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Accumulation, intracellular metabolism, and antitumor activity of high- and low-dose methotrexate in human osteosarcoma xenografts.
- Source :
-
Cancer communications [Cancer Commun] 1990; Vol. 2 (6), pp. 219-29. - Publication Year :
- 1990
-
Abstract
- High doses of methotrexate with leucovorin rescue are routinely used in the treatment of patients with osteosarcoma; the rationale for this application is controversial. Using human osteosarcoma xenografts growing in mice as a clinically relevant model, we compared the accumulation, intracellular metabolism, and tumor response of methotrexate administered as either high-dose (2400 mg/kg) or low-dose (150 mg/kg) infusions. The high-dose regimen, which included i.v. hydration and leucovorin rescue, resulted in plasma methotrexate levels that approximated those in patients receiving the drug at 12 g/m2. The low-dose infusion produced essentially the same toxicity as the higher dose level, without use of leucovorin. The HxOs33 tumor line was moderately sensitive to the high-dose infusion (55-day delay in tumor volume doubling time), whereas the second line, HxOs2, did not respond. Neither xenograft had a measurable response to low-dose methotrexate. Methotrexate was present in both tumors for up to 72 hr post-infusion, regardless of the dosage regimen. Only shorter-chain polyglutamates (MTXglu2 and MTXglu3) were detected over this period in the high-dose trial, and levels of these derivatives were uniformly higher in the resistant HxOs2 xenograft. Low-dose infusions were associated with formation of longer-chain polyglutamate species, with more abundant production in the HxOs2 line. Methotrexate polyglutamates exceeded baseline [3H]MTX binding of dihydrofolate reductase, as measured in tumor homogenates, at all testing intervals through 72 hr in both tumor lines. Nonetheless, high-dose methotrexate-induced suppression of [14C]formate incorporation into DNA was greater in the drug-sensitive HxOs33 tumor than in HxOs2. These results suggest a therapeutic advantage for high-dose methotrexate regimens in the treatment of human osteosarcoma but show that formation of tumor MTX polyglutamates is not the sole determinant of response to this agent.
- Subjects :
- Animals
Carbon Radioisotopes
DNA metabolism
Dose-Response Relationship, Drug
Formates metabolism
Humans
Liver metabolism
Mice
Neoplasm Transplantation
Polyglutamic Acid analogs & derivatives
Polyglutamic Acid metabolism
Transplantation, Heterologous
Tritium
Body Fluids metabolism
Intracellular Fluid metabolism
Methotrexate analogs & derivatives
Methotrexate metabolism
Methotrexate pharmacokinetics
Methotrexate pharmacology
Osteosarcoma drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 0955-3541
- Volume :
- 2
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cancer communications
- Publication Type :
- Academic Journal
- Accession number :
- 1696116
- Full Text :
- https://doi.org/10.3727/095535490820874407