Nursing Pharmacology Chapter 33-34: Anticancer Drugs
Antimetabolites
Classification Antifolate Analogues (e.g. Methotrexate)
Methotrexate (Trexall, Rasuvo, Otrexup, Xatmep)
Ingested folic acid is converted by enzyme catalyzed reactions to FH4 cofactors which provide CH3 groups needed for synthesis of the DNA and RNA precursors.1,8
The folic acid analog such as methotrexate inhibit FH4 metabolism thus limiting necessary one-carbon and methylation reactions needed for purine ribonucleotide and thymidine monophosphate synthesis required for DNA replication.
Folic acid is described as an important, essential dietary factor with reduced folate important in one-carbon metabolism necessary for purine biosynthesis, thymidylate synthesis and protein synthesis.
The first antifolate agent, aminopterin, which demonstrated clinical activity in childhood acute leukemia was replaced by methotrexate (MTX), another folate analog.
Cytotoxicity of methotrexate (MTX), pralatrexate (Folotyn), and pemetrexed (Alimta) is dependent on polyglutamate metabolites.8
These polyglutamate metabolites associated with each agent are characterized by 5-7 glutamyl groups coupled using a gamma-peptide link.
The effect of such polyglutamate metabolites is prolongation of cellular half-lives.
Extended half-lives are responsible for extended drug action within the tumor cell.
Furthermore, polyglutamate metabolites themselves represent direct, potent inhibitors of folate-dependent enzymes.8
These enzymes include:
Phosphoribosylglycinamide formyltransferase (GAR formyltransferase)
Phosphoribosylaminoimadazolecarboxamide formyltransferase (AICAR formyltransferase)
Thymidylate synthase (TS) and
Dihydrofolate reductase (DHFR).8
Methotrexate polyglutamates appear selectively retained in cancer cells such that their mediation of de novo purine nucleotides in thymidylate biosynthesis inhibition contribute importantly to MTX cytotoxicity.3
Methotrexate is the most broadly used antifolate analog, exhibiting activity against both hematologic cancers and many solid tumors.1,8
Methotrexate is active against hematologic malignancies including acute lymphoblastic leukemia and non-Hodgkin's lymphoma.8
Methotrexate is also useful in treating solid tumor cancer such as breast cancer, osteogenic sarcoma, bladder cancer, head and neck cancer, and gestational trophoblastic cancer.8
Methotrexate, selective toxicity and "rescue":
The designation of "partial selectivity" with respect to methotrexate action refers to its ability to kill not only rapidly dividing tumor cells but also rapidly dividing normal cells.
Examples of normal cells are those found in bone marrow and intestinal epithelium.
Cytotoxic activity of methotrexate and other folate antagonists are noted during the S phase of the cell-cycle and exhibits highest activity during rapid cellular proliferation.
"Rescue" from the effects of antifolate anticancer agents may be affected by leukovorin administration.
Leukovorin is a reduced folate coenzyme which reverses depletion of the intracellular pool of FH4 cofactors.
Cellular Entry: Folate and antifolate analogues:
Three folate transport systems that transport folate into mammalian cells have been identified.1
The folate receptor is optimized to transport folic acid with reduced ability in translocating methotrexate and related analogs.
A second transporter is the reduced folate transporter, which represents the principal transport protein for methotrexate, pemetrexed, ralitrexed and related analogs.
Finally, a pH-sensitive transporter is also found which is most sensitive at lower pH.
Some cancer types, such as hyperdiploid acute lymphoblastic leukemia (ALL) subtype, may exhibit high expression of the folate transporter.1
As a consequence, methotrexate is readily transported in this cancer type which shows dramatic methotrexate sensitivity.
Following methotrexate transport into the cell it becomes more charged as a result of polyglutamation, described above.
Therefore, methotrexate undergoes a type of ion-trapping preventing diffusion of the polyglutamated methotrexate form back out of the cell.1
The transport system is also identified as a drug-resistance mechanism.3
For example, (1). Resistance to methotrexate may occur following reduction in drug transport efficacy.
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In the presence of transport-defective cells which would normally limit methotrexate entry, use of higher dose methotrexate may overcome this deficiency.
At the higher doses accumulation of intracellular methotrexate may be sufficient to inactivate even the higher levels of DHFR.1
Extending this point is that following transport methotrexate is polyglutamated.
(2) A Reduction in formation of cytotoxic methotrexate polyglutamates would therefore decrease drug efficacy.
(3) Another resistance mechanism is based on an increase in concentration of methotrexate's target, the enzyme dihydrofolate reductase (DHFR).
Such an increase can occur by genetic mechanisms including gene amplification.
(4) The DHFR protein itself may become altered and exhibit decreased bindings (reduced affinity) for methotrexate.3
(5) Another method of resistance involves elevated expression of a transporter which facilitates movement of drugs from inside the cell to outside the cell (efflux transporter).1
The transporter in this case belongs to the MRP (Multidrug-Resistant Protein) class of proteins.
Multidrug-resistant proteins belong to a family of proteins described as ATP-binding cassette (ABC) transporters.
ABC transporters describe the largest branch of proteins in humans.
The MRP family consists of 13 members with MRP1 to MRP9 represent the major transporters which promote multidrug-resistant sin tumors through anticancer drug extrusion from the cell.
These transporters are described as lipophilic anionic transporters and apparently are able to transport not only free drug but also drug conjugates of glutathione, sulfate or glucuronidate.
References
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