Antimetabolites.
The mechanisms of action of MTX and 5-FU have been further elucidated. Such studies will be important for the design of drug combinations and for the development of novel antifolate and fluoropyrimidine analogs. A greater understanding of MTX and ara-C transport and drug levels required to optimize transport may also aid in these endeavors. Pharmacokinetic parameters have been found to be predictors of relapse in children with acute leukemia, particularly with respect to MTX, 6-MP and ara-C. The intracellular terminal half-life of ara-C was correlated with remission duration in AML. Assay systems aimed at uncovering response predictors through biochemical analysis of patient tumor samples are being developed, including an interesting use of NMR spectroscopy to study the pharmacokinetics of fluorine-19-labeled 5-FU in vivo. Such an approach may yield valuable information on 5-FU anabolism in tumors in situ. A high frequency of resistance to MTX apparently may be generated within a single cell cycle by transient exposures to DNA synthesis inhibitors. The resistance may be based on either target enzyme amplification or altered membrane transport. These important studies provided bases for the rapid emergence of clinical resistance. Further, the multidrug-resistant phenotype appears to be a much broader based phenomenon as MTX resistance was found to be a frequent event in cells selected for multidrug resistance. A variety of novel approaches have been proposed to overcome antimetabolite resistance and to improve the selectivity of these agents, including the use of guanosine nucleotides, leucovorin and allopurines as biochemical modulators of 5-FU. Efficient techniques for the transfection of resistant DHFR into tissues using retroviruses have been reported. These studies serve as starting point for the ultimate development of more effective strategies for the treatment of human malignancies.
Allegra
C J
CJ
Grem
J L
JL
Yeh
G C
GC
Chabner
B A
BA
D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D003561:Cytarabine / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008727:Methotrexate / Q000493:pharmacokinetics / Q000494:pharmacology; D011687:Purines / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D011687:Purines; D011743:Pyrimidines; D003561:Cytarabine; D008727:Methotrexate