide, estramustine could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of prostate-specific antigen (PSA) expression, an AR-target gene, by estramustine and bicalutamide was accompanied by the blockade of the mutated androgen receptor. Exposure of LNCaP cells to estramustine for 24 hr caused transcriptional inhibition of PSA in a concentration-dependent manner. The levels of PSA mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of estramustine, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of hydroxyflutamide to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of PSA expression, suggesting that hydroxyflutamide acted as an agonist of the m-AR. Our data indicate that estramustine phosphate metabolites perform as androgen antagonists of AR, an additional mechanism involved in the therapeutic effect of estramustine phosphate in patients with prostate cancer.
Androgen Antagonists↗
Synthesis of cardenolide glycosides and putative biosynthetic precursors of cardenolide glycosides.
A rapid and efficient procedure for glycosylation of steroids was established using a modified Koenigs-Knorr procedure. Peracetylated beta-glycosides were synthesized by reaction of cardenolides, various pregnanes and 23-nor-5,20(22)E-choldienic acid at room temperature with the peracetylated 1-bromo derivatives of D-glucose, D-galactose, D-fucose and cellobiose. Subsequent deprotection was performed by alkaline hydrolysis with sodium methoxide. Structures of the respective glycosides were established by NMR techniques. The complete protocol was shown to be non-destructive at all stages to the sugar moiety and the steroidal nucleus. The gamma-unsaturated lactone ring of the cardenolides was shown to remain intact and no formation of C-14 unsaturated compounds was observed.
Cardenolides↗
In vitro evaluation of synergism or antagonism with combinations of new cytotoxic agents.
New cytotoxics with significant activity both in preclinical and clinical situations continued to be applied in the clinic by empiric means. The use of defined cell lines allows unanticipated antagonism between agents to be identified and to suggest synergistic combinations which need to be tested. By means of a semi-automated MTT assay and median effect analysis, we have identified antagonism in two couplets being evaluated in the clinic: etoposide with paclitaxel and vinorelbine with gemcitabine. Optimal use of these agents in man may require spacing these agents in time to prevent an adverse drug interaction between the agents which may diminish the potential response rate.
Antineoplastic Combined Chemotherapy Protocols↗
Down-regulation of prostate-specific antigen expression by finasteride through inhibition of complex formation between androgen receptor and steroid receptor-binding consensus in the promoter of the PSA gene in LNCaP cells.
As a specific competitive inhibitor of 5alpha-reductase, an intracellular enzyme that converts testosterone to dihydrotestosterone, finasteride is being extensively used for the treatment of benign prostatic hyperplasia and in experimental settings for prostate cancer. In this study, we showed that finasteride markedly inhibited prostate-specific antigen (PSA) secretion and expression. The promoter of the PSA gene contains several well-known cis-regulatory elements. Among them, steroid receptor-binding consensus (SRBC) has been identified as a functional androgen-responsive element. Our previous study showed that PSA was not only present in conditioned medium of the PSA-positive LNCaP cells but was also detectable in small amounts in PSA-negative cell lines, PC-3 and DU-145 (L. G. Wang et al., Oncol. Rep., 3: 911-917, 1996). A strong correlation between binding of nuclear factors to SRBC and the level of PSA present in the conditioned medium and cell extracts was found in these three cell lines, whereas no such correlation with binding was obtained using Sp1 oligonucleotide as a probe. Binding of LNCaP cell nuclear proteins to SRBC was diminished when the cells were exposed to 25 microM finasteride, at which concentration 50% of both PSA mRNA and protein were inhibited. As a major component of DNA-protein complexes, the level of androgen receptor was dramatically decreased in the cells treated with finasteride. Our data indicate that inhibition of complex formation between SRBC and nuclear proteins due to the remarkable decrease in the level of androgen receptor plays a key role in the down-regulation of PSA gene expression by finasteride in LNCaP cells.
Consensus Sequence↗
Unique synergism or antagonism of combinations of chemotherapeutic and hormonal agents in human prostate cancer cell lines.
OBJECTIVE: To evaluate combinations of anti-tumour agents in tissue cultures using three established cell lines derived from patients with prostate cancer to obtain potential candidates for therapeutic testing in patients with prostate cancer. MATERIALS AND METHODS: Seventeen anti-tumour agents were tested for synergism or antagonism in combination studies in DU 145, PC 3 and LnCaP cell lines. After determining the dose required for 50% inhibition of growth in each, combinations were screened using the median-effect plot and combination-index isobolograms. RESULTS: Estramustine (the primary product of dephosphorylation of estramustine phosphate) showed strong synergism in all three cell lines with hydroxyflutamide, the non-immunosuppressive cyclosporin analogue PSC 833, and Liarozole. In the hormone-sensitive cell line LnCaP alone, synergism was also observed with vinblastine, paclitaxel, docetaxel, bicalutamide, ketoconazole and all-trans-retinoic acid. Other synergistic combinations of two agents were: Liarozole plus docetaxel in LnCaP, PSC 833 plus bicalutamide in DU 145 and PC 3, dexamethasone plus docetaxel in LnCaP, and finasteride plus hydroxyflutamide. Synergistic combinations of three agents were: estramustine plus PSC 833 and Liarozole and schedule-dependent combinations of estramustine, PSC 833, and all-trans-retinoic acid. CONCLUSION: Some of the synergistic combinations have shown clinical effects in patients with hormone-refractory prostate cancer. Based on these findings, new combinations, e.g. estramustine with either PSC 833 or Liarozole, need to be clinically evaluated.
Antineoplastic Agents, Hormonal↗
Extracellular polysaccharides produced by suspension-cultured cells from Digitalis lanata.
Extracellular polysaccharides (ECP) were isolated in yields of up to 4 mg/ml from the culture media of suspension-cultured cells from Digitalis lanata Ehrh. ECP content was increasing continuously over the first ten days of cultivation and then stayed constant until day 20. ECP were fractionated by ion-exchange chromatography into two neutral and one acidic fractions. Further fractionation was achieved by gel-permeation chromatography (GPC). One neutral fraction was separated into two distinct fractions with average molecular weights of 160 and 70 kDa, respectively. The second neutral fraction was hetero-disperse in GPC with average molecular masses of 112, 32, and 8 kDa. Polysaccharides of all neutral fractions consisted of glucose, xylose, galactose, and arabinose. Methylation analysis indicated these fractions to contain xyloglucans besides minor amounts of highly branched arabinogalactans. Xyloglucans were, using endo-beta-(1-->4)glucanase, fragmented into subunits which were identified mainly as tri- and pentasaccharides. The acidic fraction eluated as a single peak during gel-permeation chromatography with an average molecular weight of 56 kDa. Analysis of carbohydrate composition and linkage analysis indicated that this polysaccharide is an acidic arabinogalactan. 2,6-Dideoxysugars, the typical carbohydrate components of cardiac glycosides in Digitalis lanata, were not detected in ECP.
Carbohydrate Conformation↗
Isolation of cardenolides from a Brazilian cultivar of Digitalis lanata by rotation locular counter-current chromatography.
Cardenolides from a Brazilian cultivar of Digitalis lanata were isolated by rotation locular countercurrent chromatography (RLCC), employing dichloromethane-methanol-water (5:6:4, v/v) as the solvent system. Highly pure lanatoside C was obtained from the Digitalis lanata hydromethanolic extract, pre-purified either by silica gel or reversed-phase chromatography.
Cardenolides↗
Pharmacokinetic evaluation of high-dose etoposide phosphate after a 2-hour infusion in patients with solid tumors.
Etoposide phosphate, a water soluble prodrug of etoposide, was evaluated at levels potentially useful in transplantation settings in patients with malignancies. For pharmacokinetic studies of etoposide phosphate in this phase I study, 21 patients with solid tumors were treated with etoposide phosphate given as etoposide equivalents of 250, 500, 750, 1000 and 1200 mg/m2 infused over 2 h on days 1 and 2, and G-CSF 5 micrograms/kg per day starting on day 3 until WBC was > or = 10,000/microliters. Qualitative, quantitative, and pharmacokinetic analysis was performed as reported previously. Rapid conversion of etoposide phosphate into etoposide by dephosphorylation occurred at all dosage levels without indication of saturation of phosphatases. Plasma levels (C(pmax)) and area under the curve (AUC) of etoposide phosphate and etoposide demonstrated linear dose effects. For etoposide, plasma disposition demonstrated biphasic clearance, with mean T1/2 alpha of 2.09 +/- 0.61 h, and T1/2 beta of 5.83 +/- 1.71 h. An AUC as high as 1768.50 micrograms.h/ml was observed at a dose of 1200 mg/m2. The total body clearance (TBC) showed an overall mean of 15.72 +/- 4.25 ml/min per m2, and mean volume of distribution (VDss) of 5.64 +/- 1.06 l/m2. The mean residual time (MRT) for etoposide was 6.24 +/- 1.61 h. In urine, etoposide but not etoposide phosphate, was identified with large quantitative variations (1.83% to 33.45% of injected etoposide equivalents). These results indicate that etoposide phosphate is converted into etoposide with the linear dose-related C(pmax) and AUCs necessary for use of this agent at the high dosage levels needed in transplantation protocols. A comparison of pharmacokinetic parameters of high-dose etoposide with the values observed in our study with etoposide phosphate revealed comparable values for the clinically important C(pmax) and AUCs, clearance, terminal T1/2 and MRT. In contrast to the use of etoposide, etoposide phosphate can be delivered in aqueous vehicles and therefore may offer the advantage of ease of administration.
Antineoplastic Agents↗
Symptomatic improvement associated with combined estramustine and vinblastine chemotherapy for metastatic prostate cancer.
We evaluated the effectiveness of combination chemotherapy using estramustine and velban for metastatic prostate cancer. Patients with progressive metasatatic prostate cancer and rising prostate-specific antigen (PSA) values were evaluated between 1992 and 1994. All treatment was given on an outpatient basis. Vinblastine, 4 mg/m2 i.v., was given weekly for 6 weeks with a 2-week rest period. Estramustine, 10 mg/kg orally, was given in three divided doses for 6 weeks with a 2-week rest period between cycles. Of 15 patients, six (40%) had a response, in which a 25% decrease in PSA was associated with subjective improvement. There were no complete responses. Five partial responders had less pain. Median duration of response or time to progression was 9 months. Survival was 11.7 months for responders, 13.2 months for nonresponders. The combination of estramustine and velban is an effective therapy in progressive metastatic prostate cancer as measured by a decrease in PSA and improvement of symptoms.
Aged↗
Clinical pharmacokinetics of amonafide (NSC 308847) in 62 patients.
Amonafide (A) demonstrates dose-related increases in area under the curve (AUC) and Cmax values. Total body clearance for A (ranging from 44.2 to 53.8 L/hr/m2) is relatively constant within the dosing range of this study. The dose-related increase of AUC was also observed for the two identified metabolites, acetylamonafide (AA) and noramonafide (NA). A and NA plasma data could be described by a four-compartmental model (two compartments for A, one compartment each for NA and AA). The fitting for NA was poor owing to its low plasma concentration. The terminal half-lives for A, NA, and AA were in the range of 3-6 hr. No cumulative accumulation of parent compound or metabolites was detected after daily administration, The concentrations of A, NA, and AA 24 hr after dosing were either below or very close to the quantitative limits of the assay. Polymorphic disposition of A was confirmed by a frequency distribution of AUC value versus dose plot.
Adenine↗