Development and in vitro efficacy of novel MMP2 and MMP9 specific doxorubicin albumin conjugates.
Two doxorubicin albumin conjugates (A-DP1 and A-DP2), which differ in their substrate specificity for the matrix metalloproteinases MMP2 and MMP9, were prepared by binding maleimide doxorubicin peptide derivatives to the cysteine-34 position of human serum albumin. The incorporated octapeptide, Gly-Pro-Gln-Arg-Ile-Ala-Gly-Gln, in A-DP2 is not cleaved by activated MMP2 and MMP9 in contrast to Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln incorporated in A-DP1 that is cleaved efficiently by activated MMP2 and MMP9 liberating a doxorubicin tetrapeptide. A-DP1 showed antiproliferative activity in a murine renal cell carcinoma line in the low micromolar range (IC(50) value approximately 0.2 microM).
Kratz
F
F
Tumor Biology Center, Clinical Research, D-79106, Freiburg, FRG. felix@tumorbio.uni-freiberg.de
Drevs
J
J
Bing
G
G
Stockmar
C
C
Scheuermann
K
K
Lazar
P
P
Unger
C
C
D000418:Albumins / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism*; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000166:cytology; D046911:Macromolecular Substances; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000502:physiology; D013379:Substrate Specificity / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects
C435780:A-DP1doxorubicin albumin conjugate; C435779:A-DP2 doxorubicin albumin conjugate; D000418:Albumins; D000970:Antineoplastic Agents; D046911:Macromolecular Substances; D009842:Oligopeptides; D004317:Doxorubicin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D003545:Cysteine