Pharmacokinetics and biological responses after treatment of the rat R-1 rhabdomyosarcoma with methotrexate.
Time relationships of drug concentrations in tissue of a transplantable rat rhabdomyosarcoma and of tumour responses up to 120 hr after treatment with methotrexate (MTX) were analysed and compared. MTX was shown to be retained within the tumour in a substantial concentration for several days, although no evidence of MTX polyglutamation was obtained. The response data confirm that MTX is active in the tumour for up to at least 3 days after injection. Within the first day after MTX treatment the nucleotide pools are only partly depleted. This indicates that the inhibition of DNA synthesis is still incomplete at the time when salvage precursors in increasing amounts are becoming available from decaying cells. From flow cytometric analysis of cell-cycle progression it is concluded that subsequent cohorts arriving in early S-phase were retarded, but not inhibited, in their progression through the S phase. At 3 days after MTX treatment the mean rate of cell-cycle progression as well as the relative clonogenic capacity were maximally reduced to 30% and 1% of control values, respectively. From 3 to 5 days the rate of cell-cycle progression was gradually restored, whereas from day 5 onwards the clonogenic capacity increased at a high rate corresponding to the proliferation rate of exponentially growing rhabdomyosarcoma cells in culture. However, a continuous reduction of cell recovery lasting for at least 12 days after treatment contributed to an 8-day delay in tumour volume growth.
Kipp
J B
JB
Laboratory for Radiobiology, University of Amsterdam, The Netherlands.
Leyva
A
A
van Gennip
A H
AH
Kal
H B
HB
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003131:Combined Modality Therapy; D005434:Flow Cytometry; D008727:Methotrexate / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008938:Mitosis / Q000187:drug effects; D009368:Neoplasm Transplantation; D009711:Nucleotides / Q000378:metabolism; D011099:Polyglutamic Acid / Q000378:metabolism; D051381:Rats; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D014747:Vinblastine
D009711:Nucleotides; D011099:Polyglutamic Acid; D014747:Vinblastine; D008727:Methotrexate