Download - Antimetabolitesused in anticancer therapy , submitted by sayamdeep roy ;4 th year ;7th sem
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CONTENT
INTRODUCTION
CANCER – A KILLER
DIFFERENT DRUGS USED FOR THE AILMENT OF
CANCER
ANTIMETABOLITES - A BRIEF DISCURSION
DIFFERENT ANTIMETABOLITE DRUGS –THEIR
MECHANISM OF ACTION & ADVERSE EFFECT
CONCLUSION
REFERENCE
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Cancer also known as a malignant tumor or
malignant neoplasm, is a group of diseases involving
abnormal cell growth with the potential to invade or
spread to other parts of the body. Not all tumors are
cancerous; benign tumors do not spread to other parts
of the body . Possible signs and symptoms include : a
new lump, abnormal bleeding, a prolonged cough,
unexplained weight loss, and a change in bowl
movements, among others. While these symptoms may
indicate cancer they may also occur due to other
issues.
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ALKYLATING AGENTNitrogen mustard - Meclorethamine ,
chlorambucil etc.
Nitrosourea – carmustine , lomustine etc.
Aziridine – thiotepa , benzotepa etc.
Aryl sulphonates – busulphan
Miscellaneous – dacarbazinen etc.
ANTIMETABOLITEFolic acid antagonist – methotrexate ,
trimetrexate etc.
Purine antagonist – 6-mercapto purine ,
6-thioguanine etc.
Pyrimidine antagonist -5-fluoro uracil, cytarabine etc.
ANTIBIOTICAnthracyclines –daunorubicin ,
doxorubicin etc.
Miscellaneous –actinomycin D ,
mitomycin C etc.
PLANT PRODUCT vincristine , vinblastine , paclitaxel , docetaxel , colchicine , etoposide etc.
HORMONES & THEIR
ANTAGONISTS megestrol , tamoxifen , testolactone etc.
MISCELLANEOUS procarbazine , cisplatin etc.
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Antimetabolites are structurally related to normal compounds that exist within the cell.
Antimetabolites generally interfere with the availability of normal purine pyrimidine nucleotide precursors, either by inhibiting their synthesis or by competing with them in DNA or RNA synthesis.
Their maximal cytotoxic effects are in S phase ( and are therefore, cell-cycle specific).
These are analogues related to normal components of DNA or of coenzymes involved in nucleic acid synthesis. They competitively inhibit utilization of the normal substrate or get themselves incorporated forming dysfunctional macromolecules.
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GENERAL MECHANISM OF ACTION OF
ANTIMETABOLITE
Purine & Pyrimidine synthesis
Ribonucleotides
Deoxyribonucleotides
DNA
RNA
PROTEINS
6-Mercaptopurine ,
Thioguanine
Inhibit de novo purine
synthesisMETHOTREXATEinhibition of dihydrofolate
reductase leads to an
inhibition of purine ring &
dTMP biosynthesis
5-Fluorouracil
Inhibit dTMP synthesis
dTMP=DEOXYTHYMIDINE
MONOPHOSPHATE
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ANTIMETABOLITE DRUGS
Folic acid antagonist –
methotrexate , trimetrexate etc.
Purine antagonist –
6-mercapto purine , 6-thioguanine etc.
Pyrimidine antagonist –
5-fluoro uracil, cytarabine etc.
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FOLIC ACID
ANTAGONISTS
(METHOTREXATE)
We can describe the MOA of folic acid antagonist by taking METHOTREXATE as prototype. Mechanism of action of methotrexate and the effect of administration of leucovorin. FH2 = dihydrofolate; FH4 = tetrahydrofolate; dTMP = deoxythymidine monophosphate;dUMP = deoxyuridine monophosphate.
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Renal damage: Although uncommon during conventional therapy, renal
damage is a complication of high-dose MTX and its 7-OH metabolite, which can precipitate in the tubules.
Hepatic function: Hepatic function should be monitored. Long-term use of
MTX may lead to cirrhosis.
Pulmonary toxicity: This is a rare complication. Children who are being
maintained on MTX may develop cough, dyspnea.
Neurologic toxicities: These are associated with intrathecal
administration of MTX and include subacute meningeal irritation, stiff neck, headache.
Contraindications: Because MTX is an abortifacient, it should be avoided
in pregnancy.
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ANTAGONIST (6-
MERCAPTO
PURINE)
The MOA of purine antagonist can be
described by taking 6-MP as
prototype. Actions of 6-
mercaptopurine. GMP = guanosine
monophosphate; AMP = adenosine
monophosphate; XMP =xanthosine
monophosphat.
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ADVERSE EFFECT OF
6-MERCAPTO PURINE (6-MP)Bone marrow depression is the principal toxicity. Side
effects also include anorexia, nausea, vomiting, and diarrhea. Occurrence of hepatotoxicity in the form of jaundice has been reported in about one third of adult patients.
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PYRIMIDINE ANTAGONIST
(5-FLUOROURACIL) (5-FU)
Mechanism of the cytotoxic action of 5-FU. 5-FU is converted to 5-flurodeoxyuridine monophosphate (5-FdUMP), which competes with deoxyuridine monophosphate (dUMP) for the enzyme thymidylate synthetase. 5-FU = 5-Fluorouracil; 5-FUR = 5-fluorouridine; 5-FUMP = 5-fluorouridine monophosphate; 5-FUDP = 5-fluorouridine diphosphate; 5-FUTP = 5-fluorouridine triphosphate; dUMP = deoxyuridine monophosphate; dTMP = deoxythymidine monophosphate.
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ADVERSE EFFECT OF
5-FLUOROURACIL (5-
FU)In addition to nausea, vomiting, diarrhea, and
alopecia, severe ulceration of the oral and GI mucosa, bone marrow depression (with bolus injection), and anorexia are frequently encountered.
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CONCLUSION
Cancer is a disease of vital interest, some time may
be life threatening . Drugs of Antimetabolites class
has been found to have a great utility in treatment of
cancer. As they target purin, pyrimidine, DNA,
RNA synthesis they may have a bigger & greater
role as antineoplastic agent.
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ESSENTIALS OF MEDICAL PHARMACOLOGY
KD TRIPATHI
6th edition , 819-824
LIPPINCOTT’S ILLUSTRATED REVIEWS PHARMACOLOGY
RICHARD FINKEL, LUIGI X. CUBEDDU, MICHELLE A. CLARK
6th edition , 458-470
REFERENCE
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