ALBERT — All Library Books, journals and Electronic Records Telegrafenberg

11

Electronic Resource

Proliferation Indices as Molecular Pharmacodynamic Endpoints in Evaluation of Anticancer Drug Effect in Human Solid Tumors (1998)

Weaver, Jean R. ; Gan, Yuebo ; Au, Jessie L.-S.

Springer

Pharmaceutical research 15 (1998), S. 1546-1551

add to mindlist on the mindlist

Details

ISSN: 1573-904X

Keywords: proliferative indices ; molecular pharmacodynamic endpoints ; anticancer drugs ; human solid tumors ; thymidine ; bromodeoxyuridine

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. The present study compared proliferative indices, i.e. incorporation of DNA precursor (i.e. thymidine or TdR, and bromodeoxyuridine or BrdU) and expression of proliferating cell nuclear antigen (PCNA), as molecular pharmacodynamic endpoints in evaluation of anticancer drug effect in human solid tumors. Methods. Tumor specimens obtained from patients were grown as histocultures. After treatment with doxorubicin, mitomycin C, and/or paclitaxel, cells labeled by [3H]TdR were identified using autoradiography, and cells labeled by BrdU and PCNA were identified using immunohistochemical techniques. Drug effect was measured as reduction of DNA precursor-labeled cells or PCNA-expressing cells. Results. The results indicate that (a) the two DNA precursors, TdR and BrdU, labeled the same cells and resulted in identical pharmacodynamics, (b) the pharmacodynamics established using inhibition of DNA precursor incorporation were qualitatively and quantitatively different from the pharmacodynamics established using inhibition of PCNA expression, (c) the inhibition of PCNA expression was erratic in some tumors, and (d) the differences in pharmacodynamics established using the two end points are drug-specific, with greater differences for paclitaxel than for mitomycin C. Conclusions. The erratic results measured by the PCNA labeling method suggest that this method may be less reliable than the conventional DNA precursor labeling method. The finding of identical pharmacodynamics of doxorubicin and paclitaxel established using BrdU and [3H]TdR indicates that the two precursors are interchangeable. Because the methodology for detecting BrdU incorporation requires less time and does not require the use of radioactivity, we conclude that inhibition of BrdU incorporation represents a useful endpoint for evaluating the antiproliferative activity of anticancer drugs in human solid tumors.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1011998932047

Permalink

	Location	Call Number	Expected	Availability

Others were also interested in ...

Paper (German National Licenses)

Fulltext

12

Electronic Resource

Antiproliferative and Cytotoxic Effects of Geldanamycin, Cytochalasin E, Suramin and Thiacetazone in Human Prostate Xenograft Tumor Histocultures (1998)

Gan, Yuebo ; Au, Jessie L.-S. ; Lu, Jie ; [et al.]

Springer

Pharmaceutical research 15 (1998), S. 1760-1766

add to mindlist on the mindlist

Details

ISSN: 1573-904X

Keywords: suramin ; geldanamycin ; cytochalasin E ; thiacetazone ; pharmacodynamics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. We have shown that the three human prostate xenograft tumors, i.e. the androgen-dependent CWR22 tumor, and the androgen-resistant CWR22R and CWR91 tumors, are comparable to patient tumors in their expression of prostate specific antigen, multidrug resistance p-glycoprotein, p53 and Bcl-2 and in their sensitivity to doxorubicin and paclitaxel. The present study used histocultures of these xenograft tumors to evaluate the antiproliferative and cytotoxic effects of several drugs (geldanamycin, cytochalasin E and thiacetazone), which have diverse action mechanisms and have shown activity against primary cultures of human prostate cancer cells. Suramin, a clinically active compound was included for comparison. Methods. The antiproliferative effect of 96 h drug treatment was measured by inhibition of DNA precursor incorporation, and the cytotoxic or cell kill effect was measured by in situ DNA end labeling of apoptotic and necrotic cells and by reduction of live cell density. Results. The rank order of molar potency was geldanamycin 〉cytochalasin E 〉suramin ≥ thiacetazone. Thiacetazone produced antiproliferation only in CWR22 tumor and had no cytotoxicity, whereas the other three drugs produced both antiproliferation and cytotoxicity in all three tumors. Geldanamycin, but not cytochalasin E and suramin, showed greater antiproliferation and cytotoxicity in tumor cells compared to normal stromal cells. The two androgen-resistant tumors were 4 to 〉40-fold less sensitive than the androgen-dependent tumor to drug-induced antiproliferation but were about equally or 4 to 〉20-fold more sensitive to drug-induced cytotoxicity. The ratios of drug concentrations that produced 50% antiproliferation to the concentrations that produced 50% cytotoxicity ranged from 〈0.04 to 0.3 in CWR22 tumor, but ranged from 0.3 to 2.7 in CWR22R and CWR91 tumors, indicating a shift from antiproliferation as the predominant drug effect in the androgen-dependent tumor to cytotoxicity in the androgen-resistant tumors. Conclusions. Our results indicate (a) differential drug effects in human prostate xenograft tumors with antiproliferation and cytotoxicity as the predominant drug effect in the androgen-dependent and androgen-resistant tumors, respectively, (b) that progression of tumors from androgen-dependent state to androgen-resistant state appears to be associated with a lower sensitivity to drug-induced antiproliferation and an equal or greater sensitivity to drug-induced cytotoxicity, and (c) that geldanamycin but not thiacetazone warrants further development.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1011921031564

Permalink

	Location	Call Number	Expected	Availability

Others were also interested in ...

Paper (German National Licenses)

Fulltext

13

Electronic Resource

Accuracy and Precision of Pharmacodynamic Exponent (1999)

Millenbaugh, Nancy J. ; Wientjes, M. Guillaume ; Au, Jessie L.-S.

Springer

Pharmaceutical research 16 (1999), S. 170-173

add to mindlist on the mindlist

Details

ISSN: 1573-904X

Keywords: CnxT ; pharmacodynamic exponent ; dose-response relationship ; Monte Carlo simulation ; computer simulation ; data interpretation ; statistical

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1011903719732

Permalink

	Location	Call Number	Expected	Availability

Others were also interested in ...

Paper (German National Licenses)

Fulltext

14

Electronic Resource

Absorption of 2′, 3′-Dideoxyinosine from Lower Gastrointestinal Tract in Rats and Kinetic Evidence of Different Absorption Rates in Colon and Rectum (1993)

Bramer, Steven L. ; Wientjes, M. Guillaume ; Au, Jessie L.-S.

Springer

Pharmaceutical research 10 (1993), S. 763-770

add to mindlist on the mindlist

Details

ISSN: 1573-904X

Keywords: 2′, 3′-dideoxyinosine (ddI) ; didanosine ; anti-AIDS drug ; rectal infusion ; rectal bioavailability ; rectal and colonic absorption

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract This study explored the rectal route of administration for 2′,3′-dideoxyinosine (ddI). Rats were given a rectal infusion of nonradiolabeled ddI (200 mg/kg in 0.7 mL saline) over 35 min along with an intravenous (iv) bolus injection of [8-3H]ddI (20 µCi, equivalent to 2.1 µg), which was used to calculate the absolute rectal bioavailability of ddI. Maximal plasma concentrations of rectally administered unlabeled ddI were 5.4 ± 2.2 µg/mL and were reached at the end of the infusion. The rectal bioavailability averaged 15.6 ± 4.4% (n = 9). The second aim of this study was to examine the kinetics of ddI absorption from the colorectal region. Analyses of the absorption rate–time profiles by the Loo–Riegelman and deconvolution methods showed biphasic absorption: a rapid phase during infusion and a slow phase postinfusion. These profiles were inconsistent with a mammillary model with absorption from a single site with one apparent rate constant. The model which gave the best fit for infusion and postinfusion data consisted of two different sites (colon and rectum) with different apparent absorption rate constants. The two sites were connected by a first-order transfer of drug solution from rectum to colon. The apparent absorption rate constant in the rectum was 39-fold higher than that in the colon. In conclusion, these results show absorption of ddI from the colorectal region and suggest the rectal route as an alternative to the oral route. The data further suggest different absorption sites in the colorectal region, with a more rapid absorption in the rectum than in the colon.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1018928320449

Permalink

	Location	Call Number	Expected	Availability

Others were also interested in ...

Paper (German National Licenses)

Fulltext

15

Electronic Resource

Effects of bladder resorption on pharmacokinetic data analysis (1994)

Dalton, James T. ; Wientjes, M. Guillaume ; Au, Jessie L-S.

Springer

Journal of pharmacokinetics and pharmacodynamics 22 (1994), S. 183-205

add to mindlist on the mindlist

Details

ISSN: 1573-8744

Keywords: bladder resorption ; renal clearance ; computer simulations ; bladder recycling

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract In modern pharmacokinetic analysis, the urinary bladder is usually viewed as a nonreturning compartment or storage site for renally excreted compounds. Our previous studies have indicated appreciable bladder resorption of drugs. The present study used computer simulations to evaluate the quantitative importance of several potential determinants of bladder resorption, namely the bladder resorption rate constant (k a), interval between bladder voiding (Δt void),ratio of renal elimination rate constant to overall elimination rate constant (k ex:k el ratio), andk el ort 1/2. The data identifiedk a, Δt void, andk ex:k el ratio as the three most important determinants of the rate and extent of bladder resorption. We further examined the errors introduced in the derived pharmacokinetic parameters due to omission of bladder resorption. Plasma concentration-time profiles and urinary excretion-time profiles were generated by simulations using different values ofk a, Δt void, andk ex:k el ratio. These profiles were used to derive the pharmacokinetic parameters, including the renal clearance (CL renal), total body clearance (CL total), nonrenal clearance (CL nonrenal),t 1/2, mean residence time (MRT), amount and fraction of dose excreted in urine (A ex andf e), and volume of distribution at steady state (Vd ss). Data show that resorption of drug from the bladder into the systemic circulation increased the area under the plama concentration-time profile,MRT andt 1/2, but decreasedCL renal,CL total,A ex, andf e.Vd ss was relatively unchanged. Overestimation of MRT andt 1/2 was dependent onk a,k ex:k el ratio,and Δt void. Underestimation inCL renal,A ex, andf e was not dependent on thek ex:k el ratio, but was affected by changes ink a and Δt void.CL renal andf e were the most sensitive pharmacokinetic parameters, with a≥50% underestimation at ak a value that we reported previously, for the bladder absorption of antipyrine in rats with intact urothelium. In summary, these data indicate (i) alteration in the plasma concentration-time profiles and urinary excretion-time profiles due to bladder resorption, and (ii) substantial over-or underestimation in the derived pharmacokinetic parameters due to erroneous omission of bladder resorption.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF02353328

Permalink

	Location	Call Number	Expected	Availability

Others were also interested in ...

Paper (German National Licenses)

Fulltext

16

Electronic Resource

Nonlinear Disposition of Intravenous 2′,3′-Dideoxyinosine in Rats (1992)

Wientjes, M. Guillaume ; Mukherji, Elora ; Au, Jessie L-S.

Springer

Pharmaceutical research 9 (1992), S. 1070-1075

add to mindlist on the mindlist

Details

ISSN: 1573-904X

Keywords: nonlinear disposition ; 2′,3′-dideoxyinosine ; anti-AIDS drug ; dideoxynucleosides ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract The pharmacokinetics of 2′,3′-dideoxyinosine (ddI) were examined in rats given intravenous doses of 8, 40, or 200 mg/kg. The concentrations of ddI in whole blood and plasma were identical. The concentration decline was multiexponential, with mean half-lives of 2 and 20 min for the first and second phases, respectively. At the highest dose, a slower third phase with a half-life of 56 min was observed. The total-body clearances were 99, 77, and 37 ml/min-kg for the 8, 40, and 200 mg/kg doses. The steady-state volume of distribution showed a trend for a decrease with increasing doses, but the difference was not statistically significant. Twenty-four-hour urinary recovery of unchanged drug for the three doses was similar at about 20%, suggesting that a major fraction of the dose was metabolized. Urinary excretion of ddI metabolite, hypoxanthine, accounted for less than 5% of the dose. Renal and metabolic clearances decreased with increased doses, ddI was metabolized in blood; the addition of inorganic phosphate, a cosubstrate in phos-phorylase-mediated nucleoside catabolism, enhanced the degradation by about fourfold. In summary, these data indicate equal distribution of ddI in the extracellular and intracellular spaces in blood, its enzymatic degradation in blood, and nonlinear elimination kinetics.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1015866714224

Permalink

	Location	Call Number	Expected	Availability

Others were also interested in ...

Paper (German National Licenses)

Fulltext

17

Electronic Resource

A Method to Study Drug Concentration–Depth Profiles in Tissues: Mitomycin C in Dog Bladder Wall (1991)

Wientjes, M. Guillaume ; Dalton, James T. ; Badalament, Robert A. ; [et al.]

Springer

Pharmaceutical research 8 (1991), S. 168-173

add to mindlist on the mindlist

Details

ISSN: 1573-904X

Keywords: tissue concentration profile ; bladder wall ; dog ; mitomycin C

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Determination of the depth of penetration of locally applied drug therapy and evaluation of possible mechanisms of drug transport require knowledge of drug concentration-versus-tissues depth profiles. A method to determine the drug concentration–depth profile is needed. We have devised such a method and used it to determine the penetration of mitomycin C (MMC) in the dog bladder wall after intravesical drug instillation. This method is based on sectioning of frozen tissue into 40-µm segments, followed by drug extraction and high-pressure liquid chromatography analysis. Tissue concentrations could be detected with a sensitivity of 1 ng/sample, or 20 ng/g for tissue samples of approximately 2 × 2 cm. This sensitivity was sufficient to describe the penetration of MMC in the bladder wall of dogs, using an identical instillation technique, dwell time, and MMC concentration as in human patients. Tissue concentrations were expressed relative to tissue weight or tissue protein contents. For MMC, standardization to tissue weight yielded a better mathematical fit of the concentration-versus-depth profiles than standardization to protein content. The time interval between tissue harvesting and freezing was critical. The MMC concentration at the urothelial side of dog bladders was 2- to 10-fold higher in samples processed immediately after harvesting, compared to samples processed after 1 hr or longer. This significant decrease was not due to drug metabolism in situ. In separate in vitro experiments, we found that the degradation of MMC in 8% tissue homogenate was relatively slow, with only a 30% decline in concentration over 24 hr. We speculate that the decrease in concentration was due to passive diffusion of MMC, away from the urothelial side. In summary, the present study demonstrates that determination of drug penetration into tissues in vivo is feasible.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1015827700904

Permalink