Inhibition of hepatocellular carcinomas in vitro and hepatic metastases in vivo in mice by the histone deacetylase inhibitor HA-But.
OBJECTIVE
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.


METHODS
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 ((99m)Tc-HA-But). Pharmacokinetic studies showed different rates of (99m)Tc-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.
Unit of Biomolecular Determinants in Prognosis and Therapy, Experimental Department, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan. Danila.Coradini@istitutotumori.mi.it
Danila
D
Coradini
Sonia
S
Zorzet
Raffaella
R
Rossin
Ignazio
I
Scarlata
Cinzia
C
Pellizzaro
Claudia
C
Turrin
Michele
M
Bello
Silvia
S
Cantoni
Annalisa
A
Speranza
Gianni
G
Sava
Ulderico
U
Mazzi
Alberto
A
Perbellini
D000818:Animals; D020148:Butyric Acid / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000517:prevention & control; D018827:Carcinoma, Lewis Lung / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004952:Esters; D005260:Female; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D006820:Hyaluronic Acid / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008113:Liver Neoplasms / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control; D015609:Organotechnetium Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D016019:Survival Analysis; D014018:Tissue Distribution
D004791:Enzyme Inhibitors; D004952:Esters; D056572:Histone Deacetylase Inhibitors; D018960:Hyaluronan Receptors; D015609:Organotechnetium Compounds; D020148:Butyric Acid; D006820:Hyaluronic Acid