Transcript 2-Antimetabolites.ppt

PHL 425
ANTIMETABOLITES
Dr. Yieldez Bassiouni
Antimetabolites
• Antimetabolites are drugs which have similar structure to
normal metabolites which are required for normal
biochemical reactions.
• S-phase specific = CCS
• Antimetabolite are classified into:
1- Folic acid Antagonists:
Methotrexate, Pemetrexed, Nolatrexed, Raltitrexed
2- Pyrimidine Antagonists:
- 5-FU
- ORALLY BIOAVAILABLE 5′-FLUOROPYRIMIDINES
(Capecitabine, Ftorafur )
- Cytidine Analogues
- Ara-C
- Gemcitabine
- 5-Azacytidine
3- Purine Antagonists:
- 6-Mercaptopurine
- Azathioprine
Purine and pyrimidine antagonists are phosphorylated inside the body
into nucleotid form in order to be cytotoxic
Indications
- Leukemias
- Non-Hodgkin's lymphoma
- Treatment of non-neoplastic disorders including:
- Rheumatoid arthritis,
- Psoriasis
- Inflammatory bowel disease
- Ulcerative colitis
- Immunosuppressant in transplantations
1- Folic Acid Antagonists (Anti-folates)
Antifolate compounds has been proven in the treatment of a variety
of hematologic and non-hematologic malignancies.
1- Methotrexate
2- Pemetrexed
3- Nolatrexed
4- Raltitrexed
Methotrexate (MTX)
DFR
Methotrexate (MTX)
Mechanism of action:
Methotrexate inhibits DHFR enzyme, therefore, it inhibits the synthesis of DNA, RNA and
proteins. DHFR catalyses the conversion of FH2 to the active FH4 which is needed for the
de novo synthesis of the deoxynucleoside thymidine phosphate DTMP ( required for DNA
synthesis
Metabolism:
1- Converted to MTX polyglutamates (cytotoxic
metabolite) in normal and malignant tissues.
2- Converted to 7-OHMTX (Inactive metabolite) in liver
by aldhyde oxidase.
3-Converted to diaminomethyl peteroic acid (DAMPA),
Inactive metabolite, by bacterial carboxypeptidase
enzyme in GIT
Elimination:
Primarily as interact drug in urine
High Dose MTX Therapy
Rational:
- MTX enter the cells through memberane folate binding protein (MFBP).
- Some tumours lack or have reduced MFBP, therefore, the uptake of MTX
in these tumours is not achieved after normal doses.
- High dose MTX is required to increase the extracellular levels of MTX.
Under these condition, MTX is transported by passive diffusion.
- In high dose MTX therapy, the uptake of MTX into tumour cells is highly
selective because the affinity of MFBP to MTX is higher (1 uM) than
normal cells (90 uM).
- Also, high dose MTX therapy improves its penetration into tumour sites
such as testis, CNS and blood brain barrier.
High Dose MTX Therapy
Precaution:
- High dose MTX therapy is associated with severe nephrotoxicity due to
precipitation of MTX and 7-OHMTX in renal tubules.
- Dose adjustment in proportion to creatinine clearance.
- Do not administer high-dose MTX to patients with abnormal renal function
- Monitor plasma concentrations of MTX
- Intensive hydration
- Alkalinzation of urine to increase MTX solubility by Sodium Bicarbonate
3 gm/3 hours for 12 hours before therapy
- Leucovorine Rescue: Lucovorin is tetrahydrofolate and competes with MTX
for transport into mammalian cells and human targeted tissues as bone
marrow and GIT. Leucovorin allowed the conventional doses of MTX to
increased by 10-100 times.
- Monitoring serum MTX level is an obligatory during high dose MTX therapy.
- The dose of Leucovorin depends on serum MTX levels.
- MTX drug levels should be measured every 24 hr and the dosage of
leucovorin adjusted until the MTX level is <5 × 10-8 mol/L.
Glucarpidase to combat toxic levels of methotrexate in patients
In January 2012, glucarpidase (Voraxaze®) received approval from the US
Food and Drug Administration for intravenous treatment of toxic plasma
methotrexate concentrations due to impaired renal clearance. High-dose
methotrexate has been particularly useful in the treatment of leukemias and
lymphomas. However, even with aggressive hydration and urine alkalinization,
such regimens can lead to acute renal dysfunction, as indicated by decreases
in urine production and concomitant increases in blood urea nitrogen and
serum creatinine levels. Because methotrexate is largely excreted by the
kidneys, this can greatly potentiate tissue damage. Toxic levels of blood
methotrexate can be rapidly and effectively decreased by intravenous
administration of glucarpidase. Glucarpidase is a recombinant form of
carboxypeptidase G2, a bacterial enzyme that rapidly cleaves methotrexate to
form the amino acid glutamate and 2,4-diamino-N10-methylpteroic acid.
Catabolites of methotrexate are much less toxic than the parent compound,
and are primarily excreted by hepatic mechanisms
MTX Toxicity
1- Renal dysfunction
2- Hepatotoxicity.
3- Neurotoxicity
4- GIT mucositis
5- Bone marrow suppression
6- Pneumonitis (interstitial pulmonary infiltrate)
MTX Resistance
1- Decrease MTX transport into the cells.
2- Gene amplification of DHFR.
3- decrease binding affinity of DHFR to MTX.
Drug interactions:
- Toxicity to normal tissues is rescued by leucovorin calcium (ANTIDOT)
- L-Asparaginase blocks toxicity and antitumor activity.
- Pretreatment with MTX increases 5-fluorouracil and cytosine arabinoside
nucleotide formation
Toxicity:
- Myelosuppression
- Mucositis,
- Gastrointestinal epithelial denudation
- Renal tubular obstruction and injury
- Hepatotoxicity
- Pneumonitis
- Neurotoxicity
Interaction between MTX and 5-FU
1- MTX preceding 5-FU: SYNERGISTIC CYTOTOXICITY
Interaction between MTX and 5-FU
2- 5-FU preceding MTX : ANTAGONISTIC CYTOTOXICITY
Interaction between MTX and
L-Asparaginase
L-Asparaginase conversts L-Asparagine (required for acute leukemia cells) into
aspartic acid and amonia.
L-Asparaginase pretreatment blocks the antitumour effect of MTX due to:
1- Inhibition of protein synthesis and prevention of cell entry into S-phase of cell cycle
2- Inhibition of MTX polyglutamation with the consequent decrease in MTX retention in
tumour cells.
3- Inhibition of DNA synthesis lasts 10 days, a period during which cells are refractory
to MTX. Therefore, Cycles of MTX-L-Asparaginase are repeated at 14 days interval.
This combination is effective against Acute Leukemia of Childhood.
Regimen for Combined MTX and L-Asparaginase in
Treatment of Refractory Acute Leukemia
Drugs
0
L-ASPARAGINASE
13
+
Days
14 27
28
+
+
(500 IU/kg)
MTX
(100 mg/m2)
+
+
2- Pemetrexed:
Thymidylate synthetase (TS) represents a logical target for
pemetrexed.
Pemetrexed is transported into cells via the reduced-folate carrier
(memberane folate binding protein (MFBP).
and possibly by a unique transporter identified in mesothelioma
cell lines.
It is metabolized to the polyglutamated forms, which are potent
inhibitors of thymidylate synthetase (TS) enzyme.
3- Nolatrexed
Nolatrexed is a non-classic inhibitor of TS specifically
designed to avoid potential resistance mechanisms that can
limit the activity of the classic antifolate antimetabolites.
Nolatrexed is a lipophilic molecule.
Nolatrexed is a non–glutamate-containing molecule.
Nolatrexed does not require facilitated transport for uptake.
Nolatrexed does not undergo, nor require, intracellular
polyglutamylation for activity.
Nolatrexed exhibited S-phase cell-cycle arrest.
4- Raltitrexed
Raltitrexed is a water-soluble TS inhibitor that appears to have an
acceptable toxicity profile, convenient dosing schedule, and
antitumor activity in colorectal, breast, pancreatic, and a variety
of other solid cancers.
This drug is a second-generation agent designed to overcome
the major toxicity associated with its predecessor.
2- Pyrimidine antagonists
- 5-Fluorouracil
- ORALLY BIOAVAILABLE 5′-FLUOROPYRIMIDINES
- Capecitabine
- Ftorafur
- Cytidine Analogues
- Ara-C
- Gemcitabine
- 5-Azacytidine
5-Fluorouracil
5-FU resembles the Pyrimidine base URACIL (Component of
RNA) and Thymidine base (Component of DNA)
Mechanism of action:
1- Incorporation of FUTP (false nucleotide) instead of UTP into RNA
interferes with RNA synthesis and function.
2- Inhibition of thymidylate synthase by (FdUMP) leads to depletion of TMP and TTP.
3- Incorporation of FdUTP into DNA may affect DNA stability.
Intracellular activation of 5-fluorouracil (5-FU). dUTP, deoxyuridine triphosphate; FdUDP, fluorodeoxyuridine
diphosphate; FdUMP, fluorodeoxyuridylate; FdUrd, 5-fluoro-2′-deoxyuridine; FdUTP, fluorodeoxyuridine
triphosphate; FUDP, fluorouridine diphosphate; FUMP, fluorouridine monophosphate; FUrd, 5-fluorouridine;
FUTP, fluorouridine triphosphate; PPRP, phosphoribosyl phosphate.
5-flurouracil (5-FU)
Metabolism: Converted enzymatically to active nucleotide forms intracellularly.
Dihydropyrimidine dehydrogenase (DPD) catalyzes the initial, rate-limiting step in 5fluorouracil (5-FU) catabolism.
Pharmacokinetics: Primary half-life is 8–14 minutes after IV bolus.
Nonlinear pharmacokinetics from saturable catabolism: Total-body clearance
decreases with increasing doses; clearance is faster with infusional schedules.
Volume of distribution slightly exceeds extracellular fluid space.
Elimination: Approximately 90% is eliminated by metabolism. <3% and < 10%
unchanged drug excreted by kidneys with infusional and bolus 5-FU. Reduction of 5FU to dihydrofluorouracil by DPD is rate-limiting. Thereafter: dihydrofluorouracil →
fluoroureidopropionic acid → fluoro-β-alanine.
5-FU and its catabolites undergo biliary excretion.
Toxicity:
Gastrointestinal epithelial ulceration
Myelosuppression
Dermatologic
Ocular
Neurotoxicity (cognitive dysfunction and cerebellar ataxia)
Cardiac (coronary spasm)
Biliary sclerosis
Precautions:
- Nonlinear pharmacokinetics: difficulty in predicting plasma
concentrations and toxicity at high doses. (nonlinear elimination
kinetics, the drug clearance decreases with increasing drug concentration)
- Patients with deficiency of Dihydropyrimidine dehydrogenase (DPD)
may have life-threatening or fatal toxicity if treated with 5-FU.
- Duration of DPD inhibition with eniluracil (a potent inactivator of
DPD) may be prolonged
(8-week washout period recommended).
- Older, female, and poor-performance–status patients have greater
risk of toxicity.
- Closely monitor prothrombin time in patients receiving concurrent
warfarin.
Clinical Predictive Value of
Dihydropyrimidine Dehydrogenase (DPD)
in 5-Fluorouracil (5-FU) Clinical Toxicity
DPD deficiency is a pharmacogenetic syndrome in which molecular defects
in the DPD gene result in a complete (profound) or partial loss of DPD
enzyme activity. This results in markedly altered 5-FU pharmacokinetics
and in turn severe toxicity following administration of standard doses of 5FU.
The cause for this toxicity appears to be decreased drug clearance,
resulting in markedly prolonged exposure to 5-FU.
Clinical Monitoring of DPD in cancer patients before 5-FU therapy is
essential to avoid severe 5-FU toxicity.
Monitoring of DPD in peripheral Blood Mononuclear Cells.
Genetic Deficiency of DPD in patients with colorectal carcinoma is
associated with severe 5-FU toxicity.
Eniluracil Combined With 5-Fluorouracil:
The uracil analog eniluracil is a potent mechanism-based inactivator
of DPD.
Administration of eniluracil results in complete inhibition of DPD
throughout the body.
When given with eniluracil, renal excretion of 5-FU becomes the
predominant route of elimination.
Oral administration of 5-FU with eniluracil renders 5-FU completely
bioavailable.
Although eniluracil appears to be nontoxic when given alone, it shifts
the 5-FU dose toxicity-response curves to lower doses.
ORALLY BIOAVAILABLE 5′-FLUOROPYRIMIDINES
Capecitabine
Capecitabine
Capecitabine [N (4-pentoxycarbonyl-5′-deoxy-5-fluorocytidine, Xeloda] is
the first oral 5-FU prodrug to be approved in the United States, on the
basis of its activity in patients with metastatic breast cancer whose disease
is refractory to two earlier regimens.
This agent is absorbed intact as the parent drug through the GI mucosa.
It then undergoes three-step enzymatic conversion to 5-FU.
By carboxylesterase (CES), cytosolic carboxylesterase and Cytidine
deaminase,
[In the liver, 5′-deoxy-5-fluorocytidine (5′-dFCyd) formation is catalyzed by
carboxylesterase (CES), which is mainly expressed in microsomes, but a
cytosolic carboxylesterase, CES1A1, also contributes to formation of 5′dFCyd.
Cytidine deaminase, a widely distributed enzyme, produces 5′-dFUrd, and
dThd phosphorylase then generates 5-FU.
Clinical studies have documented rapid GI absorption of the parent drug]
Ftorafur: Ftorafur is a prodrug and is slowly metabolized to 5FU by two major metabolic pathways
One pathway is mediated by microsomal cytochrome P-450 oxidation
at the 5′-carbon of the tetrahydrofuran moiety, resulting in the
formation of a labile intermediate (5′-hydroxyftorafur) that
spontaneously cleaves to produce succinaldehyde and 5-FU.
The second pathway occurs in the cytosol, and is thought to be
mediated by thymidine phosphorylase.
Cytidine Analogues
- CYTOSINE ARABINOSIDE (Ara-C)
- Gemcitabine
- 5-Azacytidine
CYTOSINE ARABINOSIDE (Ara-C) Cytarabine
Ara-C is one of the most effective agents in the treatment of acute myeloid
leukemia (AML) and is incorporated into all standard induction regimens
for this disease, generally in combination with an anthracycline
(daunorubicin hydrochloride or idarubicin hydrochloride).
Ara-C is also a component of consolidation and maintenance regimens in
AML after remission is attained.
Ara-C is also active against other hematologic malignancies, including
non- Hodgkin's lymphoma, ALL, and CML but has little activity as a single
agent against solid tumors. This limited spectrum of activity has been
attributed to the lack of metabolic activation of this agent in solid tumors
and its selective action against rapidly dividing cells.
Mechanism of action: Inhibits DNA polymerase α, is incorporated into DNA, and
terminates DNA chain elongation.
Metabolism: Activated to triphosphate (Ara CTP)in tumor cells. Degraded to inactive
ara-U by deamination
Elimination:
Deamination in liver, plasma, and peripheral tissues—100%
Drug interactions: Methotrexate sodium increases ara-CTP formation
Ara-C blocks DNA repair, enhances activity of alkylating agents
Fludarabine phosphate increases ara-CTP formation
Toxicity: Myelosuppression
Gastrointestinal epithelial ulceration
Intrahepatic cholestasis, pancreatitis
Cerebellar and cerebral dysfunction (high dose)
Conjunctivitis (high dose)
Noncardiogenic pulmonary edema
GEMCITABINE
Gemcitabine (2,2-difluorodeoxycytidine, dFdC) is the most important cytidine analog to enter clinical trials since ara-C.
[- deoxycytidine kinase phosphorylates gemcitabine intracellularly to produce
difluorodeoxycytidine monophosphate (dFdCMP), from which point it is converted to its
diphosphate and triphosphate difluorodeoxycytidine (dFdCDP, dFdCTP).]
Azacytidine
Mechanism of action:
Incorporated into DNA and RNA; prevents DNA methylation
Metabolism:
Activated to a triphosphate, Degraded to inactive, unstable 5-azauridine by cytidine
deaminase
Pharmacokinetics and elimination:
Plasma half-lives not known, but the drug is chemically unstable and is rapidly
deaminated.
Drug interactions: Tetrahydrouridine (is a potent competitive inhibitor of cytidine
deaminase) inhibits deamination, increases toxicity
Toxicity:
Myelosuppression
Nausea, vomiting after bolus dose
Hepatocellular dysfunction
Muscle tenderness, weakness
Lethargy, confusion, coma
3- Purine Antagonists
6−Mercaptopurine, (6−MP):
- It is immunosuppressive cytotoxic drug. It is widely used in transplantations to
control rejection reactions.
- It is acts as a purine analogue and once enter the cell, it is converted to 6-MPribosephophate and can be incorporated into RNA and DNA resulting in non
functioning RNA & DNA & finally inducing cell cycle arrest and apoptosis.
- It also inhibits purine ring biosynthesis
Adverse reactions
Diarrhea, nausea, vomiting, loss of appetite,
Allergic reaction include rash, itching, swelling, dizziness, trouble breathing.
Mercaptopurine cause myelosuppression. Those taking mercaptopurine should get
permission from a doctor in order to receive immunizations and vaccinations.
Azathioprine:
It is one of the main immunosuppressive cytotoxic substance. It is widely used in
transplantations to control rejection reactions. It is nonenzymatically cleaved to 6 MP that acts as a purine analogue and inhibits DNA synthesis