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Improved targeting of platinum chemotherapeutics. the antitumour activity of the HPMA copolymer platinum agent AP5280 in murine tumour models.
- Source :
-
European journal of cancer (Oxford, England : 1990) [Eur J Cancer] 2004 Jan; Vol. 40 (2), pp. 291-7. - Publication Year :
- 2004
-
Abstract
- AP5280 is a novel N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound platinum (Pt) therapeutic designed to increase the therapeutic index relative to conventional, small-molecule platinum agents. The platinum-polymer construct accumulates in solid tumours on the basis of increased capillary permeability. The bound platinum moiety is present as an N,O-Pt chelate at the distal end of a tetrapeptide linker, glycine-phenylalanine-leucine-glycine, and the weight-average molecular weight (Mw) of the construct is 22 kDa. The antitumour activity and toxicity of AP5280 were assessed in the syngeneic murine B16F10 and Lewis lung tumour models, and in the human ovarian carcinoma 2008 and head and neck squamous carcinoma UMSCC10b xenograft models. The maximum tolerated dose (MTD) of AP5280 was 6-fold greater than that of carboplatin (CBDCA) in vivo. AP5280 was active in all four tumour models, and it displayed a higher therapeutic index than CBDCA in each of these tumour models. The antitumour effect of AP5280 given at 16% of its MTD was equivalent to that produced by a MTD of CBDCA. Thus, consistent with the design goal for this drug, and despite being less potent than CBDCA, AP5280 produced less systemic toxicity relative to its antitumour activity and thus has a greater therapeutic index. On the basis of the improved therapeutic index evidenced in these models, AP5280 has been advanced into clinical trials.
- Subjects :
- Acrylamides administration & dosage
Animals
Cell Division drug effects
Cell Line, Tumor
Drug Synergism
Female
Head and Neck Neoplasms pathology
Humans
Inhibitory Concentration 50
Melanoma pathology
Mice
Mice, Inbred BALB C
Neoplasm Transplantation
Organoplatinum Compounds administration & dosage
Ovarian Neoplasms pathology
Transplantation, Heterologous
Tumor Stem Cell Assay
Acrylamides therapeutic use
Antineoplastic Agents therapeutic use
Carboplatin therapeutic use
Head and Neck Neoplasms drug therapy
Melanoma drug therapy
Organoplatinum Compounds therapeutic use
Ovarian Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 0959-8049
- Volume :
- 40
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- European journal of cancer (Oxford, England : 1990)
- Publication Type :
- Academic Journal
- Accession number :
- 14728945
- Full Text :
- https://doi.org/10.1016/j.ejca.2003.09.022