Tamoxifen inhibits colorectal cancer metastases in the liver: a study in a murine model.
Liver metastases account for over 70% of deaths resulting from colorectal carcinoma, with survival rates varying between 6-18 months. At present, surgical resection offers the only hope for a cure, while chemotherapy, focal destructive techniques and selective internal radiation offer palliative care. Tamoxifen, a non-steroidal anti-oestrogen is primarily known for treating oestrogen receptor (ER)-positive breast cancer. Some studies suggest that tamoxifen may have beneficial effects in malignancies other than breast cancer. These inhibitory effects, which have been shown to be independent of the ER, highlight new mechanisms of therapeutic action. Using an intrasplenic animal model we report the efficacy of tamoxifen on experimental liver metastases. In this model, a dimethyl hydrazine-induced colon carcinoma cell suspension is introduced into the portal circulation via the spleen, which results in secondary tumour deposits in the liver in virtually all animals. Tamoxifen 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 tamoxifen on tumour growth was assessed by stereology and bromodeoxyuridine immunohistochemistry at selected time points. Data were assessed by a multiple analysis of variance where P < 0.05 was considered significant. In the control group the volume of metastases increased from 44 +/- 41 mm3 at day 10 to 517 +/- 380 mm3, 1394 +/- 598 mm3 and 2082 +/- 675 mm3 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 mm3 by day 22 compared with the control group at that time point (P = 0.00004). The inhibitory effect diminished by the fourth week recording a tumour volume of 1344 +/- 674 mm3 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 tamoxifen-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 tamoxifen has a potent inhibitory action on colorectal liver metastases by exerting an effect on cell proliferation.
Kuruppu
D
D
Department of Surgery, Monash Medical School, Alfred Hospital, Prahran, Victoria, Australia. Darsh@Alfred.Med.Monash.Edu.Au
Christophi
C
C
Bertram
J F
JF
O'Brien
P E
PE
D000818:Animals; D001973:Bromodeoxyuridine; D002277:Carcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D002455:Cell Division; D015179:Colorectal Neoplasms / Q000473:pathology*; D007150:Immunohistochemistry; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D051379:Mice; D008808:Mice, Inbred CBA; D009336:Necrosis; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D013629:Tamoxifen / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D013629:Tamoxifen; D001973:Bromodeoxyuridine