The combination of tamoxifen and 9cis retinoic acid exerts overadditive anti-tumoral efficacy in rat hepatocellular carcinoma.
OBJECTIVE
Medical treatment for hepatocellular carcinoma (HCC) remains elusive. While an acyclic retinoid improved tumor-free survival after hepatoma resection, tamoxifen finally proved ineffective. Combination therapy of both agents has not been investigated in vitro and in vivo.


METHODS
MH7777A hepatoma cells were incubated with tamoxifen (TAM) and 9-cis retinoic acid (CRA) alone or in combination. Proliferation rate and apoptosis were assessed by BrdU incorporation and flow cytometry. In vivo efficacy was studied using the Morris hepatoma model in immunocompetent rats. End points were macroscopic tumor growth, metastasis and immunohistochemistry for proliferative and apoptotic tumor cells (PCNA and TUNEL staining).


RESULTS
In vitro, CRA and TAM monotherapy was effective only in the highest concentration. Combination therapy significantly enhanced apoptosis rate and growth inhibition in hepatoma cells. While in vivo monotherapy did not reduce tumor growth or metastasis, their combination reduced tumor size after 28 days by 64.5+/-28%. This was paralleled by an increase in TUNEL positive and a decrease in PCNA positive cells.


CONCLUSIONS
The combination of TAM and CRA enhances their anti-tumoral efficacy in vitro as well as in vivo, while monotherapy is ineffective. This combination could be a promising adjunctive therapy of HCC.
Ganslmayer
Marion
M
Department of Internal Medicine I, University Erlangen-Nuernberg, Ulmenweg 18, D-91054 Erlangen, Germany.
Ocker
Matthias
M
Kraemer
Gabi
G
Zopf
Steffen
S
Hahn
Eckhart G
EG
Schuppan
Detlef
D
Herold
Christoph
C
D000077556:Alitretinoin; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004261:DNA Replication / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D008113:Liver Neoplasms / Q000188:drug therapy*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy*; D051381:Rats; D011915:Rats, Inbred BUF; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use*; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use*
D013629:Tamoxifen; D000077556:Alitretinoin; D014212:Tretinoin