II-

Antimetabolites

II- ANTIMETABOLITESII- ANTIMETABOLITES(Structural Analogues)(Structural Analogues)

Antimetabolites are structurallyAntimetabolites are structurallyrelated to normal cellularrelated to normal cellular

componentscomponents MOA: MOA: block one or more of the block one or more of the metabolic pathways involved in metabolic pathways involved in

DNA synthesisDNA synthesis Most antimetabolites interfere Most antimetabolites interfere

with nucleic acid synthesis with nucleic acid synthesis (nucleotide synthesis)(nucleotide synthesis)

II- ANTIMETABOLITESII- ANTIMETABOLITES

They inhibit the They inhibit the synthesis synthesis purine or purine or

pyrimidine pyrimidine nucleotide or by nucleotide or by

competing with them competing with them in DNA or RNA in DNA or RNA

synthesis synthesis Their maximal Their maximal

cytotoxic effects are cytotoxic effects are S-phase S-phase and are and are

therefore cell-cycle therefore cell-cycle specific drugs specific drugs (CCS)(CCS)

Examples of AntimetabolitesExamples of Antimetabolites

Folic acid Antagonists: Methotrexate (MTX)Purines antagonists: Mercaptopurine (6-MP) Pyrimidines antagonists: Fluorouracil (5-FU)

Folic Acid Folic Acid

Folic acid is needed for Folic acid is needed for the synthesis of the  the synthesis of the  thymidine, required for DNA synthesis, required for DNA synthesis

Also, folate is essential for the Also, folate is essential for the synthesis of synthesis of purine purine

nucleotides nucleotides which in turn are which in turn are essential for DNA synthesis essential for DNA synthesis

and cell division and cell division

Inhibition of dihydrofolate reductase Inhibition of dihydrofolate reductase (DFR)(DFR)

DFR

A. Folic Acid AntagonistsA. Folic Acid AntagonistsMethotrexate (MTX)Methotrexate (MTX)

MTX is structurally related to folic acid MTX is structurally related to folic acid and acts as an antagonist of that and acts as an antagonist of that

vitamin by inhibiting vitamin by inhibiting dihydrofolate dihydrofolate reductasereductase

This enzyme converts folic acid to its This enzyme converts folic acid to its active, coenzyme form (FH4); active, coenzyme form (FH4);

tetrahydrofolic acidtetrahydrofolic acid Methotrexate Methotrexate has a higher affinity than has a higher affinity than

Folate Folate for dihydrofolate reductase and for dihydrofolate reductase and thus inhibits the enzyme = depleting thus inhibits the enzyme = depleting

intracellular FH4intracellular FH4

Lack of this cofactor (FH4) Lack of this cofactor (FH4) interrupts the synthesis of interrupts the synthesis of

thymidine,thymidine, purine nucleotides purine nucleotides Thereby interfering with the Thereby interfering with the

formation of DNA, RNA, and formation of DNA, RNA, and protein leading to cell deathprotein leading to cell death

 MTX MTX is cytotoxic during the S-is cytotoxic during the S-phase of the cell cycle.phase of the cell cycle.

MTX MTX has a greater toxic effect on has a greater toxic effect on rapidly dividing cells rapidly dividing cells

(GIT, oral mucosa, BM) (GIT, oral mucosa, BM)

Therapeutic Uses Therapeutic Uses

Methotrexate, is effective against Methotrexate, is effective against acute leukemia, choriocarcinoma, acute leukemia, choriocarcinoma, non Hodgkin’s lymphoma in non Hodgkin’s lymphoma in children, breast cancer and head & children, breast cancer and head & neck carcinomaneck carcinoma

To induce abortion with misoprostolTo induce abortion with misoprostol It is effective against It is effective against certain certain

inflammatory diseases, inflammatory diseases, such as:such as: Rheumatoid arthritis Rheumatoid arthritis Severe psoriasisSevere psoriasis

Adverse Effects Adverse Effects Depression of the bone marrow Depression of the bone marrow Damage to the epithelium of the GIT; Damage to the epithelium of the GIT;

stomatitis, nausea, vomiting and diarrheastomatitis, nausea, vomiting and diarrhea Erythema, rash, urticaria, alopeciaErythema, rash, urticaria, alopecia High doses of MTX may cause renal High doses of MTX may cause renal

damage damage (crystalluria) (crystalluria) so it is so it is important to keep the important to keep the urine alkaline + urine alkaline + hydrationhydration

Intrathecal administration lead to Intrathecal administration lead to meningeal irritation, stiff neck, headachemeningeal irritation, stiff neck, headache

Hepatic and pulmonary toxicityHepatic and pulmonary toxicity

Leucovorin rescue Leucovorin rescue

Rescue normal cells by Leucovorin =folinic acid

Folinic acid bypasses the blocked enzyme and replenish the folate pool

Large doses of MTX must be followed by 'rescue' with folinic acid (a form of FH4)

Tumor resistance to MTXTumor resistance to MTX

Decreased drug transport into Decreased drug transport into the cellthe cell

Altered dihydrofolate reductase Altered dihydrofolate reductase enzyme -- lower affinity for MTXenzyme -- lower affinity for MTX

Increase in dihydrofolate Increase in dihydrofolate reductase enzyme concentration reductase enzyme concentration in the cell in the cell

II- ANTIMETABOLITESII- ANTIMETABOLITES

They inhibit the They inhibit the synthesis synthesis purine or purine or

pyrimidinepyrimidine nucleotide or by nucleotide or by

competing with them competing with them in DNA or RNA in DNA or RNA

synthesis synthesis Their maximal Their maximal

cytotoxic effects are cytotoxic effects are S-phase S-phase and are and are

therefore cell-cycle therefore cell-cycle specific drugs specific drugs (CCS)(CCS)

B. Purine AntagonistsB. Purine Antagonists

6-Mercaptopurine6-Mercaptopurine impairs the impairs the synthesis of synthesis of purine nucleotidepurine nucleotide

After oral administration, 6-After oral administration, 6-mercaptopurine undergoes first-pass mercaptopurine undergoes first-pass metabolism, inactivated by metabolism, inactivated by xanthine xanthine oxidase oxidase in the liverin the liver

Clinical uses: Clinical uses:    For remission induction For remission induction and maintenance therapy of acute and maintenance therapy of acute lymphatic leukemia.lymphatic leukemia.

MOA of 6-mercaptopurine MOA of 6-mercaptopurine

6-MP is activated inside cell

TIMP E needed for

purine synthesis

Tumor cell death

6-MP by Hypoxanthine Guanine Phospho-Ribosyl Transferase

(HGPRTase) Thiol inosine monophosphate

Toxic nucleotide (TIMP)

Incorporated into DNA“Non functional”

Adverse effects:Adverse effects: Principal toxicity is BM depressionPrincipal toxicity is BM depression N & V, diarrheaN & V, diarrhea HepatotoxicityHepatotoxicity Drug interaction:Drug interaction: AllupurinolAllupurinol; is used to ; is used to inhibit xanthine oxidase, inhibit xanthine oxidase, to to

prevent hyperuricemia associated with tumor cell lysis, prevent hyperuricemia associated with tumor cell lysis, inhibits the breakdown of 6-MP and increases 6-MP inhibits the breakdown of 6-MP and increases 6-MP effects, toxicity so dose of 6-MP must be reduced by at effects, toxicity so dose of 6-MP must be reduced by at least 25%least 25%

C. Pyrimidine antagonistsC. Pyrimidine antagonists

Fluorouracil (5-FU)Fluorouracil (5-FU) It is converted to the corresponding It is converted to the corresponding

deoxynocleotide (5-FdUMP) which deoxynocleotide (5-FdUMP) which inhibits inhibits thymidylate synthetasethymidylate synthetase

Inhibition of thymidylate synthetaseInhibition of thymidylate synthetase leads to suppression of the formation of leads to suppression of the formation of thymidine nucleotidesthymidine nucleotides. This results in . This results in inhibition of DNA synthesis through inhibition of DNA synthesis through ““Thymidine-less death”Thymidine-less death”

MOA of Fluorouracil MOA of Fluorouracil

inhibits Thymidylate synthetase

5FU 5-FdUMP

synthesis of  thymidine nucleotide DNA synthesis

Thymidine-less death

Cytotoxic effects on both RNA and DNA

Therapeutic Uses Therapeutic Uses

Fluorouracil is used primarily in the Fluorouracil is used primarily in the treatment of slowly growing solid treatment of slowly growing solid tumors such as tumors such as colorectal cancer, colorectal cancer, cancer of breast, ovary, pancreas cancer of breast, ovary, pancreas

AA creamcream incorporating fluorouracil is incorporating fluorouracil is used topically for treating skin used topically for treating skin cancerscancers

Toxic Effects:Toxic Effects:

It may lead to nausea, It may lead to nausea, vomiting, anorexia, diarrhea vomiting, anorexia, diarrhea and alopeciaand alopecia

Severe ulceration of the oral Severe ulceration of the oral and gastrointestinal mucosaand gastrointestinal mucosa

Bone marrow depressionBone marrow depression

Microtubule

inhibitors

Microtubules Microtubules InhibitorsInhibitors

Mitototic Mitototic spindle is spindle is formed during formed during cell divisioncell division

Microtubules Microtubules InhibitorsInhibitors

CCS Vinca alkaloids

Vinblastine Vincristine

Podophyllotoxins Etoposide

TaxanesPaclitaxel

Vinblastine and VincristineVinblastine and Vincristine

Belongs to Belongs to Vinca alkaloidsVinca alkaloids

Both drugs are cell cycle-specific Both drugs are cell cycle-specific (CCS) because they block mitosis (CCS) because they block mitosis

in metaphase in metaphase

Therapeutic usesTherapeutic uses Vinblastine Vinblastine is used in testicular is used in testicular

carcinoma, Hodgkin’s disease carcinoma, Hodgkin’s disease VincristineVincristine is used in the treatment of is used in the treatment of

acute leukemia in children, Wilm’s tumor, acute leukemia in children, Wilm’s tumor, and Hodgkin’s and non-Hodgkin’s and Hodgkin’s and non-Hodgkin’s lymphomaslymphomas

Adverse Effects:Adverse Effects: Common adverse effects for both drugs Common adverse effects for both drugs

include include cellulitis or phlebitis cellulitis or phlebitis if the drugs if the drugs extravasate during injectionextravasate during injection

Nausea, vomiting, diarrhea, and alopeciaNausea, vomiting, diarrhea, and alopecia

Toxicity of Vinblastine & Toxicity of Vinblastine & Vincristine Vincristine

VinBlastine Myelo-supression

Vincristine

NOT myelosuppress

ant

Peripheral neuropathy:

Depressed deep tendon reflex, paresthesia, foot drop

TaxanesTaxanes

Paclitaxel (Taxol) Paclitaxel (Taxol) shows shows good activity against good activity against metastatic metastatic breast cancer breast cancer and and advanced advanced ovarian cancerovarian cancer

Side effects; Side effects; neutropenia ‼, neutropenia ‼, peripheral neuropathyperipheral neuropathy

Filgrastim ( granulocyte colony Filgrastim ( granulocyte colony stimulating factor)stimulating factor)

IV. Cytotoxic

Antibiotics

Substances of microbial origin Substances of microbial origin that prevent mammalian cell that prevent mammalian cell

divisiondivision

Some antibiotics that affect Some antibiotics that affect DNADNA in both microbial and in both microbial and

mammalian cells can be used in mammalian cells can be used in cancer chemotherapycancer chemotherapy

Cytotoxic Antibiotics Cytotoxic Antibiotics (Antitumor Antibiotics) (Antitumor Antibiotics)

Dactinomycin (Actinomycin D)Dactinomycin (Actinomycin D) Doxorubicin (Adriamycin) Doxorubicin (Adriamycin) BleomycinBleomycin As a rule, they should not be As a rule, they should not be

given together with given together with radiotherapy, as the cumulative radiotherapy, as the cumulative toxicity is very hightoxicity is very high

Dactinomycin Dactinomycin (Actinomycin D)(Actinomycin D)

Dactinomycin was the first antibiotic used in cancer chemotherapy

It affects cells in all phases of the cell-affects cells in all phases of the cell-cycle i.e. cycle i.e. CCNSCCNS

Dactinomycin is given Dactinomycin is given intravenouslyintravenously, it , it remains unchanged and is concentrated remains unchanged and is concentrated

in the liver and excreted in in the liver and excreted in bile bile It does not cross the BBBIt does not cross the BBB

MMechanism of action of echanism of action of DactinomycinDactinomycin

Minor Groove D

D

It intercalates, in the minor groove of DNA,

between adjacent guanine-cytosine pairs

thus preventing transcription

(through an effect on topoisomerase II

that essentially unwinds the DNA helix for

replication)

Therapeutic Uses Therapeutic Uses

It is mainly used for treating It is mainly used for treating paediatric cancerspaediatric cancers

with other drugs in the treatment with other drugs in the treatment of of Wilm’s tumorWilm’s tumor, gestational , gestational choriocarcinomachoriocarcinoma

Adverse Effects:Adverse Effects: Extravasation Extravasation during injection during injection

produces severe irritation and produces severe irritation and cellulitis cellulitis

Adverse Effects (cont.)Adverse Effects (cont.)

Bone marrow depression Bone marrow depression is the is the major dose-limiting toxicitymajor dose-limiting toxicity

((leucopenialeucopenia and and thrombocytopenia)thrombocytopenia)

Nausea, vomiting, diarrhea, oral Nausea, vomiting, diarrhea, oral ulcers alopecia and skin ulcers alopecia and skin eruptions may also be notederuptions may also be noted

Dactinomycin Dactinomycin sensitizes to sensitizes to radiation; inflammation at sites radiation; inflammation at sites of prior radiation of prior radiation therapy may therapy may occuroccur

Doxorubicin Doxorubicin (Adriamycin)(Adriamycin)

Doxorubicin (Adriamycin) is the Doxorubicin (Adriamycin) is the most commonly used member of most commonly used member of the the anthracycline antibiotics, anthracycline antibiotics, given IVgiven IV

Mechanism of Cytotoxic Action:Mechanism of Cytotoxic Action: Doxorubicin exerts its cytotoxic Doxorubicin exerts its cytotoxic

actions through actions through 33 mechanisms:mechanisms:

1. intercalates in the DNA, to stabilize 1. intercalates in the DNA, to stabilize the DNA-topoisomerase II complex the DNA-topoisomerase II complex thus halting replicationthus halting replication

binding to cell membranesbinding to cell membranes to to alter fluidity and ion transportalter fluidity and ion transport

generation of oxygen free generation of oxygen free radicalsradicals (hydrogen peroxide) (hydrogen peroxide) through interaction with through interaction with molecular oxygen molecular oxygen

This action may be responsible This action may be responsible for for cardiac toxicity cardiac toxicity

(dysrhythmias and heart failure)(dysrhythmias and heart failure) The heart is devoid of superoxide The heart is devoid of superoxide

dismutase dismutase (SOD) (SOD) which protects which protects tissues against oxygen free tissues against oxygen free

radicalsradicals

Clinical indications of Clinical indications of DoxorubicinDoxorubicin

One of the most important and widely used anti- cancer

drug, used in combination with other agents in

treatment of sarcomas and cancer of breast, lung , ovary

and thyroid gland It is useful also in acute lymphoblastic leukemia, and

lymphomas

Adverse Effects:Adverse Effects: Extravasation causes tissue necrosisExtravasation causes tissue necrosis The drug may lead to severeThe drug may lead to severe

alopeciaalopecia at standard dosage *** at standard dosage *** Stomatitis and GIT disturbancesStomatitis and GIT disturbances Increased skin pigmentationIncreased skin pigmentation Doxorubicin causes Doxorubicin causes bone marrowbone marrow

depressiondepression which is of short which is of short duration, with rapid recovery duration, with rapid recovery

The drug has dark The drug has dark red color red color and and leads to red color of the urine leads to red color of the urine

Adverse Effects (cont.)Adverse Effects (cont.)

Doxorubicin cause cumulative, dose- Doxorubicin cause cumulative, dose- dependent dependent cardiac toxicitycardiac toxicity, leading , leading to dysrhythmias cardiomyopathy and to dysrhythmias cardiomyopathy and

heart failureheart failure due to generation of due to generation of free radicals and lipid peroxidationfree radicals and lipid peroxidation

Dexrazoxane Dexrazoxane , an iron chelator , , an iron chelator , decrease the formation of superoxide decrease the formation of superoxide

radicals is used to protect against radicals is used to protect against the cardiotoxicity of the drug the cardiotoxicity of the drug

Bleomycin: aBleomycin: a metal-chelating metal-chelating antibioticantibiotic

B

B

DNA- bleomycin-Fe2+ complexintercalate between

base pair

Fe

Fe Generate free radicals(superoxide, hydroxyl radicals)

DNA strands fragmentation

DNA- bleomycin-Fe3+

The liberated electrons react with oxygen

Clinical uses of Clinical uses of BleomycinBleomycin

Bleomycin is most effective in the G2 phase of the cell cycle and

mitosis, but it is also active against non-dividing cells (i.e. cells in the

G0 phase)

CCNSIt is used to treat germline cancer

Testicular carcinomaHodgkin’s lymphoma

Adverse effects of Adverse effects of BleomycinBleomycin

Skin toxicity: Alopecia , blisters and hyperkeratosis

Hypersensitivity reactions; fever, chills,…

It is not a myelosuppressant

Hydrolase ( bleomycin

inactivating enzyme) is deficient

in the lung and skin

V.

Miscellaneous

Anticancer

Agents

V- Miscellaneous Agents V- Miscellaneous Agents

L-AsparaginaseL-Asparaginase HydroxyureaHydroxyurea MitotaneMitotane Retenoic acid derivativesRetenoic acid derivatives InterferonInterferon

L- AsparaginaseL- Asparaginase

Asparagine is amino acid required for Asparagine is amino acid required for protein synthesis protein synthesis

Most normal cells can synthesize Most normal cells can synthesize asparagineasparagine

Neoplastic cells require an external Neoplastic cells require an external source of asparagine source of asparagine (from the plasma) (from the plasma) because of their limited capacity to make because of their limited capacity to make sufficient asparagine to support growthsufficient asparagine to support growth

L-Asparaginase L-Asparaginase

L-asparaginaseL-asparaginase

Asparagine Asparagine aspartic acid aspartic acid

+Ammonia+Ammonia L-Asparginase iL-Asparginase is derived from bacterias derived from bacteria

L-asparaginase hydrolyzes serum asparagine L-asparaginase hydrolyzes serum asparagine and thus deprives the tumor cells of this and thus deprives the tumor cells of this nutrient required for protein synthesisnutrient required for protein synthesis

Most normal cells can synthesize asparagine Most normal cells can synthesize asparagine and thus are less susceptible to the action of and thus are less susceptible to the action of

asparaginaseasparaginase

Theraputic uses:Theraputic uses: L-asparginase is used to treat L-asparginase is used to treat childhood childhood acute lymphocytic acute lymphocytic leukemialeukemia in combination with in combination with

vincristine and prednisonevincristine and prednisone AAdverse effects: dverse effects:

Hypersensitivity reactions, Hypersensitivity reactions, liver affection and pancreatitisliver affection and pancreatitis

HydroxyureaHydroxyurea

Hydroxyurea Hydroxyurea is an analog of urea. is an analog of urea. MOA:MOA: blocks the incorporation of the blocks the incorporation of the

thymidine nucleotide into the DNA thymidine nucleotide into the DNA strand. strand.

used in chronic myeloid leukemia used in chronic myeloid leukemia administered orally.administered orally.

Miscellaneous AgentsMiscellaneous Agents

MitotaneMitotane      Reduces excessive steroid Reduces excessive steroid

secretionsecretion used for Adrenal carcinomaused for Adrenal carcinoma

Retenoic acid derivativesRetenoic acid derivatives

Remissions -- acute leukemiaRemissions -- acute leukemia

Drug

combinations

The administration of combinations of The administration of combinations of drugs in the treatment of cancer drugs in the treatment of cancer

produces produces better results than a single better results than a single drug drug

A combination of drugs with A combination of drugs with different different toxic effectstoxic effects and and affecting affecting

different biochemical pathwaysdifferent biochemical pathways has higher anti-tumor activity without has higher anti-tumor activity without

additive toxicityadditive toxicity Therapy is Therapy is given intermittentlygiven intermittently to to allow recovery of normal tissue i.e. bone allow recovery of normal tissue i.e. bone

marrow and immune system that has marrow and immune system that has been affected by the drugsbeen affected by the drugs

Examples of drug Examples of drug combinations combinations

Acute lymphocytic leukemia:Acute lymphocytic leukemia: vincristine, methotrexate and 6-vincristine, methotrexate and 6-mercaptopurinemercaptopurine

Advanced breast cancer :Advanced breast cancer : Doxorubicin, cyclophosphamide Doxorubicin, cyclophosphamide with or without flurouracilwith or without flurouracil

Non-Hodgkin's lymphomas:Non-Hodgkin's lymphomas: Cyclophosphamide, doxorubicin, Cyclophosphamide, doxorubicin, vincristine vincristine