Threshold Methotrexate Concentration for In Vivo Inhibition of DNA Synthesis in Normal and Tumorous Target Tissues

Abstract

A B S T R A CThese studies indicate that host tissues are inhibited by extremely low concentrations of methotrexate, and indicate the importance of the slow final phase (ti = 12 h) of drug elimination from plasma in producing a prolonged exposure of sensitive host tissues to inhibitory drug concentrations.

The cytotoxic effect of methotrexate loaded bone cement on osteosarcoma cell lines

“…These concentrations were 130 to 4000 times higher than the minimum inhibitory concentration (MIC, 1×10 -8 M) required to inhibit DNA synthesis [3]. In the case of the MTX 20-mg and 50-mg pellets, the concentrations of methotrexate were 10,000 times higher than the MIC on the first day and 1400 times higher on the 28th day.…”

Relationship between RFC gene expression and intracellular drug concentration in methotrexate-resistant osteosarcoma cells

“…L5178Y (a cell line with deficient active transport) and normal transport cell lines were cultured in medium with 10 µM MTX L5178Y cell line by Chabner and Young (1973). There was a mutation of the RFC gene, causing the expression and function of the RFC gene to decline.…”

Effect of Two Cancer Chemotherapeutic Agents on the Antibacterial Activity of Three Antimicrobial Agents

“…Methotrexate, cytosine arabinoside (AraC), 6-mercaptopurine, and cyclophosphamide have all been shown to have antimicrobial activity against K. pneumoniae and E. coli, but not against P. aeruginosa (7); methotrexate has also been shown to have activity against group A streptococci (16). Whereas such preferential inhibition of patient flora by cytotoxic agents might help to explain why an unaffected microorganism such as P. aeruginosa is associated with a high infection rate, the fact that inhibitory concentrations of these drugs in vitro were higher than levels generally achievable in the blood after infusion (3,4,10) should preclude this possibility. Therefore, the current study was undertaken, first to determine if two cytotoxic agents commonly used for the treatment of leukemia exhibit antimicrobial activity at readily achievable serum levels when tested against those bacteria that most frequently cause infection in granulocytopenic cancer patients, and second to determine whether these agents exert any effect on the antimicrobial activity of some of the antibiotics most often used to treat infections in these patients.…”

“…Bacteria that had been grown overnight in MuellerHinton broth at 37°C were adjusted to a McFarland no. 3 standard, and 25 p1 of the resultant suspension was added to each well. Those control wells that received only antimicrobial agents or cancer chemotherapeutic agents and bacterial suspension were adjusted to a final volume of 100 p1 by the addition of Mueller-Hinton broth.…”