| Abstract | Improvement in the therapeutic index of doxorubicin, a cytotoxic molecule, has been sought through its chemical conjugation to short (15-23 amino acid) peptide sequences called Vectocell peptides. Vectocell peptides are highly charged drug delivery peptides and display a number of characteristics that make them attractive candidates to minimize many of the limitations observed for a broad range of cytotoxic molecules. The studies reported here characterized the in vitro and in vivo efficacy of a range of Vectocell peptides conjugated to doxorubicin through different linkers. These studies show that the in vivo therapeutic index of doxorubicin can be improved by conjugation with a specific Vectocell peptide (DPV1047) through an ester linker to C14 of doxorubicin, in both colon and breast tumor models. This conjugate was also shown to have significant in vivo antitumoral activity in a model resistant to doxorubicin, suggesting that this conjugate is able to circumvent the multidrug resistance (MDR) phenotype. These experiments therefore provide support for the use of the Vectocell technology with other cytotoxic agents. |
| Authors | Florence Meyer-Losic, Jérôme Quinonero, Vincent Dubois, Bertrand Alluis, Mireille Dechambre, Matthieu Michel, Françoise Cailler, Anne-Marie Fernandez, André Trouet, Jonathan Kearsey
(Affiliation: Diatos S.A., 166 Boulevard du Montparnasse, 75014 Paris, France. fmeyerlosic at diatos.com)
|
| Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 49
Issue 23
Pg. 6908-16
(Nov 16 2006)
ISSN: 0022-2623 United States |
| PMID | 17154520
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Antineoplastic Agents
- Peptides
- Doxorubicin
|
| Topics |
- Animals
- Antineoplastic Agents
(chemical synthesis, chemistry, pharmacology)
- Cell Line, Tumor
- Doxorubicin
(chemistry, pharmacology)
- Drug Delivery Systems
- Drug Resistance, Multiple
- Drug Resistance, Neoplasm
- Drug Screening Assays, Antitumor
- Female
- Humans
- Mice
- Neoplasm Transplantation
- Peptides
(chemistry)
- Structure-Activity Relationship
- Transplantation, Heterologous
|
