Abstract |
The folate analogue BGC9331 is a new thymidylate synthase (TS) inhibitor showing a broad spectrum of cyto-toxic activity against several human solid tumors, including colorectal cancer. In this study, we investigated the anticancer activity of BGC9331 either alone or combined with 5-fluorouracil (5-FU), MTA (multi-target antifolate), oxali-platin and SN-38, the active metabolite of the topoisomerase I inhibitor CPT-11. The antiproliferative activity of each drug and BGC9331-based combinations was investigated in the HT-29 human colorectal cancer cell line and its HT-29/5-FU counterparts selected for resistance to 5-FU. BGC9331 combined with MTA or SN-38 induced synergistic responses in HT-29 cells. Treatment of HT-29 cells with either BGC9331 or SN-38 increased caspase-3 activity and the percentage of apoptotic cells from 3 to 13%. Both drugs also augmented the proteolytic cleavage of the Rho-kinase ROCK-1 that was attenuated by the caspase-3 pathway inhibitor z-DEVD-fmk. BGC9331 combined with SN-38 further increased the percentage of apoptotic cells to 25%, and inhibited cell cycle progression and cell proliferation by 65%. This was accompanied by proteolytic activation of ROCK-1, through both caspase-3-dependent and -independent mechanisms, as shown in caspase-3-deficient MCF-7 breast cancer cells. These encouraging results warrant further preclinical investigations and clinical trials on the use of BGC9331 combined with SN-38/ CPT-11 in treatment of patients with advanced colorectal or gastric cancers.
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Authors | Anne-Marie Coudray, Christophe Louvet, Michel Kornprobst, Eric Raymond, Thierry André, Christophe Tournigand, Sandrine Faivre, Aimery De Gramont, Annette K Larsen, Christian Gespach |
Journal | International journal of oncology
(Int J Oncol)
Vol. 27
Issue 2
Pg. 553-61
(Aug 2005)
ISSN: 1019-6439 [Print] Greece |
PMID | 16010439
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Caspase Inhibitors
- Cysteine Proteinase Inhibitors
- Enzyme Inhibitors
- Folic Acid Antagonists
- Glutamates
- Intracellular Signaling Peptides and Proteins
- Oligopeptides
- Organoplatinum Compounds
- Quinazolines
- Topoisomerase I Inhibitors
- ZD 9331
- benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone
- Pemetrexed
- Oxaliplatin
- Guanine
- Irinotecan
- Thymidylate Synthase
- Protein Serine-Threonine Kinases
- rho-Associated Kinases
- CASP3 protein, human
- Caspase 3
- Caspases
- DNA Topoisomerases, Type I
- Fluorouracil
- Camptothecin
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Topics |
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Breast Neoplasms
(metabolism, pathology)
- Camptothecin
(analogs & derivatives, pharmacology)
- Caspase 3
- Caspase Inhibitors
- Caspases
(metabolism)
- Cell Cycle
(drug effects)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Colorectal Neoplasms
(metabolism, pathology)
- Cysteine Proteinase Inhibitors
(pharmacology)
- DNA Topoisomerases, Type I
(metabolism)
- Dose-Response Relationship, Drug
- Drug Synergism
- Enzyme Inhibitors
(pharmacology)
- Fluorouracil
(pharmacology)
- Folic Acid Antagonists
(pharmacology)
- Glutamates
(pharmacology)
- Guanine
(analogs & derivatives, pharmacology)
- HT29 Cells
- Humans
- Intracellular Signaling Peptides and Proteins
- Irinotecan
- Oligopeptides
(pharmacology)
- Organoplatinum Compounds
(pharmacology)
- Oxaliplatin
- Pemetrexed
- Protein Serine-Threonine Kinases
(metabolism)
- Quinazolines
(pharmacology)
- Thymidylate Synthase
(antagonists & inhibitors, metabolism)
- Time Factors
- Topoisomerase I Inhibitors
- rho-Associated Kinases
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