Critical factors for the reversal of methotrexate cytotoxicity by folinic acid

Abstract

Summary The cytotoxicity of methotrexate (MTX) on representative human tumour cell lines (two cell lines from head and neck carcinomas, two from breast carcinomas, two from osteosarcomas and one lymphoblastoid cell line) was evaluated to: (1) examine the optimal time interval between MTX and folinic acid (FA) administration; (2) (FBS) were from Gibco (Paisley, UK). Penicillin and streptomycin were from Merieux (Lyons, France). Transferrin was from Flow Laboratories (Irvin, UK). The MTT test was performed with 3-(4-5 dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) and DMSO, both from Sigma. Cell culturesThe eight human tumour cell lines used are described in Table I. Cells were routinely cultured in a humidified incubator (Sanyo) at 37'C with an atmosphere containing 8% CO2 in air. The head and neck cancer cell lines and the osteosarcoma cell lines were grown in DMEM medium supplemented with 10% FBS, penicillin (50,000 IU I1), streptomycin (86 tLM), and 1-glutamine (2 mM). The breast cancer cell lines were grown in the same medium supplemented with insulin (0.1 jIM) and transferrin (0.64 liM). The lymphoblastoid cell line was grown in RPMI 1640 medium supplemented with 10% FBS, penicillin (50,000 IU 1'), streptomycin (86 fLM) and 1-glutamine (2 mM). In brief, cells were grown in 96-well microtitration plates in their respective culture medium; 24 h later, they were exposed to MTX for 24 h. The respective initial cellular densities (Table I) were determined by a preliminary study in order to obtain optimal logarithmic growth. The MTX concentrations used (Table I)

Advances in individual prediction of methotrexate toxicity: a review

“…The side effects include reversible myelosuppression, mucositis, hepatotoxicity, and reduced kidney function, as well as both transient and persistent neurotoxicity. Except for the nephrotoxicity, these toxicities can in most cases be prevented by the administration of Leukovorin without concurrent rescue of malignant cells, as these have a higher propensity for MTX polyglutamation and lower capacity for folate accumulation than normal cells (Bernard et al , 1991). Prior to the routine monitoring of plasma MTX concentrations and dosing of Leucovorin accordingly, the incidence of fatal toxicity after HD‐MTX was approximately 5% (Widemann & Adamson, 2006), and the risk of toxicity was clearly related to MTX concentrations above 5–10 μmol/l at 24 h, 1 μmol/l at 48 h, and 0·1 μmol/l at 72 h (Widemann & Adamson, 2006).…”

High-dose methotrexate in the treatment of adult acute lymphoblastic leukemia

“…Patients should not be "over-rescued" however. Excessive LV administration can impair the antitumor activity of HDMTX [4,52], as well as too early onset of LV rescue [27,34]. In addition the effectiveness of HDMTX in the treatment of CNS leukemia may be impaired, since LV accumulates in the CSF after repeated courses [35].…”

Central nervous system prophylaxis in haematological malignancies

“…Folinic acid rescue is adapted to plasma Mtx levels in order to prevent prolonged myelo­suppression. While folinic acid rescue has reduced toxicity and allowed the Administration of higher doses of Mtx, premature administration of folinic acid can lead to ‘over rescue’ and reduced efficacy 25 . High‐dose Mtx has well‐known acute toxicities, such as renal dysfunction.…”

“…While folinic acid rescue has reduced toxicity and allowed the administration of higher doses of Mtx, premature administration of folinic acid can lead to 'over rescue' and reduced efficacy. 25 High-dose Mtx has well-known acute toxicities, such as renal dysfunction. Careful alkalinization of the urine and intravenous hydration is used to prevent this problem.…”