Combination of 5-deoxy-5-fluorouridine and tamoxifen show cell-type specific antagonistic and cooperative effects on cytotoxicity in human mammary carcinoma cells.
The effect of tamoxifen (Tam) and 5-deoxy-5-fluorouridine (5-DFUR) cotreatment on cytotoxicity was assessed in various cancer-derived cell lines. Each cell line was treated with a range of Tam and 5-DFUR concentrations alone and in combination. The cell lines we examined include MDA-MB-231 (ERalpha-/ERbeta+), T47D (ERalpha+/ERbeta+), and three MCF-7 (ERalpha+/ERbeta+) sublines. Cell growth was assessed by MTT assay at multiple time points for up to 9 days. Fluorescence-associated cell sorting (FACS) analysis was used to examine the effects of Tam and 5-DFUR cotreatment on cell cycle progression. Treatment with Tam or 5-DFUR, which is metabolized to 5-FU in target cells, produced an anti-proliferative effect that was dose- and time-dependent in all cell lines examined; variation in cell line sensitivity to each compound and cotreatment was apparent. When 5-DFUR and Tam treatment were combined, T47D, MDA-MB-231, and an MCF-7 subline demonstrated a cooperative effect at the lowest Tam concentration tested in 9-day cultures. The significance of treatment dosage and duration was obvious when 5-DFUR and Tam cotreatment was observed to be antagonistic in 3-day cultures of a second MCF-7 subline and T47D cells. Results from our studies show that there may be cytotoxic benefits in the treatment of cancer from combined therapy with Tam and 5-FU precursor drugs. Enhanced inhibition of proliferation was observed when Tam was cotreated at low concentrations in relatively long-term cultures. This has clinical relevance in that it suggests that patients undergoing chemo-endocrine therapy with orally administered 5-FU precursor drugs may benefit from lower treatment dosages relative to other adjuvant therapies.
Bollig
Aliccia
A
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Du
Qian-Qian
QQ
Fan
Shing-Tzu
ST
Yu
Ben
B
Sarkar
Fazlul H
FH
Liao
Joshua
J
D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005434:Flow Cytometry; D005467:Floxuridine / Q000494:pharmacology*; D006801:Humans; D013629:Tamoxifen / Q000494:pharmacology*; D013997:Time Factors
D000970:Antineoplastic Agents; D005467:Floxuridine; D013629:Tamoxifen; C025034:doxifluridine