antimetabolites cancer Flashcards
Folate anatgonist
purine
pyrimidine
Methotrexate
Pralatrexate
Pemetrexed
Purine antagonists
6-Mercaptopurine (6-MP)
6-Thioguanine
Pyrimidine antagonists
5-Fluorouracil (5-FU)
Folic acid and mechanism
Folic acid and many of its analogs are polar, they cross the blood-brain barrier poorly. So they
require specific transport mechanisms to enter mammalian cells.
There are three inward folate transport systems:
1) a folate receptor, which has high affinity for folic acid but much reduced ability to transport
methotrexate and other analogs;.
2) the reduced folate transporter, the major transit protein for methotrexate.
3) a transporter that is active at low pH.
The reduced folate transporter is highly expressed in the hyperdiploid subtype of acute
lymphoblastic leukemia, due to the presence of multiple copies of chromosome 21, on which its
gene resides; these cells have extreme sensitivity to methotrexate
Methotrexate mechanism of action
FUNCTION OF FOLIC ACID AND FH4 COFACTORS
EXACT MAO OF MTX
WHAT IS THE ULTIMATE EFFECT ;COFACTORS ARE NOT SYNTHESIZED
INTERFERENCE
Folic acid is an essential dietary factor that is converted by enzymatic reduction to a series
of tetrahydrofolate (FH4) cofactors that provide methyl groups for the synthesis of
precursors of DNA (thymidylate and purines) and RNA (purines).
Methotrexate is a folic acid antagonist that binds to the active catalytic site of dihydrofolate
reductase (DHFR).
Inhibition of DHFR leads to partial depletion of the FH4 cofactors (5-10 methylene
tetrahydro-folic acid and N-10 formyl tetrahydrofolic acid) required for the respective
synthesis of thymidylate and purines. Thus interfering with the formation of DNA, RNA
and protein.
Interference with FH4 metabolism reduces the synthesis of purine ribonucleotides and
thymidine monophosphate (TMP), thereby inhibiting DNA replication.
methotrexate another MAO
Recognition that methotrexate, an inhibitor of dihydrofolate reductase (DHFR), also
directly inhibits the folate-dependent enzymes of de novo purine and thymidylate synthesis
led to development of antifolate analogs that specifically target these other folate dependent
enzymes.
Methotrexate is only partially selective for tumor cells and kills rapidly dividing normal
cells, such as those of the intestinal epithelium and bone marrow. Folate antagonists kill
cells during the S phase of the cell cycle and are most effective when cells are proliferating
rapidly
RESISTANCE TO METHOTREXATE
Impaired transport of methotrexate into cells
Production of altered forms of DHFR that have decreased affinity for the inhibitor
Increased concentrations of intracellular DHFR through gene amplification or altered gene
regulation
Decreased ability to synthesize methotrexate polyglutamates
THERAPEUTCIS METHOTREXATE
Methotrexate is a critical drug in the management of acute lymphoblastic leukemia (ALL)
in children.
The intrathecal administration of methotrexate has been employed for treatment or
prophylaxis of meningeal leukemia or lymphoma and for treatment of meningeal
carcinomatosis.
Methotrexate is of established value in choriocarcinoma and related trophoblastic tumors of
women; cure is achieved in ~75% of advanced cases treated sequentially with methotrexate
and dactinomycin and in >90% when early diagnosis is made.
Methotrexate is a component of regimens for carcinomas of the breast, head and neck,
ovary, and bladder.
ADRS METHOTREXATE
Bone marrow suppression,
haemorrhage,
alopecia,
dermatitis,
allergic reactions,
nephrotoxicity,
neurotoxicity.
The toxic effects of methotrexate may be terminated by administering leucovorin, a fully reduced
folate coenzyme, which filled the intracellular pool of FH4 cofactors. But it does not reverse
neurotoxicity.
PURINE ANTAGONISTS
6-mercaptopurine
6-Thioguanine
6-MP is metabolized into monophosphate nucleotide 6-thioinosinic acid in the presence of
hypoxanthine-guanine phosphoribosyl transferase (HGPRT).
Which by inhibiting different enzymes inhibit de novo purine nucleotide synthesis.
Monophosphate form of 6-MP may be converted into triphosphate form which may also
incorporate into DNA and RNA.
Significant active metabolites of 6-MP are thioguanylic acid and 6-methylmercaptopurine
ribonucleotide,that contribute to cytotoixc action
6-MP is converted to an inactive metabolite (6-thiouric acid) by an oxidation reaction catalyzed by xanthine oxidase, whereas
6-TG undergoes deamination
EFFICACY AND metabolism , ADRS of PURINES
The thiopurines are also metabolized by the enzyme thiopurine methyltransferase (TPMT),
in which a methyl group is attached to the thiopurine ring.
Patients who have a pharmaco-genetic syndrome involving partial or complete deficiency
of this enzyme are at increased risk for developing severe toxicities in the form of
myelosuppression and gastrointestinal toxicity with mucositis and diarrhea.
6-Mercaptopurine (6-MP) was the first of the thiopurine analogs found to be effective in
cancer therapy. This agent is used primarily in the treatment of childhood acute leukemia,along with clostely related azithioprine
PYRIMIDINES FU
5-Fluorouracil (5-FU) is inactive in its parent form and requires activation via a complex series of enzymatic reactions to ribosyl and deoxyribosyl nucleotide metabolites. One of these metabolites,
5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP), forms a covalently bound ternary complex with the enzyme TS and the reduced folate 5,10-methylenetetrahydrofolate, a reaction critical
for the de novo synthesis of thymidylate. This results in inhibition of DNA synthesis through “thymineless death.”
5-Fluorouracil undergoes biotransformation to form 5-fluorodeoxyuridine monophosphate.
This active form acts as pseudo-substrate for the enzyme thymidylate synthetase which
convert deoxyuridine monophosphate (dUMP)to deoxythymidylate monophosphate
(DTMP).
5-FU is converted to 5-fluorouridine-5′-triphosphate (FUTP), which is then incorporated into RNA, where it interferes with RNA processing and
mRNA translation.
5-FU is also converted to 5-fluorodeoxyuridine5′-triphosphate (FdUTP), which can be incorporated into cellular
DNA, resulting in inhibition of DNA synthesis and function.
Thus, the cytotoxicity of 5-FU is thought to be the result of combined effects on both DNA- and RNA-mediated events.
Therapeutic uses PYRIMIDINES
5-FU produces partial responses in 10-20% of patients with metastatic colon carcinomas,
upper GI tract carcinomas, and breast carcinomas but rarely is used as a single agent.
5-FU remains the most widely used agent in the treatment of colorectal cancer, both as adjuvant therapy and for advanced disease.
It also has activity against a wide variety of solid tumors, including cancers of the breast, stomach, pancreas, esophagus, liver, head and neck, and anus
5-FU in combination with leucovorin and oxaliplatin or irinotecan in the adjuvant setting is
associated with a survival advantage for patients with colorectal cancers(widely used)
why polyglutamate are necessary
Intracellular
formation of polyglutamate metabolites, with the addition of up to
5–7 glutamate residues, is critically important for the therapeutic
action of MTX, and this process is catalyzed by the enzyme folylpolyglutamate synthase (FPGS).
MTX polyglutamates are selectively retained within cancer cells, and they display increased
inhibitory effects on enzymes involved in de novo purine nucleotide and thymidylate biosynthesis, making them important determinants of MTX’s cytotoxic action
CI CLASSES FOR METHOTREXATE
Care must also be taken when MTX is used
in the presence of drugs such as aspirin, nonsteroidal anti-inflammatory agents, penicillin, and cephalosporins, as these agents
inhibit the renal excretion of MTX. T
KINETICS METHOTREXATE
MTX is administered by the intravenous, intrathecal, or oral
route. However, oral bioavailability is saturable and erratic at doses
greater than 25 mg/m2
. Renal excretion is the main route of
elimination and is mediated by glomerular filtration and tubular
secretion. As a result, dose modification is required in the setting
of renal dysfunction.
6 thioguanine
6-Thioguanine (6-TG) also inhibits several enzymes in the de novo purine nucleotide biosynthetic pathway
Various metabolic lesions result, including inhibition of purine nucleotide interconversion; decrease in intracellular levels of guanine nucleotides, which leads to inhibition of glycoprotein synthesis; interference with the formation of DNA and RNA; and
incorporation of thiopurine nucleotides into both DNA and RNA. 6-TG has a synergistic action when used together with
cytarabine in the treatment of adult acute leukemia
