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Titolo:
Extravascular transport of the DNA intercalator and topoisomerase poison N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA): Diffusion and metabolism in multicellular layers of tumor cells
Autore:
Hicks, KO; Pruijn, FB; Baguley, BC; Wilson, WR;
Indirizzi:
Univ Auckland, Expt Oncol Grp, Auckland Canc Soc Res Ctr, Fac Med & Hlth Sci, Auckland 1, New Zealand Univ Auckland Auckland New Zealand 1 & Hlth Sci, Auckland 1, New Zealand
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 3, volume: 297, anno: 2001,
pagine: 1088 - 1098
SICI:
0022-3565(200106)297:3<1088:ETOTDI>2.0.ZU;2-4
Fonte:
ISI
Lingua:
ENG
Soggetto:
POTENTIAL ANTITUMOR AGENTS; IN-VITRO; MULTIDRUG-RESISTANCE; BIOREDUCTIVE DRUGS; ANTICANCER DRUGS; CELLULAR UPTAKE; SOLID TUMORS; PENETRATION; MODEL; CYTOTOXICITY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
40
Recensione:
Indirizzi per estratti:
Indirizzo: Hicks, KO Univ Auckland, Expt Oncol Grp, Auckland Canc Soc Res Ctr, Fac Med & Hlth Sci, Private Bag 92019, Auckland 1, New Zealand Univ Auckland Private Bag 92019 Auckland New Zealand 1 Zealand
Citazione:
K.O. Hicks et al., "Extravascular transport of the DNA intercalator and topoisomerase poison N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA): Diffusion and metabolism in multicellular layers of tumor cells", J PHARM EXP, 297(3), 2001, pp. 1088-1098

Abstract

There is considerable evidence that DNA intercalating drugs fail to penetrate tumor tissue efficiently. This study used the multicellular layer (MCL)experimental model, in conjunction with computational modeling, to test the hypothesis that a DNA intercalator in phase II clinical trial, N-[2-(dimethylamino)-ethyl]acridine-4-carboxamide (DACA), has favorable extravasculartransport properties. Single cell uptake and metabolism of DACA and the related but more basic aminoacridine 9-[3-(dimethylamino)propylamino]acridine(DAPA), and penetration through V79 and EMT6 MCL, were investigated by high-performance liquid chromatography. DACA was accumulated by cells to a lesser extent than DAPA and was metabolized to the previously unreported acridan by V79 but not EMT6 cells. Despite this metabolism, flux of DACA throughMCL was much faster than that of DAPA, Modeling MCL transport as diffusionwith reaction (metabolism and reversible binding) showed that the faster flux of DACA was due to a 3-fold higher free drug diffusion coefficient and 10-fold lower binding site density. The MCL transport parameters were used to develop a spatially resolved pharmacokinetic model for the extravascularcompartment in tumors, which provided a reasonable prediction of measured average tumor concentrations from plasma pharmacokinetics in mice, Area under the curve was essentially independent of distance from blood vessels, although the combined pharmacokinetic/pharmacodynamic model predicted a modest decrease in cytotoxicity (from 1.8 to 1.1 logs of cell kill) across a 125-mum region. In conclusion, this study demonstrates that it is possible to design DNA intercalators that diffuse efficiently in tumor tissue, and thatthere is little impediment to DACA transport over distances required for its antitumor action.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 16/07/20 alle ore 19:28:16