Raloxifene and selective cell cycle specific agents: a case for the inclusion of raloxifene in current breast cancer treatment therapies.

BACKGROUND: Breast cancer patients are at increased risk of osteoporosis. Contributing factors include age and/or chemotherapy. The selective estrogen modulator, raloxifene (RAL), effective in the prevention of breast cancer and approved for the treatment and prevention of osteoporosis, may prove beneficial in current breast cancer treatment modules. The purpose of this study was to evaluate RAL in combination with 5-fluorouracil (5-FU) and trimetrexate (TMX) to determine the most effective sequence in which to administer these cell cycle specific agents while taking into consideration the cellular mechanism of action. The goal was to maintain cytotoxicity to breast cancer cells and capitalize on the selective estrogen receptor modulatory effects of RAL. MATERIALS AND METHODS: MCF-7 cells were exposed to (i) TMX, 5-FU or RAL alone, or (ii) RAL 24 h prior to 5-FU followed 2 h later by TMX, or (iii) 5-FU 2 h prior to TMX followed 24 h later by RAL. The cell viability was determined using the Quick Cell Proliferation Assay. RESULTS: The growth rate of MCF- 7 cells exposed to early RAL was 68.25 +/- 4.11% that of the control, however, late RAL exposure produced a growth of 34.75 +/- 4.79% that of the control. Late RAL maintained the cytotoxicity of the regimen. The findings were further supported by cell flow cytometry and Western blot analysis data. CONCLUSION: RAL given prior to 5-FU/TMX significantly compromised cytotoxicity to breast cancer cells.

Sequential combination chemotherapy in human breast cancer: a basis for increased antineoplastic activity and bone marrow protection.

These studies were designed to develop procedures that would capitalize on the growth inhibitory effects of tamoxifen (Tam) and methotrexate (MTX) in breast cancer, while protecting bone marrow with a priming dose of 5-fluorouracil (5-FU). High-dose MTX (10 microM) cytotoxicity is maintained in MCF-7 breast cancer cells but reduced in human bone marrow by a priming and nontoxic dose of 5-FU (10 microM). MTX cytotoxicity is decreased in MCF-7 breast cancer cells when the selective estrogen receptor modulator (SERM) Tam (10 microM) is administered 24 hours prior to 5-FU (10 microM) followed two hours later by MTX (early Tam) resulting in a growth rate of 57.42 +/- 4.38% of the control rate. However, when breast cancer cells are exposed to Tam 24 hours after 5-FU + MTX (late Tam), the interaction between MTX and Tam is not antagonistic, the percentage of the control is 29.47 +/- 4.54%. Bone marrow exposure to these drug combinations exhibits a protective effect to the MTX cytotoxicity, with the early Tam combination yielding 59.45 +/- 16.38% of the control for MTX alone. These studies suggest that a) Tam in combination with a priming dose of 5-FU protects bone marrow from MTX cytotoxicity, b) the interactions between Tam and MTX are sequence-dependent, c) Tam decreases the effect of MTX when Tam administration precedes MTX.

The interaction of the steroidal antagonist faslodex and methotrexate.

Faslodex (FAS, ICI 182, 780), a novel steroidal estrogen antagonist decreased high-dose methotrexate (MTX) cytotoxicity in MCF-7 breast cancer cells. When FAS is given at least 24 hr prior to MTX, the resultant interaction is antagonistic. However, when breast cancer cells are exposed to FAS 24 hr after MTX, the interaction between FAS and MTX is not antagonistic. The proliferation of cells exposed to 0.1 microM FAS and 10 microM MTX alone or in combination with FAS 24 hr prior to MTX was in the following order: FAS>FAS 24 hr prior to MTX>MTX. MTX administration 24 hr prior to FAS had the following inhibitory effects on the growth of cells: MTX 24 hr prior to FAS >MTX>FAS 24 hr prior to MTX>FAS>control (no drug exposure). To determine if the antagonistic interaction between FAS and MTX was a function of sequence and time, cells were exposed to FAS 24 hr and 36 hr prior to MTX exposure. The percentages of control rates were 42.70 +/- 4.60% and 57.89 +/- 0.55%, respectively, from a 24 hr and 36 hr exposure of FAS prior to MTX. The growth rates after 24 and 36 hr exposures to MTX alone were 30.30 +/- 0.61% and 33.11 +/- 2.57% of control rates, respectively. These studies suggest that: a) the interactions between FAS and MTX are sequence-dependent; b) FAS antagonizes the effect of MTX when FAS administration precedes MTX, and c) FAS antagonism to MTX is a function of time.