Inhibition of hepatocellular carcinomas in vitro and hepatic metastases in vivo in mice by the histone deacetylase inhibitor HA-But
| Autor: | C. Pellizzaro, Ulderico Mazzi, Danila Coradini, Annalisa Speranza, Gianni Sava, Ignazio Scarlata, Claudia Turrin, Sonia Zorzet, Silvia Cantoni, Raffaella Rossin, Alberto Perbellini, Michele Bello |
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| Přispěvatelé: | Coradini, D., Zorzet, Sonia, Rossin, R., Scarlata, I., Pellizzaro, C., Turrin, C., Bello, M., Cantoni, S., Speranza, A., Sava, Gianni, Mazzi, U., Perbellini, A. |
| Jazyk: | angličtina |
| Rok vydání: | 2004 |
| Předmět: |
Cancer Research
Carcinoma Hepatocellular Cell Survival Melanoma Experimental Carcinoma Lewis Lung Mice Route of administration Pharmacokinetics In vivo Cell Line Tumor medicine Carcinoma Animals Humans Tissue Distribution hepatic metastases hepatic metastase Enzyme Inhibitors Hyaluronic Acid Neoplasm Metastasis histone deacetylase inhibitor model of hepatocarcinoma in mouse biology Melanoma Liver Neoplasms CD44 Lewis lung carcinoma Esters Organotechnetium Compounds Flow Cytometry medicine.disease Survival Analysis Histone Deacetylase Inhibitors Mice Inbred C57BL Hyaluronan Receptors Oncology Mice Inbred DBA Hepatocellular carcinoma Mice Inbred CBA Cancer research biology.protein Butyric Acid Female |
| Popis: | Purpose: The purpose is to evaluate the CD44-mediated cellular targeting of HA-But, a hyaluronic acid esterified with butyric acid (But) residues, to hepatocellular carcinoma cell lines in vitro and to hepatic tumor metastases in vivo. Experimental Design: In vitro, the CD44-dependent cytotoxicity in two human hepatocellular carcinoma cell lines (HepB3 and HepG2) with high and low CD44 expression was investigated; in vivo, the effect on liver metastases originating from intrasplenic implants of Lewis lung carcinoma (LL3) or B16-F10 melanoma in mice was compared with the pharmacokinetics of organ and tissue distribution using different routes of administration. Results: HepB3 and HepG2 cell lines showed different expression of CD44 (78 and 18%, respectively), which resulted in a CD44-dependent HA-But inhibitory effect as demonstrated also by the uptake analysis performed using radiolabeled HA-But (99mTc-HA-But). Pharmacokinetic studies showed different rates of 99mTc-HA-But distribution according to the route of administration (i.v., i.p., or s.c.): very fast (a few minutes) after i.v. treatment, with substantial accumulation in the liver and spleen; relatively slow after i.p. or s.c. treatment, with marked persistence of the drug at the site of injection. The effect of s.c. and i.p. treatment with HA-But on liver metastases originating from intrasplenic implants of LL3 carcinoma or B16-F10 melanoma (both CD44-positive: 68 and 87%, respectively), resulted in 87 and 100% metastases-free animals, respectively (regardless of the route of administration), and a significant prolongation of the life expectancy compared with control groups. Conclusions: HA-But tends to concentrate in the liver and spleen and appears to be a promising new drug for the treatment of intrahepatic tumor lesions. |
| Databáze: | OpenAIRE |
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