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By:By:

Abdulaziz bin SaeedanAbdulaziz bin SaeedanPPh.D.h.D.Department of PharmacologyDepartment of Pharmacology E mail: E mail: a.binsaeedan@sau.edu.saa.binsaeedan@sau.edu.sa

PPharmacology – IVharmacology – IVPHL-425PHL-425

ChapterChapter 3: 3:

CANCER CHEMOTHERAPY CANCER CHEMOTHERAPY

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Classification Classification

Cell Cycle–Specific (CCS) Agents Cell Cycle–Nonspecific (CCNS) Agents

Antimetabolites (S phase) Alkylating agents Capecitabine Altretamine Cladribine Bendamustine Clofarabine Busulfan Cytarabine (ara-C) Carmustine Fludarabine Chlorambucil 5-Fluorouracil (5-FU) Cyclophosphamide Gemcitabine Dacarbazine 6-Mercaptopurine (6-MP) Lomustine

Methotrexate (MTX) Mechlorethamine 6-Thioguanine (6-TG) Melphalan

Temozolomide Epipodophyllotoxin (topoisomerase II inhibitor) (G1–S phase)

Thiotepa

Etoposide Anthracyclines Taxanes (M phase) Daunorubicin Albumin-bound paclitaxel Doxorubicin Docetaxel Epirubicin Paclitaxel Idarubicin Vinca alkaloids (M phase) Mitoxantrone

Vinblastine Antitumor antibiotics

Vincristine Dactinomycin Vinorelbine Mitomycin Antimicrotubule inhibitor (M phase) Camptothecins (topoisomerase I

inhibitors) Ixabepilone Irinotecan

Topotecan Antitumor antibiotics (G2–M phase) Platinum analogs

Bleomycin Carboplatin Cisplatin

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Alkylating agentsAlkylating agents

Cyclophosphamide Cyclophosphamide CisplatinCisplatin Procarbazine Procarbazine BusulfanBusulfan Mechlorethamine Mechlorethamine

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MOAMOA Alkylating agents

Contain chem grps that Contain chem grps that covalently bind cell covalently bind cell nucleophilesnucleophiles

Impt properties of drugsImpt properties of drugs Can form carbonium ionsCan form carbonium ions Bifunctional (2 reactive grps)Bifunctional (2 reactive grps)

Allow cross-linkingAllow cross-linking DNA becomes cross-linked w/ agentDNA becomes cross-linked w/ agent

Intra- or inter-strandIntra- or inter-strand Decr’d transcr’n, repl’nDecr’d transcr’n, repl’n Chain scission, so strand Chain scission, so strand

breaksbreaks

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Alkylating Agents- Alkylating Agents- Used in wide variety of Used in wide variety of hematologic and solid tumorshematologic and solid tumors

Thiotepa – Thiotepa – ovarian cancerovarian cancer Busulfan Busulfan -Pulmonary fibrosis.-Pulmonary fibrosis. ***Nitrosoureas***Nitrosoureas (Carmustine and lomustine ) - brain (Carmustine and lomustine ) - brain

tumorstumors Highly lipid soluble drugs hence reach high concentration in the Highly lipid soluble drugs hence reach high concentration in the

brain and CSF. brain and CSF. StreptozocinStreptozocin – insulin-secreting islet cell carcinoma of – insulin-secreting islet cell carcinoma of

the pancreasthe pancreas Mechlorethamine Mechlorethamine – Prodrug.– Prodrug. It is a highly irritant drug so It is a highly irritant drug so

care should be taken to avoid extravasation during IV care should be taken to avoid extravasation during IV administrationadministration

Chlorambucil (Leukeran):Chlorambucil (Leukeran): Slow acting and least toxic Slow acting and least toxic nitrogen mustard. nitrogen mustard.

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Cyclophosphamide Cyclophosphamide It is a prodrug and is activated by the P-It is a prodrug and is activated by the P-

450 enzymes to its active form 450 enzymes to its active form phosphoramide mustardphosphoramide mustard

The active drug alkylates nucleophilic The active drug alkylates nucleophilic groups on DNA basesgroups on DNA bases Particularly at the N-7 position of guanineParticularly at the N-7 position of guanine

This leads to cross linking of bases, This leads to cross linking of bases, abnormal base pairing and DNA strand abnormal base pairing and DNA strand breakagebreakage

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Mechanism of resistanceMechanism of resistance

The mechanisms mentioned below are The mechanisms mentioned below are common for all the alkylyting agentscommon for all the alkylyting agents

Increased DNA repairIncreased DNA repair Decreased drug permeabilityDecreased drug permeability Production of “trapping” agents (thiols)Production of “trapping” agents (thiols)

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Uses Uses

Non-Hodgkin’s lymphomaNon-Hodgkin’s lymphoma Breast CancerBreast Cancer Ovarian CancerOvarian Cancer Neuroblastoma Neuroblastoma

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ADRADR Acrolein is the metaboliteAcrolein is the metabolite Responsible for causing hemorrhagic Responsible for causing hemorrhagic

cystitiscystitis Suprapubic painSuprapubic pain HematuriaHematuria Cyctoscopic findings Cyctoscopic findings

This is prevented/treated by This is prevented/treated by MESNA (mercaptoethanesulfonate)MESNA (mercaptoethanesulfonate)

Rarely cyclophosphamide can cause Rarely cyclophosphamide can cause pulmonary toxicitypulmonary toxicity

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Cisplatin Cisplatin Platinum analogPlatinum analog Same MOA as cyclophosphamideSame MOA as cyclophosphamide **Used in testicular carcinoma**Used in testicular carcinoma Also used for Ca of bladder, lung and ovaryAlso used for Ca of bladder, lung and ovary Carboplatin is new drug with better safety profileCarboplatin is new drug with better safety profileADRADR Nephrotoxicity (prevented by Amifostine)Nephrotoxicity (prevented by Amifostine) Ototoxicity (acoustic nerve damage)Ototoxicity (acoustic nerve damage) Peripheral neuritisPeripheral neuritis Severe nausea and vomiting Severe nausea and vomiting

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Procarbazine Procarbazine

MOA: forms hydrogen peroxide, which MOA: forms hydrogen peroxide, which generates free radicals that cause DNA generates free radicals that cause DNA damagedamage

Important component of regimens Important component of regimens especially for Hodgkin’s lymphomaespecially for Hodgkin’s lymphoma

ADRADR Disulfiram like reactionsDisulfiram like reactions

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Antimetabolites

Folic Acid Analogs Purine Analogs Pyrimidine Analogs

Methotrexate Mercaptoguanine Fluorouracil

TrimetrexatePemetrexed

ThioguanineFludarabine PhosphateCladribine

Cytarabine GemcitabineCapecitabine

They are structurally similar to endogenous compoundsThey are structurally similar to endogenous compounds They act as antagonists of:They act as antagonists of:

Folic acid (methotrexate)Folic acid (methotrexate) Purines (Mercaptopurine and thioguanine)Purines (Mercaptopurine and thioguanine) Pyrimidine (fluorouracil, cytarabine)Pyrimidine (fluorouracil, cytarabine)

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Antimetabolits: sites of drug actionAntimetabolits: sites of drug action

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Methotrexate Methotrexate

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Methotrexate (MTX)Methotrexate (MTX) MTX is a folic acid analog that binds with high affinity to the MTX is a folic acid analog that binds with high affinity to the

active catalytic site of dihydrofolate reductase (DHFR)active catalytic site of dihydrofolate reductase (DHFR)

Thus it interferes with the synthesis of tetrahydrofolate (THF)Thus it interferes with the synthesis of tetrahydrofolate (THF)

THF serves as the key one-carbon carrier for enzymatic THF serves as the key one-carbon carrier for enzymatic processes involved in de novo synthesis of thymidylate, processes involved in de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and purine nucleotides, and the amino acids serine and methionine. methionine.

Inhibition of these various metabolic processes thereby Inhibition of these various metabolic processes thereby interferes with the formation of DNA, RNA, and key cellular interferes with the formation of DNA, RNA, and key cellular proteins. proteins.

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Mechanism of Resistance

1. Decreased drug transport

2. Altered DHFR3. Decreased

polyglutamate formation

4. Increased levels of DHFR

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MTXMTX Most commonly used anticancer drug. Most commonly used anticancer drug. Cell cycle specific (CCS) drug and acts during S phase of the cell cycle. Cell cycle specific (CCS) drug and acts during S phase of the cell cycle. Antineoplastic, immunosuppressant and antiinflammatoryAntineoplastic, immunosuppressant and antiinflammatory Used in RA, psoriasisUsed in RA, psoriasis Well absorbed orally; can also be given IM, IV or intrathecally. Well absorbed orally; can also be given IM, IV or intrathecally. It is bound to plasma proteins, It is bound to plasma proteins, does not cross the BBBdoes not cross the BBB and most of the drug and most of the drug

is excreted unchanged in urine.is excreted unchanged in urine. It is a weak acid and so is excreted better at high urine pH. Appropriate It is a weak acid and so is excreted better at high urine pH. Appropriate

hydration and alkalinizing the urine is important to prevent renal tox with MTXhydration and alkalinizing the urine is important to prevent renal tox with MTX

ADR:ADR: Bone marrow suppression (BMS)Bone marrow suppression (BMS) Folic acid deficiency Folic acid deficiency The toxic effects of MTX on normal cells is reduced by The toxic effects of MTX on normal cells is reduced by

administering folinic acid (leucovorin)administering folinic acid (leucovorin) This is called leucovorin rescue **** This is called leucovorin rescue **** Higher the dose of MTX more the leucovorin you give**Higher the dose of MTX more the leucovorin you give**

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Leucovorin RescueLeucovorin Rescue

Mechanism of action of methotrexate Mechanism of action of methotrexate and the effect of administration of and the effect of administration of leucovorin.leucovorin.

FH2 = dihydrofolateFH2 = dihydrofolate FH4 = tetrahydrofolateFH4 = tetrahydrofolate dTMP = deoxythymidine dTMP = deoxythymidine

monophosphatemonophosphate dUMP = deoxyuridine mono dUMP = deoxyuridine mono

phosphate. phosphate.

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6-Mercaptopurine (6-MP) & Thioguanine6-Mercaptopurine (6-MP) & Thioguanine

Both 6-MP and Thioguanine are Both 6-MP and Thioguanine are activated by HGPRT to toxic activated by HGPRT to toxic nucleotides that inhibit several nucleotides that inhibit several enzymes involved in purine enzymes involved in purine metabolismmetabolism

***Resistance is due to cancer cells ***Resistance is due to cancer cells having having d activity of HGPRTd activity of HGPRT

Cancer cells also Cancer cells also es alkaline es alkaline phosphatase that inactivate toxic phosphatase that inactivate toxic nucleotidesnucleotides

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6-MP & Allopurinol6-MP & Allopurinol 6-MP is metabolized in the liver by xanthine oxidase and 6-MP is metabolized in the liver by xanthine oxidase and

the inactive metabolites are excreted in the urinethe inactive metabolites are excreted in the urine Allopurinol is used frequently to treat/prevent Allopurinol is used frequently to treat/prevent

hyperuricemia caused by many anticancer drugs.hyperuricemia caused by many anticancer drugs. If Allopurinol is used with 6-MP then the dose of 6-MP is If Allopurinol is used with 6-MP then the dose of 6-MP is

reduced by more than 75%reduced by more than 75%

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Cytarabine (Ara-C)Cytarabine (Ara-C) Cytarabine arabinoside is a pyrimidine antimetabolite Cytarabine arabinoside is a pyrimidine antimetabolite

The drug is activated by kinases to AraCTPThe drug is activated by kinases to AraCTP This acts as an inhibitor of DNA polymeraseThis acts as an inhibitor of DNA polymerase

Of all antimetabolites, this is the most specific for S phase of Of all antimetabolites, this is the most specific for S phase of tumor cell cycletumor cell cycle

It is an important component in acute lukemia regimensIt is an important component in acute lukemia regimens

ADR: ADR: High doses cause neurotoxicity (cerebellar dysfunction and High doses cause neurotoxicity (cerebellar dysfunction and

peripheral neuritis)peripheral neuritis) Hand-foot syndromeHand-foot syndrome

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5-FU5-FUMechanism of the cytotoxic action of 5-FUMechanism of the cytotoxic action of 5-FU

5-FU is converted to 5-FdUMP, 5-FU is converted to 5-FdUMP, which competes with deoxyuridine which competes with deoxyuridine monophosphate (dUMP) for the monophosphate (dUMP) for the enzyme thymidylate synthetase.enzyme thymidylate synthetase.

5-FU = 5-fluorouracil5-FU = 5-fluorouracil 5-FUR = 5-fluorouridine5-FUR = 5-fluorouridine 5-FUMP = 5-fluorouridine monophosphate5-FUMP = 5-fluorouridine monophosphate 5-FUDP = 5-fluorouridine diphosphate5-FUDP = 5-fluorouridine diphosphate 5-FUTP = 5-fluorouridine triphosphate5-FUTP = 5-fluorouridine triphosphate dUMP = deoxyuridine monophosphatedUMP = deoxyuridine monophosphate dTMP = deoxythymidine monophosphatedTMP = deoxythymidine monophosphate 5-FdUMP = 5-fluorodeoxyuridine 5-FdUMP = 5-fluorodeoxyuridine

monophosphate. monophosphate.

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5-FU causes, “thymidineless death” of cells5-FU causes, “thymidineless death” of cells

Resistance is due to Resistance is due to d activation of 5-FU and increased thymidylate d activation of 5-FU and increased thymidylate synthase activitysynthase activity

Uses Uses Metastatic carcinomas of the Metastatic carcinomas of the breast and the GI tract, hepatomabreast and the GI tract, hepatoma

Carcinomas of the Carcinomas of the ovary, cervix, urinary bladder, prostate, pancreas, ovary, cervix, urinary bladder, prostate, pancreas, and and oropharyngeal areasoropharyngeal areas

Combined with levamisole for Rx of Combined with levamisole for Rx of colon cancercolon cancer

ADR:ADR: nausea, mucositis, diarrhea, nausea, mucositis, diarrhea, hand and foot syndromehand and foot syndrome, Alopecia, , Alopecia,

hyperpigmentation, neurologic deficits, bone marrow depressionhyperpigmentation, neurologic deficits, bone marrow depression

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THANK YOUTHANK YOU