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Relationship between in vivo drug exposure of the tumor interstitium and inhibition of tumor cell growth in vitro: a study in breast cancer patients (2000)

Müller, Markus ; Bockenheimer, Julia ; Zellenberg, Ulrike ; [et al.]

Springer

Breast cancer research and treatment 60 (2000), S. 211-217

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ISSN: 1573-7217

Keywords: breast cancer ; 5-fluorouracil ; methotrexate ; pharmacodynamics ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract A novel approach is described to simulate effect site pharmacodynamics of anticancer drugs. This approach is based on (i) the in vivo measurement of unbound, interstitial drug pharmacokinetics (PK) in solid tumor lesions in patients and (ii) a subsequent pharmacodynamic (PD) simulation of the time versus drug concentration profile in an in vitro setting. For this purpose, breast cancer cells (MCF-7) were exposed in vitro to the time versus interstitial tumor concentration profiles of 5-fluorouracil (5-FU) and methotrexate (MTX) from primary breast cancer lesions in patients. This led to a maximal reduction in the viable cell count of 69 on day 4, and of 71 on day 7 for 5-FU and MTX, respectively. This effect was dependent on the initial cell count and was characterized by a high interindividual variability. For 5-FU there was a significant correlation between the maximum antitumor effect and the intratumoral AUC (r = 0.82, p = 0.0005), whereas no correlation could be shown for MTX (r = 0.05, p = 0.88). We conclude, that the in-vivo-PK / in-vitro-PD model presented in this study may provide a rational approach for describing and predicting pharmacodynamics of cytotoxic drugs at the target site. Data derived from this approach support the concept that tumor penetration of 5-FU may be a response-limiting event, while the response to MTX may be determined by events beyond interstitial fluid kinetics.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1006497202341

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Einfluß verschiedener Anionen auf die Kinetik der Säurehydrolyse des Tetraaquamono(salicylaldehydato)chrom(III)-Kations (1978)

Elias, Horst ; Erb, Peter ; Lang, Gerald ; [et al.]

Weinheim : Wiley-Blackwell

Berichte der deutschen chemischen Gesellschaft 111 (1978), S. 1315-1322

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ISSN: 0009-2940

Keywords: Chemistry ; Inorganic Chemistry

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Chemistry and Pharmacology

Description / Table of Contents: Influence of Various Anions on the Kinetics of the Acid Hydrolysis of the Cation Tetraaquamono(salicylaldehydato)chromium(III)The kinetics of the acid hydrolysis of the cation tetraaquamono(salicylaldehydato)chromium(III) in perchloric acid were studied at 70°C at constant ionic strength as a function of various anions added to the system. The hydrolysis is strongly accelerated by oxyanions like sulfate and nitrate, while halide anions like chloride and bromide affect the rate only slightly. The findings are explained on the basis of the „cis-effect“ of the oxyanions. The reaction is interpreted by an associative interchange mechanism (Ia).

Notes: Die Kinetik der Säurehydrolyse des Tetraaquamono(salicylaldehydato)chrom(III)-Kations in perchlorsaurer Lösung wurde in Abhängigkeit vom Zusatz verschiedener Anionen bei 70°C und konstanter Ionenstärke untersucht. Die Hydrolyse wird durch die Oxyanionen Sulfat und Nitrat stark beschleunigt, während die Halogenid-Ionen Chlorid und Bromid die Reaktionsgeschwindigkeit nur geringfügig erhöhen. Dieses Ergebnis wird mit dem „cis-Effekt“ der Oxyanionen erklärt. Der Reaktionsablauf wird mit einem assoziativen Interchange-Mechanismus (Ia) interpretiert.

Additional Material: 2 Ill.