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Biomedical subjects

V Sandor

Publications and source records attributed to V Sandor.

At least 19 recordsLinked to original sources
PubMed2003

SarCNU, a nitrosourea analog on a day 1, 5, and 9 oral schedule: a phase I and pharmacokinetic study in patients with advanced solid tumors.

PURPOSE: 2-Chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) is a novel chloroethylnitrosourea that demonstrates selective cytotoxicity in athymic mice bearing human glioma. SarCNU demonstrates selective cytotoxicity in vitro against human glioma at least in part because of the selective SarCNU uptake by the extraneuronal monoamine transporter. The purpose of this phase I study was to determine the maximum-tolerated dose (MTD), the toxicity profile, the pharmacokinetics profile, and recommended phase II dose. PATIENTS AND METHODS: Forty-three eligible patients with advanced solid tumors were enrolled. SarCNU was administered orally on days 1,5, and 9 every 28 days. The dose ranged from 30 to 1,075 mg/m2. Pharmacokinetic evaluation was done on the first cycle (one dose was given intravenously on day 1 or 5 of the first cycle to determine bioavailability). RESULTS: Delayed myelosuppression (thrombocytopenia and neutropenia occurring 4 to 6 weeks after administration) was the dose-limiting toxicity (DLT). Anemia occurred but was mild. Nonhematologic toxicity was generally mild, but one patient died with pulmonary toxicity that was probably secondary to SarCNU. There were no partial or complete responses, but eight patients had stable disease for 19 to 46 weeks. The oral bioavailability of SarCNU was 80% +/- 37%. The terminal phase half-life was similar after intravenous (58.4 +/- 23.5 minutes) or oral (64.0 +/- 34.8 minutes) administration. The total plasma clearance was 20.4 +/- 8.8 L/h/m2, and the apparent volume of distribution was 29.9 +/- 17.6 L/m2. The area under the plasma concentration-time profile increased proportionally with the dose, and the pharmacokinetics seemed to be independent of the route of administration and the number of doses. CONCLUSION: SarCNU was well tolerated and the MTD was 1,075 mg/m2. The recommended starting dose for phase II trials is 860 mg/m2 orally on days 1, 5, and 9 every 6 weeks.

Administration, Oral↗
PubMed2001

Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report.

Depsipeptide, FR901228, has demonstrated potent in vitro and in vivo cytotoxic activity against murine and human tumor cell lines. In the laboratory, it has been shown to be a histone deacetylase (HDAC) inhibitor. In a phase I trial of depsipeptide conducted at the National Cancer Institute, 3 patients with cutaneous T-cell lymphoma had a partial response, and 1 patient with peripheral T-cell lymphoma, unspecified, had a complete response. Sézary cells isolated from patients after treatment had increased histone acetylation. These results suggest that inhibition of HDAC is a novel and potentially effective therapy for patients with T-cell lymphoma.

Acetylation↗
PubMed2000

P21-dependent g(1)arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228.

Depsipeptide, FR901228, a novel cyclic peptide inhibitor of histone deacetylase with a unique cytotoxicity profile is currently in phase I clinical trials. Here we demonstrate that, in addition to G2/M arrest, FR901228 causes G1 arrest with Rb hypophosphorylation. In vitro kinase assays demonstrated no direct inhibition of CDK activity, however, an inhibition was observed in CDKs extracted from cells exposed to FR901228. Cyclin D1 protein disappeared between 6 and 12 hours after treatment with FR901228, whereas cyclin E was upregulated. While it did not induce wt p53, FR901228 did induce p21(WAF1/CIP1)in a p53-independent manner. Cell clones lacking p21 were not arrested in G1 phase, but continued DNA synthesis and were arrested in G2/M phase following FR901228 treatment. Finally, FR901228 blunted ERK-2/MAPK activation by EGF whereas early signal transduction events remained intact since overall cellular tyrosine phosphorylation after EGF stimulation was unaffected. Thus, FR901228, while not directly inhibiting kinase activity, causes cyclin D1 downregulation and a p53-independent p21 induction, leading to inhibition of CDK and dephosphorylation of Rb resulting in growth arrest in the early G1 phase. In contrast to the G1 arrest, the G2/M arrest is p21-independent, but is associated with significant cytotoxicity.

Anti-Bacterial Agents↗
PubMed2000

FR901228 causes mitotic arrest but does not alter microtubule polymerization.

FR901228, a natural cyclic depsipeptide, shows high cytotoxicity against human cancer cell lines (low nM IC50 values). Cells exposed to FR901228 arrest with G1 or G2/M DNA content; S phase is depleted. G2/M cells include cells arrested in mitosis. We wished to understand the mitotic arrest by this compound. Mitotic arrest is often due to interference with microtubules and COMPARE testing in the NCI drug screen indicated a possible taxane-like mechanism. Testing of FR901228 for tubulin binding or alteration of in vitro MT assembly failed to reveal any effect. Likewise, examination of cellular microtubules following exposure to FR901228 did not reveal any change. Similar G2/M accumulation was observed in MCF7, MCF10 and PC3 cells. About 50% of G2/M cells were mitotic and contained microtubule spindles. Mitotic cells peaked at about 14-16 h drug exposure and declined to near 0% by 24-30 h. The block was at prometaphase, with numerous chromosomes unattached to the spindle. We conclude that FR901228 induces formation of aberrant spindles probably by interfering with chromosome attachment, causing mitotic accumulation without affecting mitotic microtubules.

Anti-Bacterial Agents↗
PubMed1999

Synchronous inflammatory breast cancer and advanced ovarian carcinoma: a case with prolonged disease-free survival.

Despite the known association of these malignancies, the incidence of a synchronous presentation of breast and ovarian cancer is low, and the current literature does not address an approach to this clinical problem directly. We report a greater than 2.5 year disease-free survival in a patient treated for synchronous stage IIIB inflammatory breast cancer and stage IIIC epithelial ovarian cancer. The prolonged disease-free survival in our case may provide some guidance in this unusual clinical situation.

Breast Neoplasms↗
PubMed1998

Future perspectives for the development of P-glycoprotein modulators.

Resistance to chemotherapeutic agents constitutes one of the major obstacles to the successful treatment of cancer. While several mechanisms underlying drug resistance have been elucidated, the most widely studied mechanism involves the efflux of antineoplastic drugs from cancer cells by P-glycoprotein, the 170 kD glycoprotein product of the MDR-I gene. The observation that several compounds are able to inhibit P-glycoprotein in vitro created optimism that the problem of multidrug resistance in cancer could be quickly resolved by moving these compounds into the clinic. However, despite a large number of clinical trials with several different putative Pgp modulators, the value of Pgp modulation in clinical oncologic practice remains unresolved. While these initial trials have not answered the question of whether Pgp is an important mechanism of resistance in human cancers, or whether modulation of Pgp is likely to positively impact on the treatment of cancer, they have provided insights regarding the problems inherent in conducting trials of this nature. These clinical insights, along with knowledge gained from continued basic research on drug resistance mediated by Pgp and related transporters, will form a strong foundation for future research into the role of Pgp and Pgp modulation in the treatment of cancer. The ubiquitous nature of transporters and the high prevalence of transporter substrates among antineoplastic drugs, compel the development of modulators that can be used to prevent or reverse drug resistance.

Journal Article↗
PubMed1998

Using the national cancer institute anticancer drug screen to assess the effect of MRP expression on drug sensitivity profiles.

The MRP gene contributes to one form of multidrug resistance. To identify drugs interacting with MRP, we measured MRP mRNA expression by quantitative PCR in 60 cell lines of the National Cancer Institute Anticancer Drug Screen. Expression was detected in all cell lines (highest in lung carcinomas and central nervous system tumors) with a range of 14-fold. A mean graph of MRP mRNA levels was constructed to determine Pearson correlation coefficients (PCCs) with mean graphs of >40,000 compounds using the COMPARE analysis. Only 20 compounds had PCCs of >/=0.500. The PCCs for VP-16, doxorubicin, and vincristine were 0.008, 0.13, and 0.257, respectively. Initially, 36 compounds with PCCs of >/=0.428 were analyzed using two MRP-overexpressing cell lines; low levels of cross-resistance was demonstrated for 23 compounds (1.3-9.4-fold). Twenty-four compounds also were available for further studies. Using a fluorescence activated cell sorter assay to measure competition of calcein efflux from MRP-overexpressing cells, 10 compounds were found to increase calcein retention by >/=2-fold. Ten compounds also were able to reduce ATP-dependent [3H]LTC4 transport into vesicles from MRP-overexpressing cells. These results contrast with previous studies with MDR-1 in which high correlations were found and confirmed for a large number of compounds. Although other assays may be more revealing, in these unselected cell lines, MRP mRNA expression was a poor predictor of drug sensitivity. This raises the possibility that other factors, including conjugating enzymes, glutathione levels, or other transporters, confound the MRP effect.

ATP-Binding Cassette Transporters↗
PubMed1998

Phase II trial of chemotherapy alone for primary CNS and intraocular lymphoma.

PURPOSE: Primary CNS lymphoma (PCNSL) and primary intraocular lymphoma (IOL) are usually treated with radiation therapy alone or in combination with chemotherapy. The neurotoxicity of these treatments can be substantial. This study attempts to define the toxicity and efficacy of the treatment of this disease with chemotherapy alone. PATIENTS AND METHODS: Fourteen nonimmunocompromised patients were accrued to a chemotherapy regimen that incorporated a 24-hour infusion of high-dose methotrexate total dose of 8.4 g/m2 with leucovorin rescue; thiotepa 35 mg/m2; vincristine 1.4 mg/m2; dexamethasone; and intrathecal cytarabine (Ara-C) and methotrexate (MTV) administered in 21-day cycles. Seven patients were prospectively followed up with formal neuropsychologic assessments for evidence of CNS toxicity. RESULTS: The response rate was 100% with 11 (79%) complete responses and three (21%) partial responses. Cumulative survival and progression-free survival rates at more than 4.5 years were 68.8% and 34.3%, respectively. Median survival has not been reached, and median progression-free survival was 16.5 months. Toxicity included severe leukoencephalopathy that was clearly attributable to chemotherapy (two patients), grade 3 or 4 neutropenia in 50% of the cycles administered, ileus (one patient), and seizures (two patients). Mucositis and renal and hepatic toxicity were mild and not therapy limiting. CONCLUSION: The MTV regimen is generally well tolerated and produces a high complete response rate. Chemotherapy alone should be investigated further in this disease to assess the necessity of initial radiation therapy, either alone or in combined modality regimens, for the achievement of optimal response and survival.

Adult↗
PubMed1997

The role of MDR-1 in refractory lymphoma.

Although lymphoma is one of the few solid tumours for which chemotherapy can be curative, the treatment of refractory lymphoma remains a major clinical problem. P-glycoprotein (Pgp), the drug efflux pump encoded by the MDR-1 gene is associated with multidrug resistance in several laboratory models of drug resistance, and a number of investigators have attempted to establish a role for Pgp in refractory lymphoma. Despite a considerable variability in the results of these studies investigating Pgp expression in lymphoma, the preponderance of the data suggests that Pgp may at least in part account for drug resistance in this disease. Several clinical trials using Pgp modulating compounds have attempted to reverse the drug resistant phenotype of refractory lymphoma. These studies, although difficult to interpret because of the effect of Pgp modulators on chemotherapeutic drug pharmacokinetics, also suggest a role for Pgp in mediating drug resistance in a subset of patients with refractory lymphoma. Studies with newer Pgp modulating agents with phase III designs will be needed before Pgp modulation can be considered for incorporation into routine oncologic practice.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Quantitation of the diastereoisomers of L-buthionine-(R,S)-sulfoximine in human plasma: a validated assay by capillary electrophoresis.

An assay for the diastereoisomers of the biochemical modifier L-buthionine-(R,S)-sulfoximine (BSO) in human plasma has been developed using capillary electrophoresis (CE). Separation of the diastereoisomers is achieved by the micellar electrokinetic chromatography (MEKC) mode of CE. Plasma is injected directly onto the separation capillary without any extraction step, and BSO is detected directly by ultraviolet absorbance measurements at 190 nm without prior derivatization. The whole assay, including capillary conditioning, takes approximately 30 min. Intra- and inter-day R.S.D. values are approximately 7% at sample concentrations around 25 micrograms ml-1, and approximately 3% at sample concentrations around 500 micrograms ml-1. The limit of detection in plasma is 3.9 micrograms ml-1 (S/N = 2). The assay has been used to quantitate the diastereoisomers of BSO in patient samples in a pharmacokinetic study.

Electrophoresis, Capillary↗
PubMed1993

The mechanism involved in the central effect of 5-leu enkephalin on the calcitonin secretion.

Calcitonin (CT) secretion is not exclusively under the control of calcium levels in the plasma, but also depends on the sympathetic-adrenergic tone. In previous experiments we stressed out the possible role played by 5-leu enkephalin (5-LE) in the nervous regulation of the CT secretion. Intracerebroventricular (i.c.v.) 5-LE in doses of 100 micrograms could act at a central level through a mechanism independent from the noradrenergic pathways, since i.c.v. 6-OHDA and propranolol could not interfere with its stimulatory effect on the CT content of the thyroid. In the present experiments, performed in anaesthetized Wistar-Bratislava rats, we studied the involvement of mu and delta receptors in the central effect of 5-LE on the CT content of the thyroids and the CT levels in the plasma. These parameters were measured in parallel, by means of a competitive radioimmunoassay with double antibodies (Peninsula Lab.). 5-LE probably bound to both mu and delta receptors, since its effect on the CT secretion was reversed by 13 micrograms of naloxone (i.c.v.). A partial blockade, comparable to naloxone, was noticed after 382 micrograms of CTOP (i.c.v.), a specific antagonist of the mu receptors--stressing out their involvement in the stimulatory effect of 5-LE on the CT secretion. 250 Ug of ICI 174864 (i.c.v.), a selective antagonist the the delta receptors completely blocked the stimulation induced by 5-LE on the CT secretion to values significantly lower as compared to the controls and even to the sympathectomized group. This suggests the tonic role played by enkephalins in the CT secretion, through the central activation of delta receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Central antiarrhythmic effects of imidazole in anesthetized rats.

In urethane anesthetized rats, the intracerebroventricular (icv.) microinjection of sodium glutamate or KCl induced cardiac arrhythmias. These cardiac rhythm disorders could be prevented by the icv. administration of imidazole. The i.v. injection of the same doses of imidazole elicited cardiac arrhythmias. The antiarrhythmic activity of imidazole is probably due to its ability to stimulate phosphodiesterase activity, which leads to a decrease in cGMP and/or cAMP cerebral levels.

Anesthesia↗
PubMed1986

Central antiarrhythmic activity of adenosine in anesthetized rats.

In urethane-anesthetized rats the intracerebroventricular (icv.) administration of sodium glutamate or desipramine induced cardiac arrhythmias. These cardiac rhythm disturbances could be prevented by icv. administration of adenosine. The i.v. injection of adenosine had an arrhythmogenic action. The antiarrhythmic effect of adenosine could be reversed by icv. aminophylline. It is suggested that the antiarrhythmic activity of adenosine is due to the central inhibition of release of acetylcholine, and/or noradrenalin, produced by the decreased availability of calcium for the excitation-secretion coupling.

Adenosine↗