Abstract | PURPOSE: Rho-associated coiled-coil-forming protein kinase (ROCK) is pivotally involved in invasion by tumor cells and their evolution to metastasis. We have developed a novel inhibitor of ROCK, Wf-536 [(+)-(R)-4-(1-aminoethyl)-N-(4-pyridyl) benzamide monohydrochloride]. In the present study, we investigated its effect on in vitro invasion and in vivo pulmonary metastasis of B16 melanoma. METHODS: RESULTS:
Wf-536 inhibited in vitro invasion by B16BL6 cells significantly and in a concentration-dependent manner and displayed an anti-invasive effect under conditions of both chemotaxis and chemokinesis. No cytotoxic effect was observed at any of the concentrations used. In vivo, Wf-536 administration suppressed tumor colony formation on the lung surface in a dose-dependent manner (0.3-3 mg/kg per day), with a metastasis inhibition rate of 95% at 3 mg/kg per day. In experimental metastasis of B16F10 melanoma, oral administration of Wf-536 significantly decreased tumor colony formation in the lung, with an inhibition rate of 41% at 3 mg/kg per day. The inhibition rate of paclitaxel (5 mg/kg per day) was 27%. The combination of Wf-536 and paclitaxel produced a synergistic effect on B16F10 metastasis and a 68% inhibition rate. Wf-536 administration at the doses used did not alter body weight, blood pressure or the health of treated animals as compared to vehicle-treated controls. CONCLUSION:
|
Authors | Masahide Nakajima, Kazutaka Hayashi, Yasuhiro Egi, Ken-ichi Katayama, Yusaku Amano, Masayoshi Uehata, Makio Ohtsuki, Akihiro Fujii, Koh-ichi Oshita, Hirotoshi Kataoka, Kenji Chiba, Nobuharu Goto, Takao Kondo |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 52
Issue 4
Pg. 319-24
(Oct 2003)
ISSN: 0344-5704 [Print] Germany |
PMID | 12783205
(Publication Type: Journal Article)
|
Chemical References |
- Antineoplastic Agents
- Antineoplastic Agents, Phytogenic
- Benzamides
- Enzyme Inhibitors
- Intracellular Signaling Peptides and Proteins
- Pyridines
- Y 32885
- Protein Serine-Threonine Kinases
- rho-Associated Kinases
- Paclitaxel
|
Topics |
- Animals
- Antineoplastic Agents
(pharmacology)
- Antineoplastic Agents, Phytogenic
(therapeutic use)
- Benzamides
(pharmacology)
- Cell Line, Tumor
- Cell Movement
(drug effects)
- Cell Survival
(drug effects)
- Enzyme Inhibitors
(pharmacology)
- Intracellular Signaling Peptides and Proteins
- Lung Neoplasms
(drug therapy, secondary)
- Melanoma, Experimental
(drug therapy, pathology)
- Mice
- Neoplasm Invasiveness
(prevention & control)
- Paclitaxel
(therapeutic use)
- Protein Serine-Threonine Kinases
(antagonists & inhibitors)
- Pyridines
(pharmacology)
- rho-Associated Kinases
|