Inhibition of hepatocellular cancer by EB1089: in vitro and in vive study.
BACKGROUND
Despite significant antiproliferative potential, clinical application of 1,25 dihydroxy vitamin D3 [1,25(OH)2VD3] in the treatment of cancer has been hindered due to the development of hypercalcemia. Various derivatives of 1,25(OH)2VD3 have been synthesized to overcome this side-effect. Seocalcitol (EB1089) is a vitamin D analog that has been extensively studied and shown to have profoundly reduced hypercalcemic effects. Here the effects of EB1089 were evaluated in Hep 3B, SKHEP-1, PLC/PRF/5, HTC and Novikoff hepatocellular cancer (HCC) cell lines.


METHODS
In vitro, cells were treated with different concentrations of EB1089 (1-1000 nM). Analytical tests were then performed including cell count and 3H thymidine assay. For in vivo analysis, SKHEP-1 cells were xenografted into nude male mice. Twenty-four hours after inoculation, mice were randomly assigned to a control group (n=10) or one of the treatment groups (3 groups of 10 mice) receiving 0.02, 0.1 or 0.5 microg/kg/day of EB1089. Control animals received the vehicle (propylene glycol). To minimize the number of intraperitoneal injections, oral and intraperitoneal routes were used on alternate days. Tumor size was measured every third day and the volumes were estimated using the formula 0.5 x length x (width)2.


RESULTS
In vitro: Proliferation of Hep 3B, PLC/PRF/5 and SKHEP-1 HCC cells was significantly inhibited at all EB1089 concentrations tested, while HTC cells only responded to 1000 nM concentration of EB1089. Proliferation of Novikoff cells was unaffected by the drug at all concentrations examined. In vivo: EB1089 effectively inhibited SKHEP-1 tumor growth without inducing hypercalcemia (p<0.05).


CONCLUSIONS
Results of the present study indicate that EB1089 is an effective growth inhibitor of HCC tumors.
Ghous
Zahid
Z
Cancer Research Laboratories, University of New South Wales, Australia.
Akhter
Javed
J
Pourgholami
Mohammad H
MH
Morris
David L
DL
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013936:Thymidine / Q000378:metabolism; D014316:Tritium; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D014316:Tritium; D002117:Calcitriol; C078903:seocalcitol; D013936:Thymidine