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P Mistry

Publications and source records attributed to P Mistry.

At least 55 records · Page 3Linked to original sources
PubMed1992

Establishment and characterization of an in vitro model of acquired resistance to cisplatin in a human testicular nonseminomatous germ cell line.

Clinically, human testicular nonseminomatous germ cell tumors exhibit remarkable sensitivity to platinum-based chemotherapy. To define better the mechanistic basis for this unusual sensitivity, the biochemical determinants of platinum-induced cytotoxicity have been investigated in a human testicular tumor cell line (GCT27) established from a previously untreated patient and in an in vitro derived 5.6-fold cisplatin-resistant stable variant (GCT27cisR). Compared to 12 ovarian and 5 cervical human tumor cell lines, the parent GCT27 line was among the most sensitive to the cytotoxic effects of both cisplatin (dosage producing 50% inhibition, 0.2 microM) and carboplatin (dosage producing 50% inhibition, 2.9 microM), thus reflecting clinical data. A 4-day exposure sulforhodamine B-staining assay was used to determine that GCT27cisR was cross-resistant to carboplatin and iproplatin and the classical bifunctional alkylating agents melphalan and chlorambucil. Partial cross-resistance was observed to tetraplatin, methotrexate, and mitomycin C. No cross-resistance was observed to Adriamycin, etoposide, vinblastine, bleomycin, 1-beta-D-arabinofuranosylcytosine, and 5-fluorouracil. Intracellular cisplatin accumulation across the dose range 2.5-100 microM (for 2 h) was 1.6 +/- 0.39-fold (mean +/- SD) greater for the parent line. There was no significant difference in glutathione levels between the two lines. The acquired resistance line was 1.9-fold more resistant than the parent line to the cytotoxic effects of cadmium chloride. There was no significant difference between the two lines, however, in the total amounts of platinum bound to DNA after cisplatin exposure (25, 50, or 100 microM for 2 h). The removal of total platinum adducts from DNA was significantly faster for GCT27cisR compared to the parent line (half-times of removal, 32 and 67 h, respectively). These data suggest that the abnormal sensitivity of the parent testicular tumor cell line to platinum-containing anticancer drugs may be due predominantly to an inherent defect in the ability of these cells to remove platinum from their DNA. This defect is apparently lost in the acquired resistance counterpart. Reduced intracellular accumulation and increased cytoplasmic concentrations of metallothionein may also contribute, in part, to the acquisition of cisplatin resistance in this model.

Antineoplastic Agents↗
PubMed1992

Ammine/amine platinum(IV) dicarboxylates: a novel class of platinum complex exhibiting selective cytotoxicity to intrinsically cisplatin-resistant human ovarian carcinoma cell lines.

Using a panel of six human ovarian carcinoma cell lines varying by two orders of magnitude in terms of cisplatin cytotoxicity, we have investigated the in vitro antitumor activity of a series of novel alkylamine ammine dicarboxylatodichloroplatinum(IV) complexes of the general formula c,t,c-[PtCl2(OCOR1)2NH3(RNH2)]. A clear relationship existed between increasing the number of carbons in the R1 substituent and increasing cytotoxicity up to R1 = C5H11. In terms of changing the R group, maximum cytotoxic effects were conferred by alicyclic substituents. Furthermore, increasing the alicyclic ring size from cyclobutane through to cycloheptane resulted in increasing cytotoxicity. The agents with longer axial chains (e.g., JM300, R = cyclohexyl, R1 = C6H13) were significantly more cytotoxic than cisplatin and, moreover, exhibited a selective cytotoxic effect against the most intrinsically cisplatin-resistant cell lines (e.g., for HX/62, cisplatin 50% inhibitory concentration, 12.6 microM; SKOV-3, cisplatin 50% inhibitory concentration, 4.4 microM and 41 M; cisplatin 50% inhibitory concentration, 0.23 microM; JM300 was 840-, 440-, and only 34-fold more active, respectively). The dicarboxylates JM221 (R = cyclohexyl, R1 = C3H7) and JM244 (R = n-propyl, R1 = C6H5) also retained activity against a 4-fold cisplatin-acquired resistant variant of the 41M cell line. At least part of the increased cytotoxicity of the dicarboxylate, JM221, over cisplatin appeared to be attributable to an increased intracellular accumulation. This novel class of platinum compound represents a valuable lead in the development of a "third-generation" agent capable of exhibiting activity against clinical disease currently resistant to cisplatin.

Antineoplastic Agents↗
PubMed1992

Reduced drug accumulation as a major mechanism of acquired resistance to cisplatin in a human ovarian carcinoma cell line: circumvention studies using novel platinum (II) and (IV) ammine/amine complexes.

Acquired resistance to cisplatin (cis-diamminedichloroplatinum (II)) has been generated in vitro in the 41M human ovarian carcinoma cell line, established from a previously untreated patient. Three cisplatin-resistant variants were selected at approximately 2, 4 and 6-fold resistance (in terms of 50% inhibitory concentrations), in order to study the underlying mechanisms of acquired cisplatin resistance. Compared to the parent line, platinum accumulation following exposure to equimolar concentrations of cisplatin was on average (across the entire concentration range) 2.9, 3.6 and 4.8-fold lower in the 41McisR2, 41McisR4 and 41McisR6 cell lines, respectively. Thus the difference in uptake corresponded closely with their resistance factor in the three resistant variants. Moreover, a significant reduction in platinum accumulation was observed as early as 5 min after exposure to cisplatin in the 41M vs 41McisR6 cell lines. Platinum accumulation was similar in all cell lines following exposure to equitoxic concentrations (2 h IC50) of cisplatin. Enhanced efflux of drug was not observed between the 41M and 41McisR6 cells. In addition, there was no difference in intracellular glutathione (GSH) levels. Our previous studies have shown no indication of metallothionein involvement and the decrease in cisplatin uptake in the 41McisR6 cells was reflected by a similar reduction in DNA interstrand cross-links (ISC) formation. These results suggest that the mechanism of acquired resistance to cisplatin in the 41McisR6 cell line may be predominantly due to reduced drug uptake. The 41McisR6 cells were not found to be cross-resistant to ouabain, a postulated specific inhibitor of sodium-potassium adenosine triphosphatase (Na+, K(+)-ATPase), suggesting that decreased cisplatin accumulation in these cells is probably not regulated by alterations in their Na+, K(+)-ATPase levels, and Na+ potential across the plasma membrane. Cellular accumulation of a novel class of platinum (IV) ammine/cyclohexylamine dicarboxylates, which exhibit enhanced cytotoxicity over cisplatin and completely circumvent resistance to cisplatin in the 41McisR line, was also examined. The data suggests that increased accumulation of these compounds, as a result of their enhanced lipophilicity, could account for the dramatic increase in their potency over cisplatin.

Carcinoma↗
PubMed1991

Electrospray ionization mass spectrometry of platinum anticancer agents.

Quantification and identification of platinum drugs and their metabolites in biological samples has always been difficult because these compounds are thermally unstable, non-volatile and insoluble. We have demonstrated that electrospray ionization mass spectrometry can be a valuable technique for direct mass spectral analysis of platinum anticancer agents and for obtaining structural information as a result of fragmentation. Full-scan spectra were obtained with approximately 10 pmol samples. These results show the potential of applying this technique in pharmacokinetic studies of platinum anticancer drugs.

Antineoplastic Agents↗
PubMed1991

The effects of cisplatin on the concentration of protein thiols and glutathione in the rat kidney.

The effect of a nephrotoxic dose of cisplatin (5 mg/kg) on the concentrations in the rat kidney of both glutathione and protein-bound thiols was investigated. Total glutathione and oxidised glutathione were measured in the cortex and outer medulla using specific enzyme-based assays. The high-molecular-weight thiols were quantified in cells of the proximal tubule using a cyto-chemical technique. The concentration of total glutathione (oxidised and reduced) in the kidney cortex and outer medulla was significantly higher than that of controls at 1 h following cisplatin administration. The amount by which the concentration in treated animals exceeded that in controls increased to 50% at 72 h and remained significantly elevated for 120 h following treatment. This increase was mainly attributable to an increase in the concentration of reduced glutathione. In contrast, the concentration of protein thiols in the proximal tubules decreased significantly at 8 h after dosing, reaching a nadir 29% below that of controls at 120 h, thus coinciding with the maximal functional disturbance in the kidney as reflected by the concentration of blood urea. The decrease in protein thiols could not be correlated stoichiometrically with the platinum concentration in the cortex and outer medulla, which reached a peak of 16.3 +/- 0.3 micrograms/g wet tissue at 72 h after treatment. Evidently cisplatin perturbs the equilibrium that is said to exist between the concentration of reduced glutathione and that of protein thiols. This perturbation occurs well before the onset of overt functional disturbance of the kidney and is evident before the point at which the damage to the kidney caused by cisplatin becomes irreversible.

Animals↗
PubMed1991

Historical aspects of glutathione and cancer chemotherapy.

This presentation sets in historical context the impact of glutathione and its metabolism upon the efficacy of several anticancer drugs. The basic biochemistry of the tripeptide is reviewed briefly, highlighting its role in oxido-reduction and in the gamma-glutamyl cycle. The ability of selective modulators of glutathione metabolism, such as buthionine sulfoximine, as adjuncts to chemotherapy is also discussed.

Animals↗
PubMed1991

The relationships between glutathione, glutathione-S-transferase and cytotoxicity of platinum drugs and melphalan in eight human ovarian carcinoma cell lines.

The role of glutathione (GSH) and GSH-S-transferase (GST) activity in modulating the cytotoxicity of four platinum drugs and melphalan was evaluated in eight human ovarian carcinoma cell lines. The cell lines were established from solid and ascitic tumours from pretreated and untreated patients, and showed a wide spectrum of sensitivity to several platinum II and platinum IV drugs; cisplatin, carboplatin, CHIP and tetraplatin. Intracellular glutathione concentration measured in the cell lines showed a significant (P = 0.05) correlation with IC50 values for cisplatin (r = 0.91), carboplatin (r = 0.87) and CHIP (r = 0.88). The correlation between GSH levels and IC50 values for melphalan (r = 0.76) or tetraplatin (r = 0.60) was not as significant. GST activity showed no correlation with IC50 values, for the four platinum drugs. To determine the significance of the elevated GSH concentration in the refractory cell lines, the effect of D,L-buthionine-S, R-sulfoximine (BSO) mediated GSH depletion on platinum drug cytotoxicity was examined in one of the most sensitive (CH1) and two of the least sensitive (relatively resistant; SKOV-3, HX/62) cell lines. Comparison was made with the effect of GSH depletion on melphalan cytotoxicity in these three lines. These lines were differentially sensitive to BSO, with the two most platinum drug resistant lines being more tolerant to BSO than the sensitive CH1 line. Depletion of cellular GSH, ranging between 61 and 88%, had a differential effect on the sensitivity to PtII vs PtIV drugs in the three cell lines: cytotoxicity of the PtIV drugs, tetraplatin and CHIP, was substantially enhanced in both the resistant and sensitive cell lines; in contrast, the cytotoxicity of the PtII drugs, cisplatin and carboplatin, was only significantly increased in one of the two relatively resistant lines (SKOV-3) and in the sensitive (CH1) line after GSH depletion. Moreover the dose modification factor (DMF) for the PtII agents were lower than those for PtIV agents in the three cell lines. The dose modification factor for tetraplatin after BSO treatment was similar to that observed for melphalan in all three cell lines. In the SKOV-3 cell line extending the BSO pretreatment period to 48 h from 24 h marginally reduced the cytotoxicity of cisplatin, whereas the cytotoxicity of the other three drugs remained similar to that observed after 24 h BSO pretreatment. In contrast, extending the BSO treatment to 24 h after drug exposure potentiated the cytotoxicity of cisplatin, CHIP and tetraplatin.(ABSTRACT TRUNCATED AT 400 WORDS)

Carboplatin↗
PubMed1991

Short report: plasma aluminium concentration and 24-hour urinary aluminium excretion before, during and after treatment with sucralfate.

Ten dyspeptic patients were treated with 1 g sucralfate q.d.s. for six weeks. The plasma aluminium concentration and 24-h urinary aluminium excretion were measured at 3-weekly intervals before, during and after treatment with sucralfate. Compared with before treatment, there were significant rises in the median plasma aluminium concentration at 3 and 6 weeks during treatment with sucralfate (6 micrograms/L to 13 and 12 micrograms/L). The median 24-h urinary aluminium excretion rose significantly from a pretreatment level of 20 micrograms to 71 and 78 micrograms after 3 and 6 weeks of treatment; the significant increase of urinary aluminium excretion persisted for three weeks after cessation of treatment (52 micrograms/24 hours), but thereafter urinary excretion was not significantly different from pretreatment. The results are consistent with significant absorption and tissue accumulation of aluminium during standard treatment with sucralfate in individuals with normal renal function.

Adult↗
PubMed1990

The absorption of bismuth and salicylate from oral doses of Pepto-Bismol (bismuth salicylate).

Plasma bismuth and plasma salicylate concentrations were measured before and after three 30-ml oral doses of bismuth salicylate (Pepto-Bismol liquid) in 10 fasting healthy subjects. From 0 to 120 min following the first dose of bismuth salicylate, the plasma bismuth concentration was less than 1 ng/ml. The peak median plasma bismuth concentration was at +240 min (1.7 ng/ml; range 0.8-5.3 ng/ml). Salicylate appeared in the plasma of all subjects at +30 min, and it reached a peak at +120 min (median 61 mg/L; range 46-104 mg/L). The study demonstrates that, despite rapid and substantial absorption of salicylate, there is negligible absorption of bismuth into the bloodstream from standard oral doses of bismuth salicylate.

Adult↗
PubMed1990

Intravenous albumin infusion is an effective therapy for hyponatraemia in cirrhotic patients with ascites.

The treatment of moderate to severe hyponatraemia in patients with decompensated liver disease is unsatisfactory. We report our preliminary experience using intravenous infusion of albumin to treat this condition. Three patients with cirrhosis, ascites, and hyponatraemia responded satisfactorily to treatment; one patient with fulminant hepatitis B did not respond. Intravenous albumin infusion is a safe and effective therapy for patients with cirrhosis complicated by hyponatraemia. Its main role may be in preparing patients for surgery, particularly liver transplantation.

Aged↗
PubMed1990

Plasma fibrinogen levels in stroke.

Plasma fibrinogen levels were estimated in 56 patients of stroke, admitted in the hospital within 24 hours of symptoms. The levels were found to be raised significantly (531.73 +/- 74 mg%) compared to those of the age and sex matched control group (445.78 +/- 92.28 mg%). When the levels in stroke group with one risk factor were compared to those of individuals with comparable control group with same risk factor, a significant difference was observed in hypertensive, smokers, alcoholics and atherosclerotic stroke groups, which indicates that the observed rise is related to phenomenon of stroke rather than the associated risk factors. However, the rise observed in hypertensive stroke group (554.26 +/- 47.08 mg%) is significantly more (p. less than 0.01) than that occurring for nonhypertensive stroke group (497.82 +/- 93.12 mg%) indicating that the presence of hypertension does contribute to the rise.

Adult↗
PubMed1989

Inhibition of platelet aggregation by abnormal high density lipoprotein particles in plasma from patients with hepatic cirrhosis.

ADP-induced aggregation of normal washed platelets was measured by nephelometry in the presence of plasma high density lipoprotein (HDL) from normal subjects and from 30 patients with hepatic cirrhosis. HDL, at one-eighth of its plasma concentration, inhibited platelet aggregation; the effect of cirrhotic HDL (40% [SD 29%] inhibition) was significantly greater than that of normal HDL (16% [11%]). The mean apolipoprotein E content of cirrhotic HDL was significantly higher than that of normal HDL, and strongly inhibitory HDL contained twice as many apolipoprotein-E-rich particles as weakly inhibitory HDL. Inhibition of platelet aggregation was correlated with the apolipoprotein E content of HDL from patients with cirrhosis.

Adenosine Diphosphate↗
PubMed1989

Intracellular metabolites of cisplatin in the rat kidney.

The appearance of low-molecular-weight metabolites of cisplatin in the cytosol of cells from the cortex and outer medulla of the rat kidney has been examined using HPLC up to 24 h following cisplatin administration. Comparison was made between these metabolites and those present in plasma, urine and liver. The effect of sodium chloride (NaCl) pretreatment, which is known to reduce cisplatin-induced nephrotoxicity, on these metabolites was also investigated. Platinum levels in the kidney cortex and medulla and the cytosol reached maximal levels within 1 h of i.p. injection of 5 mg/kg cisplatin. At least six platinum species, including cisplatin, were present 1 h post-dosing, with the principal species being the parent drug; all of these species were either neutral or negatively charged. Although the concentration of most of the platinum species fell with time, that of one species eluting before cisplatin rose, and by 24 h it was the major metabolite. Cisplatin and two other major cytosolic platinum species were also present in urine and plasma, both of which also contained a number of charged species that were absent from the cytosol. The liver cytosol contained at least five metabolites 1 h post-dosing, but, in contrast to the kidney cytosol at the same time, the predominant species was that eluting before cisplatin and not cisplatin itself. One of the metabolites in the cytosol and urine had the same retention time as an adduct of cisplatin with glutathione and with cysteine. Urinary samples also contained a metabolite coeluting with aquated cisplatin. Pretreatment of animals with NaCl significantly reduced the platinum concentration in the kidney, with a corresponding decrease in the cytosolic metabolites; this may have contributed significantly to the reduction in cisplatin-induced nephrotoxicity after NaCl pretreatment. NaCl also significantly reduced a possible aquated species present in the urine, which may also have contributed to the reduction in nephrotoxicity. The data suggest that cisplatin itself may be the nephrotoxic species, since it is the intracellular platinum compound present in highest concentration during the early critical period after its administration.

Animals↗
PubMed1988

Implementing RECONSIDER, a diagnostic prompting computer system, at the Georgetown University Medical Center.

RECONSIDER, a computer program for diagnostic prompting developed at the University of California, San Francisco, has been implemented at the Georgetown University Medical Center as part of the Integrated Academic Information Management System Model Development grant project supported by the National Library of Medicine. The system is available for student use in the Biomedical Information Resources Center of the Dahlgren Memorial Library. Instruction on use of the computer system is provided by the library and instruction on medical use of the knowledge base is directed by the faculty. The implementation, capabilities, enhancements such as the addition of Current Medical Information and Terminology (5th ed.), and evaluation of the system are reported.

Computer User Training↗
PubMed1986

Endogenous C19-steroids and oestradiol levels in human primary breast tumour tissues and their correlation with androgen and oestrogen receptors.

Endogenous levels of testosterone, 5 alpha-dihydrotestosterone (5 alpha-DHT), androstenedione and oestradiol as well as levels of androgen (AR) and oestrogen (ER) receptors were measured in human primary breast tumour samples. The purification procedure developed allowed simultaneous quantitation of the four steroids, by radioimmunoassay, in small samples with adequate precision, sensitivity and accuracy. The majority of the tumours analysed contained detectable levels of the four steroids in the homogenate or cytosol fractions. There was no significant correlation between steroid content of the tissue and the age of the patient for any of the four steroids. A positive correlation (r = 0.71) was found between the levels of 5 alpha-DHT and testosterone in tumours. In general, tissue steroid concentrations decreased with an increase in dedifferentiation. Fifty-two per cent of the tumours analysed for receptor content were found to be ER positive, and a similar proportion were AR positive. No relationship was observed between AR status and age although receptor concentration was significantly (P = 0.004) higher in post-menopausal women when only receptor positive tumours were evaluated. The mean values for AR and ER were higher in tumours containing both receptors than in tumours showing either receptor alone; there was, however, no significant relationship between concentrations of the two receptors. No correlation was observed between tumour AR or ER status and any of the four steroids measured in either fraction. In addition, the ratio between the combined levels of 5 alpha-DHT and testosterone compared to oestradiol in the same tumour, only showed a maximum value of 40. Thus, in vivo these two androgens are unlikely to influence oestrogen action in human primary breast tumours by interfering with the association of oestradiol with its receptor.

Adult↗
PubMed1986

A low molecular weight lead-binding protein in brain attenuates lead inhibition of delta-aminolevulinic acid dehydratase: comparison with a renal lead-binding protein.

A low molecular weight high-affinity lead-binding protein (PbBP) in kidney appears to account, at least in part, for the relative insensitivity of renal delta-aminolevulinic acid dehydratase (ALAD) to Pb inhibition. A PbBP is also known to exist in brain cytosol but is not a major Pb-binding constituent in liver. This study was undertaken to examine the relative sensitivity of brain and liver ALAD to Pb inhibition in vitro and to determine if inhibition of hepatic ALAD by Pb could be reversed by addition of partially purified brain PbBP to liver cytosol. This effect was also compared with that of a previously described renal PbBP. Finally, the mechanism(s) of reversal of Pb inhibition of ALAD by these tissue-specific PbBPs were studied. A concentration-dependent reversal of Pb-induced inhibition of hepatic ALAD activity was observed for both brain and kidney PbBPs. Inhibition of hepatic ALAD activity by 0.1 to 1.6 microM Pb was partially reversed by a single concentration of brain PbBP. No differences in sensitivity of ALAD to Pb inhibition in various brain regions were observed. Kinetic analysis of both brain and liver ALAD activity at an IC50 Pb showed a "mixed" or noncompetitive inhibition pattern. Addition of brain PbBP reduced markedly the inhibitory effects of Pb on the Vmax of the liver enzyme. Incubation of 65Zn-labeled PbBP fractions from brain and kidney with purified bovine liver ALAD demonstrated that the PbBPs donate Zn to ALAD.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗