TAMOXIFEN INHIBITS COLORECTAL-CANCER METASTASES IN THE LIVER - A STUDY IN A MURINE MODEL

Liver metastases account for over 70% of deaths resulting from colorec tal carcinoma, with survival rates varying between 6-18 months. At pre sent, surgical resection offers the only hope for a cure, while chemot herapy, focal destructive techniques and selective internal radiation offer palliative care. Tamoxifen, a non-steroidal anti-oestrogen is pr imarily known for treating oestrogen receptor (ER)-positive breast can cer. Some studies suggest that tamoxifen may have beneficial effects i n malignancies other than breast cancer. These inhibitory effects, whi ch have been shown to be independent of the ER, highlight new mechanis ms of therapeutic action. Using an intrasplenic animal model we report the efficacy of tamoxifen on experimental liver metastases. In this m odel, a dimethyl hydrazine-induced colon carcinoma cell suspension is introduced into the portal circulation via the spleen, which results i n secondary tumour deposits in the liver in virtually all animals. Tam oxifen was administered at a dose of 1 mg/kg suspended in 1.0% methyl cellulose. The control group received an equal volume of the vehicle. The reagents were administered s.c. on the day of metastases induction and were continued daily over a 4 week period. The effect of tamoxife n on tumour growth was assessed by stereology and bromodeoxyuridine im munohistochemistry at selected time points. Data were assessed by a mu ltiple analysis of variance where P < 0.05 was considered significant. In the control group the volume of metastases increased from 44 +/- 4 1 mm(3) at day 10 to 517 +/- 380 mm(3), 1394 +/- 598 mm(3) and 2082 +/ - 675 mm(3) by days 16, 22 and 28, respectively. Daily administration of tamoxifen exerted an inhibitory effect on tumour growth during the first 3 weeks, recording a volume of 421 +/- 299 mm(3) by day 22 compa red with the control group at that time point (P = 0.00004). The inhib itory effect diminished by the fourth week recording a tumour volume o f 1344 +/- 614 mm(3) by day 28. Inhibition of tumour growth at day 22 coincides with a reduction of cells in the S phase of the cell cycle. The percentage of brdU-positive nuclear profiles in metastases of tamo xifen-treated mice at 3 weeks was 35.87 +/- 5.60% compared with 48.01 +/- 3.96% in the control group (P = 0.001). These data suggest that ta moxifen has a potent inhibitory action on colorectal liver metastases by exerting an effect on cell proliferation.