In vitro and in vivo antitumor effects of (4-methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone
- 204 Downloads
(4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone (PHT) is a phenstatin analog compound. PHT is a known tubulin inhibitor that has potent cytotoxic activity. In the present study, PHT was synthesized and its antitumor activity was determined using in vitro and in vivo experimental models.
The in vitro cytotoxic activity of the PHT was determined by the MTT assay. The antimitotic and hemolytic effects were determined based on the inhibition of sea urchin embryo development and lysis of mouse erythrocytes, respectively. In vivo antitumor activity was assessed in mice inoculated with sarcoma 180 cells.
In vitro, PHT displayed cytotoxicity in tumor cell lines, showing IC50 values in the nanomolar range. In addition, it inhibited sea urchin embryo development during all phases examined, first and third cleavage and blastula stage. However, PHT did not induce hemolysis using mouse erythrocytes, suggesting that the cytotoxicity of PHT does not involve membrane damage. The in vivo study demonstrated tumor inhibition rates of 30.9 and 48.2% for PHT at doses of 20 and 40 mg/kg, respectively. In addition, PHT was also able to increase the response elicited by 5-fluorouracil (5-FU) from 33.3 to 55.7%. The histopathological analysis of liver, kidney, and spleen showed that they were just moderately affected by PHT treatment. Neither enzymatic activity of transaminases nor urea levels were significantly affected. Hematological analysis showed leukopenia after 5-FU treatment, but this effect was prevented when 5-FU was combined with PHT.
In conclusion, PHT exhibited in vitro and in vivo antitumor effects without substantial toxicity.
KeywordsPhenstatins Tubulin inhibitor Antitumor activity Sarcoma 180 Toxicity
We wish to thank CNPq, CAPES, Instituto Claude Bernard, FUNCAP and FINEP for their financial support in the form of grants and fellowship awards. The authors also thank the National Cancer Institute (Bethesda, MD, USA) for the donation of the tumor cell lines used in this study. The authors thank Silvana França dos Santos, Luciana França and Maria de Fátima Teixeira for technical assistance. Dr. A. Leyva helped with English editing of the manuscript.
- 1.Vernon B, Powell S (2004) Localized delivery system for phenstatin using N-isopropylacrylamide, WO 2004009127Google Scholar
- 2.Pettit GR, Grealish MP (2001) Synthesis of hydroxyphenstatin and the prodrugs thereof as anticancer and antimicrobial agents, WO 2001081288Google Scholar
- 21.Fusetani N (1987) Marine metabolites which inhibit development of echinoderm embryos. In: Scheur PJ (ed) Biorganic marine chemistry. Springer, Berlin, pp 61–92Google Scholar
- 24.Kaufman DC, Chabner BA (2001) Clinical strategies for cancer treatment: the role of drugs. In: Chabner BA, Longo DL (eds) Cancer chemotherapy & biotherapy. Lippincott Williams & Wilkins, Philadelphia, pp 1–16Google Scholar
- 28.McGee JOD, Isaacson PA, Wright NA (1992) Oxford textbook of pathology: pathology of systems. Oxford University Press, New YorkGoogle Scholar
- 29.Scheuer PJ, Lefkowitch JH (2000) Drugs and toxins. In: Scheuer PJ, Lefkowitch JH (eds) Liver biopsy interpretation, 6th edn. W. B. Saunders, London, pp 134–150Google Scholar
- 30.Kummar V, Abbas A, Fausto N (2004) Robbins and cotran pathologic basis of disease, 7th edn. W.B., SaundersGoogle Scholar
- 31.Curran RC (1990) Color atlas of histopathology. Oxford University Press, New YorkGoogle Scholar
- 32.Olsen S, Solez K (1994) Acute tubular necrosis and toxic renal injury. In: Tisher CC, Brenner BM (eds) Renal pathology: with clinical and functional correlations. JB Lippincott, Philadelphia, pp 769–809Google Scholar