Effect of Wf-536, a novel ROCK inhibitor, against metastasis of B16 melanoma.

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:

The following were evaluated: the anti-invasive effect of Wf-536 against the motility of mouse B16BL6 melanoma cells through a culture insert layered with reconstituted basement membrane (Matrigel); the cytotoxic effect of Wf-536 in the same cell line; the antimetastatic effect of Wf-536, administered by osmotic pump, on spontaneous pulmonary metastasis following subcutaneous injection of B16BL6 melanoma in mice; and the inhibitory effect of orally administered Wf-536, alone or in combination with the antineoplastic drug paclitaxel, on pulmonary metastasis of intravenously injected B16F10 melanoma in mice.

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:

The results suggest that Wf-536 is a potentially valuable drug for preventing tumor metastasis both in monotherapy and in combination with an antineoplastic drug.

• 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