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Publications à Abstracts |
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In
vitro and in vivo study of an albumin-binding prodrug of doxorubicin that is cleaved by cathepsin B Khalid Abu Ajaj, Ralph Graeser,
Iduna Fichtner, Felix Kratz Cancer Chemotherapy &
Pharmacology, 2009,
64 (2), 413–418 Keywords:
albumin-binding prodrug; albumin; cathepsin B; 1,6-self-immolative spacer; doxorubicin Abstract: Purpose: This study was designed to evaluate the in vitro
and in vivo antitumor activity of an albumin-binding prodrug
of doxorubicin 1 which incorporates a maleimide
moiety and a para-aminobenzyloxycarbonyl (PABC) spacer coupled to the dipeptide
Phe-Lys that is cleaved by cathepsin
B. Methods: Cleavage
of the albumin conjugate was studied with cathepsin B and in homogenates of MDA-MB 435 tumors. For in vivo studies, nude mice
were injected with (a) glucose
buffer, (b) doxorubicin (2
× 8 mg/kg, i.v, on days 10 and 17), or (c) compound 1 (3 × 24 mg/kg
doxorubicin equivalent, on
days 10, 17 and 24). Results: Prodrug 1 once bound to albumin was effectively cleaved by cathepsin
B and in tumor homogenates releasing
doxorubicin. Cytotoxicity assay of the albumin conjugate of 1
in two human tumor cell lines
showed that doxorubicin was ~6 times more active than the conjugate. In contrast, in an in vivo study, the prodrug exhibited superior antitumor activity (T/C 15%) compared to doxorubicin (T/C 49%) in an equitoxic
comparison. Conclusions: The cathepsin
B cleavable spacer Phe-Lys-PABC
incorporated in an albumin-binding prodrug is an effective way to increase the therapeutic
index of doxorubicin. |
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