antimetabolitesused in anticancer therapy , submitted by sayamdeep roy ;4 th year ;7th sem

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

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.

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.

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.

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

ANTIMETABOLITE DRUGS

Folic acid antagonist –

methotrexate , trimetrexate etc.

Purine antagonist –

6-mercapto purine , 6-thioguanine etc.

Pyrimidine antagonist –

5-fluoro uracil, cytarabine etc.

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.

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.

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.

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.

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.

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.

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.

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