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Cancer
Normal cells Differentiate, grow, mature, divide

ANTICANCER DRUGS
Durdana Waseem Lecturer RIPS

Regulated, balanced; cell birth=cell death Neoplasia: abnormal growth/invasion of cells

New growth forming Neoplasms (tumors) Irreversible Cells replicate, grow w/out control
Two major types: benign, malignant

Cell Cycle = Growth, Division

Cell Cycle Phases

Oncogenesis
Process of Tumor

18_02_four_phases.jpg
Premitotic synthesis of structures, molecules

Development

Inactivation of

tumor suppressor gene (p-53) Activation of protooncogenes to oncogenes

Synthesis of DNA precursors, proteins, etc.

Classification
(A) . Cytotoxic Drugs
1- Alkylating Agents

(d). Nitrosoureas:
Semustine Streptozocin

Lomustine

Carmustine

Chlorozotocin

(e). Triazenes & Other Related Drugs:

(a). Nitrogen Mustards {Bis(chloroethyl) Amines}: Cyclophosphamide Melphalan Ifosfamide Chlorambucil Estramustine Procarbazine Thiotepa Dacarbazine

Temozolomide

(f) Methylhydrazine derivative

Mustine Hcl b). Aziridines:

Triethylenemelamine (TEM)

(c). Alkyl Sulfonates: Busulfan

(g) Ethyleneimines
Tresulfan

Altretamine

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2- Antimetabolites
(a). Folate Analogs: Methotrexate (b). Pyrimidine Analogs: 5-Fluorouracil Cytarabine Gemcitabine (c). Purine Analogs: 6-Mercaptopurine Azathioprine 6-Thioguanine Fludarabine PO4 Floxuridine Azaribine Capecitabine Pemetrexed

3- Natural Products: ( Plant Derivatives) (a). Vinca Alkaloids: Vincristine (b). Epipodophyllotoxins: Etoposide (c). Taxanes: Paclitaxel (d).Camptothecins: Toptecan Irinotecan Docetaxel Teniposide Vinblastine Vinorelbine (semi-synth)

4 - Cytotoxic (Anti-tumor) Antibiotics: (a). Anthracyclines: Daunorubicin Epirubicin Doxorubicin Mitozantrone Idarubicin

(d). Purine synthesis inhibitors(Inhibit adenosine de-aminase): Pentostatin

(b). Other Anti-tumor Antibiotics: Bleomycin Dactinomycin Mitomycin Plicamycin

5- PlatinumCoordination Complexes: Cisplatin Carboplatin Oxaliplatin

(B) - Enzymes: L Asparaginase (C) - Hormones: (a). Glucocorticoids: Prednisolone (b). Estrogens: Ethinyl estradiol Hydrocortisone Diethylstilboestrol Toremifene Megesterol

(c). Anti-estrogens: Tamoxifen

6- Radioactive Isotopes: Radioactive iodine (l) Radiophosphorus (P) Radiogold

(d). Progestins:

Medroxyprogesterone Hydroxyprogesterone

(e). Androgens:

Dromostenolone

Fluoxymesterolone Bicalutamide Nilutamide

(f). Antiandrognes: Flutamide

(g). Gonadotropin Releasing Hormone Agonists: Goserelin acetate (h) Aromatase Inhibitors Aminoglutethimide Leuprolide Anastrozole Exemestane

(D) - Retinoic Acid Derivatives:

Tretinoin( All Trans. Retinoic Acid) Isotretinoin

(H) - Conjugated Monoclonal Antibodies

( 13-cis Retinoic Acid)

Trastuzumab Rituximab Cetuximab

Alemtuzumab Tositumomab

(E) - Misc. Anticancer Drugs:

Arsenic Trioxide Imatinib, Mitotane Gefitinib (Inhibitor of T.K. domain of EGF receptor)

(I) - Gene Therapy Interleukin-2

(F)- Biological Response Modifiers:

Interferons

(G)- Bone Marrow Factors:

(J) - Newer Agents

Suramin (Inhibitor of G.F. like fibroblast G.F. & others)

Filgrastim

( Grannulocyte colony stimulating factor(G-CSF)

Pegfilgrastim Sargrastim ( Granolycyte macrophoge colony stimmulatingfactor)

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(B) . Cell Cycle Nonspecific Drugs:

Cell cycle - Classification

(A) . Cell Cycle Specific 1. Anti-Metabolites (Structural Analogs)
a)

1. a) b) c) d) e) f) 2. 3. a) b) 4. a) b)

Alkylating Agents Nitrogen Mustards Alkylsulphonates Nitrosoureas Aziridines & related copounds Platinium derivatives Triazines & others related drugs Anthracyclines Antitumor antibiotics Dactinomycin Mitomycin Camptothecins (Natural Compounds) Irinotecan Topotecan

Folic Acid Antagonist Purine derivatives Pyrimidine derivatives

b) c)
2. a) b) c) d)

Natural Compounds Vinca Alkaloids Epipodophyllotoxins Taxanes Antitumor Antibiotic. eg, Bleomycin

Mechanisms of Antineoplastic Drugs

3. Interfering with the transcription to inhibit RNA synthesis
Most antineoplastic drugs act on the proliferating cycle of cell 1. e.g. dactinomycin, dauoruicin, and doxorubicin

Destruction of DNA or inhibition of DNA duplication

e.g. alkylating agents, mitomycinC

4. Inhibition of protein synthesis

e.g. vinca alkaloids, epipodophylotoxins, and paclitaxel

2.

Inhibition of nucleic acid (DNA and RNA) synthesis

e.g. 5-fluorouracil, 6-mercaptopurine, methotrexate,

5. Interfering with hormone balance

e.g. adrenal corticosteroids, estrogens, tamoxifen

cytarabine

Cytotoxic Drugs
Common Adverse Effects

Renal stones (kidney damage) Precipitation of gout Potent nauseating & emetic agents

Mylosupression Impaired wound healing Alopecia & dermatitis Stomatits Diarrhea Desquamation of GIT epithelium Growth retardation Terratogenicity Carcinogenicity

Lymphocytopenia Immunosuppression

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ALKYLATING AGENTS
Mechanism
Act via a reactive alkyl group that reacts to form covalent bonds with nucleic acids follows cross-linking of the two strands of DNA preventing replication DNA breakage All alkylating agents are phase nonspecific. Kill rapidly proliferating cells, also kill nonproliferating cells

Cyclophosphamide
Most common Prodrug liver metab by

Uses of cyclophosphamide

Ac lymphocytic leukemia (maintenance) Chronic Myelogenic leukemia Non hodgkins lymphomas (cop) Multiple myeloma Polycythemia vera Neuroblastoma Colon cancer Testicular cancer As immunosuppressant (pronounced effect on lymphocytes)

CYP P450
Effects lymphocytes

Also immunosuppressant Oral or IV usually Side effects: N/V, bone

marrow depression, hemorrhagic cystitis

Nitrogen Mustards
Reactive ethylene immonium derivative

Nitrosoureas
Lomustine & Carmustine Activated in vivo Cause Alkylation + carbamoylation Highly lipophilic Cross B.B.B Brain tumors & Meningeal tumors

Mechlorethamine
the first drug used in the treatment of cancer mainly used for Hodgkin's disease and non-Hodgkin's

Protein carbamoylation causes toxicity Bone marrow toxicity

lymphomas
Streptozocin
Pancreatic islet cell tumor Non hodgkin lymhomas

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Busalphan
Alkyl sulfonate Selective action on bone marrow Specific for myloid elements, Granulocyte precursors most sensitive Used in chronic Granulocytic leukemia Drug of choice for Chronic Myloid Leukemia Little effect on GIT & lymphoid tissues

Alkylating Agent Temozolomide

Mechanism of Action Methylates DNA and inhibits DNA synthesis and function Same as Temozolomide

Clinical Applications Brain cancer, melanoma

Acute Toxicity Nausea and vomiting, headache and fatigue Central nervous system depression

Delayed Toxicity Myelosuppression , mild elevation in liver function tests, photosensitivity Myelosuppression , hypersensitivity reactions

Procarbazine

Hodgkin's and nonHodgkin's lymphoma, brain tumors

Toxicity
Thrombocytopenia Hyperuricemia Pulmonary fibrosis

Dacarbazine

Same as Temozolomide

Same as Nausea and Procarbazine vomiting

Myelosuppression , central nervous system toxicity

PLATINUM ANALOGS
Alkylating Agent
Cisplatin

ANTIMTABOLITES
Acute Toxicity Delayed Toxicity
Nephrotoxicity, peripheral sensory neuropathy, ototoxicity, nerve dysfunction

Mechanism of Action
Forms intrastrand and interstrand DNA cross-links; binding to nuclear and cytoplasmic proteins Same as cisplatin

Clinical Applications

Lung cancer, breast Nausea and cancer, bladder vomiting cancer, gastroesophageal cancer, head and neck cancer, ovarian cancer Same as above Same as above

Methotrexate
Folate antagonist

Carboplatin

Myelosuppression; rarely: peripheral neuropathy, renal toxicity, hepatic dysfunction Myelosuppression, peripheral sensory neuropathy, diarrhea

Oxaliplatin

Same as cisplatin

Colorectal cancer, gastroesophageal cancer, pancreatic cancer

Same as above

uses
1. 2. 3. 4. 5. 6. 7. 8. 9.

Adverse Effects
Hepatotoxicity Neurological toxicity BM Depression GIT

Acute Lymphoblastic leukemia in children Choriocarcinoma , Hydatidiform mole Osteosarcoma Non- Hodgkin Lymphomas Colorectal carcinoma Breast, ovarian, lung, head & neck cancers Severe psoriasis Organ transplantation Dermatomyositis

Stomatitis, NVD, Desequamation

Pneumonitis & mucositis Renal damage ( high dose) because of precipitation in renal

tubules
Leucovorin rescue can prevent life threatening neutropenia &

mucositis

10. Rheumatoid Arthritis

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Pemetrexed
Mechanism
Inhibits TS, DHFR, and purine nucleotide synthesis

5-fluorouracil
Pyrimidine antagonist Prodrug Converted to abnormal nucleotide

Use
Mesothelioma, non-small cell lung cancer

(fluoro deoxy-uridine mono PO4)

Inhibit thymidylate synthase & DNA

ADR
Myelosuppression, skin rash, mucositis, diarrhea, fatigue

Synthesis
Also inhibit-RNA synth. by being

incorporated into nucleic Acid chain

Cross B.B.B Oral, IV, topical

uses
Metastatic breast Cancer Ovarian, cervix and bladder carcinoma GIT carcinoma (Stomach, Colon, Rectum, Oropharynx) Prostrate & pancreatic cancer

Toxicity

B.M Leucopenia (most common) Because of poor oral absorption, severe GIT toxicity NVD, Stomatitis,

Cerebral disturbances Hand- foot syndrome (Painful erythematous swollen palms & soles) Cardiotoxic (Chest pain, tightness, Dyspnoea Cardiogenic shock)

Topically Basal cell carcinoma Psoriasis

Cytarabine
Inhibit conversion of cytidine to deoxycytidine Inhibits DNA synth & replication & chain elongation

6- Mercaptopurine

Purine antagonist Prodrug In the cells converted to active nucleotide metabolite Fraudulent nucleotide 6-thioinosine 5 PO4

Used in
Acute mylocytic leukemia Non lymphocytic Leukemia

Inhibit first step in Purine synthesis Interfere with formation of DNA & RNA Metabolized by xanthine oxidase to 6 thiouric acid

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6-Thioguanin
Inhibits de novo purine nucleotide synthesis; incorporation of

MITOTIC INHIBITORS
TAXANES Paclitaxel, Docetaxel (Taxus baccata/brevifolia)
increase tubulin polymerization in the

VINCA ALKALOIDS Vincristine, Vinblastine (Vinca rosea)

inhibit tubulin polymerization disrupts assembly of microtubules

triphosphate into RNA; incorporation of triphosphate into DNA Used in

acute lymphoblastic leukemia; AML, acute myelogenous leukemia
absence of microtubule-associated proteins & guanosine triphosphate

ADRs
Myelosuppression, immunosuppression, and hepatotoxicity

Breast cancer, non-small cell and small cell lung cancer, ovarian cancer, gastroesophageal cancer, prostate cancer, bladder cancer, head and neck cancer

Hodgkin's and non-Hodgkin's lymphoma Breast cancer, Kaposi's sarcoma, Rhabdomyosarcoma, Neuroblastoma, Wilms' tumor

TOPISIOMRASE INHIBITORS
Taxanes
ADRs Nausea, vomiting, hypotension, arrhythmias, hypersensitivity Myelosuppression, Neurotoxicity, fluid retention

Vinca alkaloids

Epipodophyllotoxins

Drug

Mechanism of Action Inhibits topoisomerase II Inhibits topoisomerase I Inhibits topoisomerase I

Clinical Applications

Toxicity Nausea, vomiting, hypotension, Alopecia, myelosuppression Diarrhea, nausea, vomiting, myelosuppression Nausea and vomiting, Myelosuppression

Camptothecins

ADRs Myelosuppression, mucositis, peripheral neuropathy, SIADH, constipation

Etoposide

Non-small cell and small cell lung cancer; non-Hodgkin's lymphoma, gastric cancer Colorectal cancer, gastroesophageal cancer, non-small cell and small cell lung cancer Small cell lung cancer, ovarian cancer

Irinotecan

Topotecan

ANTITUMOR ANTIBIOTICS
Bleomycin Metal chelator, Fe3+ O2 free radicals Mitomycin cross-links with DNA alkylating agent

Daunorubicin

Doxorubicin

O2 free radicals

Mechanism Semiquinone & O2 radicals break DNA strands; inhibits topoisomerase II; intercalates into DNA Uses Breast cancer, Hodgkin's and nonHodgkin's lymphoma, soft tissue sarcoma, ovarian cancer, lung cancer, thyroid cancer, Wilms' tumor, neuroblastoma

DNA strand breaks Uses Hodgkin's and nonHodgkin's lymphoma, germ cell cancer, head and neck cancer ADRs Allergic reactions, fever, hypotension, pulmonary fibrosis, mucositis, alopecia

Uses Superficial bladder cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer (in combination with radiotherapy)

Uses AML, ALL

ADRs Allergic reactions, anorexia and fatigue, hemolytic-uremic syndrome

ADRs Nausea, fever, red urine (not hematuria), Cardiotoxicity, alopecia, myelosuppression

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Hormonal agents
Estrogen antagonist Tamoxifen breast cancer Progestins Medroxyprogesterone endometrialcancer Aromatase inhibitor Anastrozole breast cancer Androgen antagonist Flutamide prostate cancer GnRH receptor modulator Leuprolide/Goserelin prostate

ASPARAGINASE
Hydrolyzes circulating L-asparagine to aspartic acid & ammonia resulting in rapid inhibition of protein synthesis Used for acute lymphoblastic leukemia (children)

ADRs
Hepato & renal toxicity Dysfunctional blood coagulation Mental depression Pancreatitis

cancer
Corticosteroid Prednisone hematologic malignancies (i.e.

lymphocytic leukemias, lymphomas, multiple myeloma)

Drug

Mechanism of Action Inhibits EGFR tyrosine kinase leading to inhibition of EGFR signaling Same as above Inhibits Bcr-Abl tyrosine kinase and other RTK Binds to EGFR and inhibits downstream EGFR signaling; enhances response to chemotherapy and radiotherapy Same as above Inhibits binding of VEGF to VEGFR leading to inhibition of VEGF signaling; inhibits tumor vascular permeability but enhances tumor blood flow and drug delivery Inhibits multiple RTKs, including raf kinase, VEGF leading to inhibition of angiogenesis, invasion, and metastasis

Clinical Applications Non-small cell lung cancer, pancreatic cancer Non-small cell lung cancer Gastrointestinal stromal tumor, ALL Colorectal cancer, head and neck cancer (used in combination with radiotherapy), non-small cell lung cancer Colorectal cancer

Kinase Inhibihots
Imatinib Gefitinib

Erlotinib Gefitinib Imatinib

Cetuximab

Panitumumab

Bevacizumab

Colorectal cancer, breast cancer, non-small cell lung cancer, renal cell cancer

Sorafenib

Renal cell cancer, hepatocellular cancer

Thank You