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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 4: 4:

CANCER CHEMOTHERAPY CANCER CHEMOTHERAPY

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Plant Alkaloids

Vinca Alkaloids Podophyllotoxins Camptothecins Taxanes

Vinblastine Etoposide Topotecan Paclitaxel

VinblastineVincristineVinorelbine

Teniposide Irinotecan Docetaxel

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Vinca alkaloids (Vinblastine, Vinca alkaloids (Vinblastine, vincristine)vincristine)

These drugs block the These drugs block the formation of mitotic formation of mitotic spindle by spindle by preventing preventing the assemblythe assembly of tubulin of tubulin dimers into microtubulesdimers into microtubules

They act primarily on the They act primarily on the M phase of cancer cell M phase of cancer cell cyclecycle

Resistance is due to Resistance is due to d d efflux of drugs from tumor efflux of drugs from tumor cellscells

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VVininBBlastine lastine VVininCCristine (oncovan)ristine (oncovan)

Uses ; Uses ; (ABVD)(ABVD)

Hodgkin’s disease Hodgkin’s disease LymphomasLymphomas

Carcinoma Carcinoma BBreastreast

Testicular tumorsTesticular tumors

Toxicity:Toxicity:

BBone marrow one marrow

suppression, anorexia, suppression, anorexia,

nausea, vomiting & nausea, vomiting &

Diarrhea, AlopeciaDiarrhea, Alopecia

UsesUses: (MOPP): (MOPP)

CChildhood leukemiashildhood leukemias

CChildhood tumors-Wilm’s hildhood tumors-Wilm’s tumor, Neuroblastoma, tumor, Neuroblastoma, Hodgkin’s diseaseHodgkin’s disease

Toxicity:Toxicity:

Peripheral neuritis with Peripheral neuritis with

Paresthesia, Muscle Paresthesia, Muscle weaknessweakness

Vincristine has marrow Vincristine has marrow sparing effect sparing effect

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Etoposide & TeniposideEtoposide & Teniposide

Acts by inhibiting topoisomerase IIActs by inhibiting topoisomerase II These drugs are most active in late S and early These drugs are most active in late S and early

G2 phaseG2 phase Used in combination Tx of small cell carcinoma Used in combination Tx of small cell carcinoma

of lung, prostrate and testicular carcinomasof lung, prostrate and testicular carcinomas

Other topoisomerase inhibitors:Other topoisomerase inhibitors: Topotecan, IrinotecanTopotecan, Irinotecan

Both act by inhibiting topoisomerase-IBoth act by inhibiting topoisomerase-I

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Topoisomerase inhibitors Topoisomerase inhibitors

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Paclitaxel & DocetaxelPaclitaxel & Docetaxel

These drugs act by interfering with These drugs act by interfering with mitotic spindlemitotic spindle

They They prevent microtubule prevent microtubule disassembly disassembly into tubulin monomersinto tubulin monomers

ADRADR NeutropeniaNeutropenia Peripheral neuropathyPeripheral neuropathy

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Anticancer Antibiotics Anticancer Antibiotics

Anthracyclines:Anthracyclines: Doxorubicin (Adriamycin)Doxorubicin (Adriamycin) DaunorubicinDaunorubicin

BleomysinBleomysin DactinomycinDactinomycin Mitomycin Mitomycin

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Doxorubicin & Daunorubicin Doxorubicin & Daunorubicin These drugs intercalate These drugs intercalate

between base pairs, inhibit between base pairs, inhibit topoisomerase II and also topoisomerase II and also generate free radicalsgenerate free radicals

They block RNA and DNA They block RNA and DNA synthesis and cause strand synthesis and cause strand scissionscission

These are CCNS drugsThese are CCNS drugs Used as a component in Used as a component in

ABVD regimen in Hodgkin’s ABVD regimen in Hodgkin’s lymphomalymphoma

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ADRADR

Cardiac toxicity Cardiac toxicity (due to generation of free (due to generation of free radicals)radicals)

Acute form: arrthythmias, ECG changes, Acute form: arrthythmias, ECG changes, pericarditis, myocarditispericarditis, myocarditis

Chronic form: Chronic form: Dilated cardiomyopathyDilated cardiomyopathy, heart , heart failurefailure

RxRx with with dexrazoxane dexrazoxane This is an inhibitor of iron mediated free radical This is an inhibitor of iron mediated free radical

generation generation Bone marrow depression, Total alopeciaBone marrow depression, Total alopecia

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Bleomycin Bleomycin Acts through Acts through binding to DNAbinding to DNA, which , which

results in single and double strand results in single and double strand breaks following breaks following free radical formation free radical formation and inhibition of DNA synthesisand inhibition of DNA synthesis

The DNA fragmentation is due to The DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II) oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal complex and leads to chromosomal aberrationsaberrations

CCS drug that causes accumulation of CCS drug that causes accumulation of cells in Gcells in G22

UsesUses ABVD regimen for Hodgkin’sABVD regimen for Hodgkin’s Intracavitary therapy in ovarian and Intracavitary therapy in ovarian and

breast cancersbreast cancersADRADR Pulmonary fibrosisPulmonary fibrosis

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Hormonal agentsHormonal agents

GlucocorticoidsGlucocorticoids Sex hormone antagonistsSex hormone antagonists GnRH analogsGnRH analogs Aromatase inhibitorsAromatase inhibitors

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Glucocorticoids (Prednisone)Glucocorticoids (Prednisone) Because of their marked lympholytic action, they Because of their marked lympholytic action, they

are used in acute leukemias and lymphomas.are used in acute leukemias and lymphomas. Have anti-inflammatory effectHave anti-inflammatory effect Increase appetiteIncrease appetite Produce euphoria (feeling of well being)Produce euphoria (feeling of well being) Increase body weightIncrease body weight Suppress hypersensitivity reaction due to certain Suppress hypersensitivity reaction due to certain

anticancer drugsanticancer drugs Control hypercalcemiaControl hypercalcemia Control bleedingControl bleeding Have non-specific antipyretic effectHave non-specific antipyretic effect Increase the antiemetic effect of Increase the antiemetic effect of

ondansetron/granisetron/ metoclopramideondansetron/granisetron/ metoclopramide

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Sex hormone antagonistsSex hormone antagonists

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Tamoxifen Tamoxifen Blocks the binding of estrogen to receptors of Blocks the binding of estrogen to receptors of

estrogen sensitive cancer cellsestrogen sensitive cancer cells It is used in receptor positive breast carcinomaIt is used in receptor positive breast carcinoma Also useful in progestin resistant endometrial Also useful in progestin resistant endometrial

carcinomacarcinomaADR:ADR: Hot flushes, vaginal bleeding and venous Hot flushes, vaginal bleeding and venous

thrombosisthrombosisOther drugsOther drugs Flutamide: androgen receptor antagonist used in Flutamide: androgen receptor antagonist used in

prostatic carconima prostatic carconima ADR for flutamide includes: gynecomastia, hot ADR for flutamide includes: gynecomastia, hot

flushesflushes

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MOA of drugs MOA of drugs

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GnRH (Gonadotropin-releasing hormone) GnRH (Gonadotropin-releasing hormone) Analogs Analogs

Leuprolide, Gosarelin and NaferelinLeuprolide, Gosarelin and Naferelin Effective in management of Prostatic carcinomasEffective in management of Prostatic carcinomas When given in When given in constant dosesconstant doses they inhibit release of they inhibit release of

pituitary LH and FSHpituitary LH and FSH These drugs suppress gonadal function due to down These drugs suppress gonadal function due to down

regulation and desensitization of Gn-RH receptorsregulation and desensitization of Gn-RH receptorsADRADR Leuprolide may cause gynecomastia, hematuria, impotence Leuprolide may cause gynecomastia, hematuria, impotence

and testicular atrophyand testicular atrophy

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Aromatase inhibitors Aromatase inhibitors

The aromatase reaction is responsible for the The aromatase reaction is responsible for the extra-adrenal synthesis of estrogen from extra-adrenal synthesis of estrogen from androstenedioneandrostenedione

This takes place in liver, fat, muscle, skin, and This takes place in liver, fat, muscle, skin, and breast tissue, including breast malignancies. breast tissue, including breast malignancies.

Peripheral aromatization is an important source Peripheral aromatization is an important source of estrogen in postmenopausal women. of estrogen in postmenopausal women.

Aromatase inhibitors decrease the production of Aromatase inhibitors decrease the production of estrogen in these women. estrogen in these women.

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Contd..Contd..

2020

Contd..Contd..

Anastrozole and LetrozoleAnastrozole and Letrozole These drugs inhibit the aromatase enzyme These drugs inhibit the aromatase enzyme Used in Tx of postmenopausal women Used in Tx of postmenopausal women

with metastatic breast ca (1with metastatic breast ca (1stst line drug) line drug) ADR includes: bone pain and peripheral ADR includes: bone pain and peripheral

edemaedema

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Miscellaneous agentsMiscellaneous agents

AsparaginaseAsparaginase

ImatinibImatinib

InterferonsInterferons

Monoclonal antibodiesMonoclonal antibodies

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Asparaginase Asparaginase L-Asparaginase catalyzes the deamination of L-Asparaginase catalyzes the deamination of

asparagine to aspartic acid and ammonia. asparagine to aspartic acid and ammonia. L-Asparaginase is used in combination therapy L-Asparaginase is used in combination therapy

to treat childhood acute lymphocytic leukemia to treat childhood acute lymphocytic leukemia Its mechanism of action is based on the fact that Its mechanism of action is based on the fact that

some neoplastic cells require an external source some neoplastic cells require an external source of asparagine because of their limited capacity of asparagine because of their limited capacity to synthesize sufficient amounts of that amino to synthesize sufficient amounts of that amino acid to support growth and function. acid to support growth and function.

L-Asparaginase hydrolyzes blood asparagine L-Asparaginase hydrolyzes blood asparagine and, thus, deprives the tumor cells of this amino and, thus, deprives the tumor cells of this amino acid, which is needed for protein synthesisacid, which is needed for protein synthesis

ADR ADR Acute pancreatitisAcute pancreatitis

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Contd.. Contd..

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Imatinib Imatinib

Example of a drug, whose development Example of a drug, whose development was guided by knowledge of a specific was guided by knowledge of a specific oncogeneoncogene

Used for the treatment of chronic myeloid Used for the treatment of chronic myeloid leukemia leukemia

Acts by inhibiting tyrosine kinase activity of Acts by inhibiting tyrosine kinase activity of the protein product of the Bcr-Abl the protein product of the Bcr-Abl oncogeneoncogene

This gene is expressed in CMLThis gene is expressed in CML

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MOA of Imatinib MOA of Imatinib

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Monoclonal AntibodiesMonoclonal Antibodies

They are created from B lymphocytes (from immunized They are created from B lymphocytes (from immunized mice or hamsters) fused with “immortal” B-lymphocyte mice or hamsters) fused with “immortal” B-lymphocyte tumor cells. tumor cells.

The resulting hybrid cells can be individually cloned, and The resulting hybrid cells can be individually cloned, and each clone will produce antibodies directed against a each clone will produce antibodies directed against a single antigen type. single antigen type.

Recombinant technology has led to the creation of Recombinant technology has led to the creation of “humanized” antibodies that overcome the immunologic “humanized” antibodies that overcome the immunologic problems previously observed following administration of problems previously observed following administration of mouse (murine) antibodies. mouse (murine) antibodies.

Currently, several monoclonal antibodies are available in Currently, several monoclonal antibodies are available in the United States for the treatment of cancer. the United States for the treatment of cancer.

Trastuzumab, Rituximab, Bevacizumab, and CetuximabTrastuzumab, Rituximab, Bevacizumab, and Cetuximab

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Trastuzumab Trastuzumab

In patients with metastatic breast cancer, In patients with metastatic breast cancer, overexpression of transmembrane human overexpression of transmembrane human epidermal growth factor–receptor protein 2 epidermal growth factor–receptor protein 2 (HER2) is seen in 25 to 30 % of patients. (HER2) is seen in 25 to 30 % of patients.

Trastuzumab is a recombinant DNA–produced, Trastuzumab is a recombinant DNA–produced, humanized monoclonal antibody, specifically humanized monoclonal antibody, specifically targets the extracellular domain of the HER2 targets the extracellular domain of the HER2 growth receptor that has intrinsic tyrosine kinase growth receptor that has intrinsic tyrosine kinase activity. activity.

Trastuzumab binds to HER2 sites in breast Trastuzumab binds to HER2 sites in breast cancer tissue and inhibits the proliferation of cancer tissue and inhibits the proliferation of cells that overexpress the HER2 protein, thereby cells that overexpress the HER2 protein, thereby decreasing the number of cells in the S phase. decreasing the number of cells in the S phase.

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FDA approved MAb FDA approved MAb

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InterferonsInterferons Human interferons have been classified into three types—α, β, and Human interferons have been classified into three types—α, β, and

—on the basis of —on the basis of the type of cell that produces the interferon and the the type of cell that produces the interferon and the functional characteristics of the proteinfunctional characteristics of the protein. .

The α interferons are primarily leukocytic, whereas the β and The α interferons are primarily leukocytic, whereas the β and interferons are produced by connective tissue fibroblasts and T interferons are produced by connective tissue fibroblasts and T lymphocytes, respectively.lymphocytes, respectively.

Recombinant DNA techniques in bacteria have made it possible to Recombinant DNA techniques in bacteria have made it possible to

produce two species designated interferon-α-2a and -2b used in Tx produce two species designated interferon-α-2a and -2b used in Tx of neoplastic diseases. of neoplastic diseases.

Interferon-α-2a is presently approved for the management of hairy-Interferon-α-2a is presently approved for the management of hairy-cell leukemia, chronic myeloid leukemia, and acquired cell leukemia, chronic myeloid leukemia, and acquired immunodeficiency syndrome (AIDS)–related Kaposi sarcoma. immunodeficiency syndrome (AIDS)–related Kaposi sarcoma.

Interferon-α-2b is approved for the treatment of hairy-cell leukemia, Interferon-α-2b is approved for the treatment of hairy-cell leukemia, melanoma, AIDS-related Kaposi's sarcoma, and follicular lymphoma. melanoma, AIDS-related Kaposi's sarcoma, and follicular lymphoma.

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Treatment of Specific cancersTreatment of Specific cancersHodgkin’s disease:Hodgkin’s disease: ABVD regimen ABVD regimen

(doxorubicin,bleomycin,vinblastine,dacarbazine)(doxorubicin,bleomycin,vinblastine,dacarbazine) MOPP regimen MOPP regimen

(mechorethamine,vincristine,procarbazine,prednisone)(mechorethamine,vincristine,procarbazine,prednisone) Non-Hodgkin's lymphoma:Non-Hodgkin's lymphoma: CHOP regimen CHOP regimen

(cyclophosphamide,doxorubicin,vincristine,prednisone)(cyclophosphamide,doxorubicin,vincristine,prednisone) Multiple myeloma :Multiple myeloma : MP protocol (melphalan and MP protocol (melphalan and

prednisone)prednisone)Breast ca: Breast ca: CMF protocol (cyclophosphamide-MTX-fluorouracil)CMF protocol (cyclophosphamide-MTX-fluorouracil) TamoxifenTamoxifen Anastrozole, letrozoleAnastrozole, letrozole

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Prevention/management of Cancer Prevention/management of Cancer Chemotherapy induced ADRChemotherapy induced ADR

Nausea and vomiting : 5-Ht3 antagonist Nausea and vomiting : 5-Ht3 antagonist (ondansetron)(ondansetron)

Bone marrow suppression : Filgrastim, Bone marrow suppression : Filgrastim, Sargramastim.Sargramastim.

MTX toxicity : LeucovorinMTX toxicity : Leucovorin Cyclophosphamide toxicity : MESNACyclophosphamide toxicity : MESNA Cisplatin toxicity : AmifostineCisplatin toxicity : Amifostine Anthracycline toxicity ; Dexaroxazone Anthracycline toxicity ; Dexaroxazone

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THANK YOUTHANK YOU