Selectivity of Very High Dose Methotrexate in Mcf-7 and Normal Cells Using a Priming and Non-Toxic 5-Fluorouracil Dose
Abstract
The purpose of this study is designed: (1) to improve the quality of life by exploiting differences in the biochemical pharmacology of methotrexate (MTX) in human MCF-7 and MDA-MB-436 breast cancer cells and human bone marrow (Hs 824.T) cells, and (2) to provide a clear basis for intracellular protection of susceptible host cells from MTX toxicity when high-dose MTX is used in combination with a priming and nontoxic dose of 5-fluorouracil (5-FU). High-dose MTX cytotoxicity is maintained in MCF-7 and MDA-MB-436 breast cells but reduced in bone marrow cells by a priming and nontoxic 5-FU dose. The combinations of 5-FU 2h prior to MTX, MTX 2h prior to 5-FU, and MTX alone inhibited breast cancer cells to the same degree. In bone marrow cells, only MTX 2h prior to 5-FU and MTX alone affected growth similarly, but 5-FU 2h prior to MTX protected against MTX inhibitory effects. Similar patterns to bone marrow emerges in platelets. A comparison of the cell killing effects of MTX and the nonpolyglutamable antifolate trimetrexate (TMX) alone and in combination with 5-FU was made in an attempt to indirectly explore the role of polyglutamylation in breast cancer and bone marrow cells. Significant protection occurred only in bone marrow when 5-FU was administered before MTX or TMQ. It is unlikely that MTX-polyglutamylation plays a significant role in bone marrow. Hence, these studies suggest that a priming and nontoxic 5-FU dose in combination with high-dose MTX: (1) sustains MTX cytotoxicity in breast cancer but; (2) protects against MTX toxicity to bone marrow.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2000
- Accession Number
- ADA392325
Entities
People
- Donnell Bowen
Organizations
- Howard University