Presentation on

Anti-cancer drugsMd: Shariful Islam

South east universityE-mail: sharifislam.islam97@gmail.com

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Cancer is a term used for diseases in which abnormal cells

divide without control and are able to invade other tissues.

Cancer cells can spread to other parts of the body through

the blood and lymph systems, this process is called

metastasis.

Cancer

Cancer

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Categorized based on the functions/locations of the cells from which they originate:

1. Carcinoma - skin or in tissues that line or cover internal organs. E.g., Epithelial cells. 80-90% reported cancer cases are carcinomas.

2. Sarcoma - bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue.

3. Leukemia - White blood cells and their precursor cells such as the bone marrow cells.

4. Lymphoma - cells of the immune system that affects lymphatic system.

5. Myeloma - B-cells that produce antibodies, spreads through lymphatic system.

6. CNS cancers - cancers that begin in the tissues of brain and spinal cord.

Cancer Therapeutic Modalities (classical)

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1. Surgery

2. Radiation

3. Chemotherapy

1/3 of patients without metastasis Respond to surgery and radiation.

If diagnosed at early stage, close to 50% cancer could be cured.

50% patients will undergo chemotherapy, to remove micrometastasis. However,chemotherapy is able to cure only about 10-15% of all cancer patients.

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New types of cancer treatment

Hormonal Treatments: These drugs are designed to prevent

cancer cell growth by preventing the cells from receiving

signals necessary for their continued growth and division. E.g.,

Breast cancer – tamoxifen after surgery and radiation

Specific Inhibitors: Drugs targeting specific proteins and

processes that are limited primarily to cancer cells or that are

much more prevalent in cancer cells.

Antibodies: The antibodies used in the treatment of cancer have

been manufactured for use as drugs. E.g., Herceptin, avastin

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New types of cancer treatment

Biological Response Modifiers: The use of naturally

occuring, normal proteins to stimulate the body's own

defenses against cancer. E.g., Abciximab, rituxmab

Vaccines: Stimulate the body's defenses against cancer.

Vaccines usually contain proteins found on or produced by

cancer cells. By administering these proteins, the treatment

aims to increase the response of the body against the cancer

cells.

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Cancer Chemotherapy (Background)

A. Most of the recent progress using antineoplastic therapy is based on:1. Development of new combination therapy of using

existing drugs.2. Better understanding of the mechanisms of antitumor

activity.3. Development of chemotherpeutic approaches to

destroying micrometastases.4. Understanding the molecular mechanisms concerning

the initiation of tumor growth and metastasis.5. Recognition of the heterogeneity of tumors

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Cancer Chemotherapy (Background)

B. Recently developed principles which have helped guide the treatment of neoplastic disease

1. A single clonogenic cell can produce enough progeny to kill the host.

2. Unless few malignant cells are present, host immune mechanisms do not play a significant role in therapy of neoplastic disease.

3. A given therapy results in destruction of a constant percentage as opposed to a constant number of cells, therefore, cell kill follows first order kinetics.

Cancer Chemotherapy

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C. Malignancies which respond favorably to chemotherapy:

1. choriocarcinoma, 2. Acute leukemia,3. Hodgkin's disease,4. Burkitt's lymphoma, 5. Wilms' tumor,6. Testicular carcinoma,7. Ewing's sarcoma, 8. Retinoblastoma in children, 9. Diffuse histiocytic lymphoma and10.Rhabdomyosarcoma.

D. Antineoplastic drugs are most effective against rapidly dividing tumor cells.

E. The Main Goal of Antineoplastic Agents

IS to eliminate the cancer cells without affecting normal tissues (the concept of differential sensitivity).  In reality, all cytotoxic drugs affect normal tissues as well as malignancies - aim for a favorable therapeutic index (aka therapeutic ratio).

Therapeutic Index =LD50

-----ED50

A therapeutic index is the lethal dose of a drug for 50% of the population (LD50) divided by the minimum effective dose for 50% of the population (ED50).

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Cancer Chemotherapy

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General rules of chemotherapy Aggressive high-dose chemotherapy

• Dose- limiting is toxicity towards normal cells• Cyclic regimens - repeated administrations with appropriate

intervals for regeneration of normal cells (e.g., bone marrow cells) • Supportive therapy - to reduce toxicity

hematotoxicity – bone marrow transplantation, hematopoietic growth factors Specific antagonists: antifolate (methotrexate) – folate (leucovorin)MESNA - donor of –SH groups, decreased urotoxicity of cyclophosphamide. Detoxifying agent. dexrazoxane: chelates iron, reduced anthracycline cardiotoxicityamifostine: reduces hematotoxicity, ototoxicity and neurotoxicity of alkylating agents

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Alkylating agentsTopoisomerase inhibitors Antimetabolites

Molecularly targeted

busulfan dactinomycin cytarabine erlotinibcarboplatin daunomycin clofarabine imatinibcarmustine doxorubicin fludarabine sorafenibcisplatin etoposide gemcitabine sunitinibcyclophosphamide etoposide phosphate mercaptopurine tretinoindacarbazine idarubicin methotrexate Herceptinifosfamide irinotecan nelarabine Miscellaneouslomustine liposomal daunomycin thioguanine arsenic trioxidemechlorethamine liposomal doxorubicin Tubulin binders asparaginasemelphalan mitoxantrone docetaxel bleomycinoxaliplatin teniposide ixabepilone dexamethasoneprocarbazine topotecan vinblastine hydroxyureatemozolomide vincristine mitotanethiotepa vinorelbine PEG-asparaginase

paclitaxel prednisone

Antineoplastic Agents

Cell cycleCell cycle can be divided into: G0: This may be a temporary resting

period or more permanent. An example of the latter is a cell that has reached an end stage of development and will no longer divide (e.g. neuron).

G1: Cells increase in size in G0, produce enzymes needed for DNA synthesis

S Phase: To produce two similar daughter cells, the complete DNA instructions in the cell must be duplicated. DNA replication occurs during this S (synthesis) phase.

Gap 2 (G2): It is the gap between DNA synthesis and mitosis, the cell will continue to grow and produce new proteins & RNA.

Mitosis or M Phase: Cell growth and protein production stop at this stage in the cell cycle. All of the cell's energy is focused on the complex and orderly division into two similar daughter cells.

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G0 = resting phaseG1 = pre-replicative phaseG2 = post-replicative phaseS = DNA synthesisM = mitosis or cell division

M

S

G G2 1 Hydrocortisone

Vincristine, Vinblastine

G 0

CyclophosphamideBleomycinActinomycin D

Actinomycin D5-FluorouracilCytosine arabinosideMethotrexate6-Mercaptopurine6-Thioguanine

Purine antagonistsMethotrexateCyclophosphamide5-FluorouracilCytosine arabinosideDaunomycin

Paclitaxel, Docetaxel

resting

Cell cycle specificity of Anti-Neoplastic Agents

Cancer chemotherapeutic agents

They are classified into:• Cell-cycle non specific agents(CCNS): are cytotoxic in any

phase of the cycle even on G0 phase and so are more effective against large slowly growing tumors. E.g. Bleomycin.

• Cell-cycle specific (CCS): are cytotoxic on all phases but not on cells out of the cycle(at G0 ) and so are more effective against rapidly growing tumors. Work better in combination than alone

E.G. Mitomycin, doxorubicin,….etc.

• Phase specific: act on specific phase of the cycle E.g. Vinca alkaloids act more in M-phase ,antimetabolites

(mainly act on S-phase.)

Anticancer DrugsThere are three Major Groups of Anticancer Drugs:1) Cytotoxic Drugs (largest group)

-Alkylating agents -Antimetabolites -Antitumor antibiotics -Plant alkaloids -Miscellaneous cytotoxic drugs

2) Hormones and hormone antagonists These are among the best-tolerated chemotherapeutics

because they target specific receptors, and thus only specific cell types e.g. Tamoxifen

3) Immunomodulators• -Immunostimulants, including interferons and interleukins• -Immunosuppressant

I-Alkylating Agents (CCNS)Mechanism of action• These drugs work by alkylation with nucleophilic substitution.

They alkylate a variety of cellular constituents, such as cell membranes, proteins, and most importantly DNA. More specifically, the nitrogenous bases of DNA are alkylated.

• The drugs start off as pro-drugs that become activated when a chlorine atom is extracted. A carbonium ion is thus formed. This “carbonium ion” is very electrophilic and will then attack any free pair of electrons (i.e. on the N7 of guanine). This electrophilic attack results in a bond being formed between the drug and the guanine of DNA. As a result of this “alkylation”, there are a few consequences:1) Miscoding (In transcription)2) Cross linking- this only occurs if the drug is bifunctional

The net result is cancer cell undergo apoptosis.

I-Alkylating Agents (CCNS)

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Crosslinking: Joining two or more molecules by a covalent bond. This can either occur in the same strand (intrastrand crosslink) or in the opposite strands of the DNA (interstrand crosslink). Crosslinks also occur between DNA and protein. DNA replication is blocked by crosslinks, which causes replication arrest and cell death if the crosslink is not repaired.

An Example of DNA Crosslinking

H2N

O

N

N

HN

N

HO

O

OP

O

NH2

O

N

N NH

N

OOP

OHO

NR

Major Clinically Useful Alkylating Agents

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Bis(mechloroethyl)amines Nitrosoureas Aziridines

1) Nitrogen mustards (Mechlorethamine, Melphalan, Chlorambucil, Cyclophosphamide)

2) Nitrosoureas (Carmustine, Lomustine, Semustine)3) Alkyl sulfonates (Busulphan)4) Ethylenimines and methyl melamines (Thiotepa, Hexamethyl

melamine)

1) Nitrogen MustardsMechlorethamine

- first alkylating agent employed clinically - bifunctional, thus can crosslink DNA- extremely unstable and is inactivated within a few minutes following administration. Thus it is given IV.

Clinical Uses-Hodgkin’s Disease-Non-Hodgkin’s Lymphoma

I-Alkylating Agents (CCNS)

Cyclophosphamide -It acts as cytotoxic and immunosuppressor agent.- Prodrug which must be activated by the cytochrome p450 system,

which turns it into a nitrogen mustard. - bifunctional agent-most widely used alkylating agent

Clinical Uses- Hodgkin’s Disease- Non-Hodgkin’s lymphoma- Solid tumors of head, neck, ovaries, and breast- frequently used in combination with methotrexate (anti-

metabolite) or doxorubicin (anti-tumor antibiotic), or fluorouracil as adjuvant therapy post breast cancer surgery

- Organ transplant recipients (due to immunosuppressive actions)

I-Alkylating Agents (CCNS)

ChlorambucilActs by interfering with DNA replication and damaging the DNA in

a cell. The DNA damage induces cell cycle arrest and cellular apoptosis via the accumulation of cytosolic p53 and subsequent activation of Bax, an apoptosis promoter.

Clinical UsesMainly in chronic lymphocytic leukemia, Can be used for treating some types of non-Hodgkin lymphoma,

Waldenström macroglobulinemia, and ovarian carcinoma.Also used as an immunosuppressive drug for various autoimmune

and inflammatory conditions.

I-Alkylating Agents (CCNS)

Melphalan

Melphalan chemically alters through alkylation of the DNA

nucleotide guanine, and causes linkages between strands of

DNA. This chemical alteration inhibits DNA synthesis and RNA

synthesis.

Clinical Uses It is used to treat multiple myeloma ovarian cancer occasionally malignant melanoma.

I-Alkylating Agents (CCNS)

2) Nitrosoureas (Carmustine and Lomustine) - bifunctional- active against broad spectrum of neoplastic disease- inhibits synthesis of both DNA and RNA, as well as proteins- highly lipophilic, so they can easily cross BBB, and are great for CNS

tumors.- Major toxicity is DELAYED bone marrow depression & Pulmonary

fibrosis.

Clinical uses- primary and metastasis tumors of the brain- Hodgkin’s Disease- Non-Hodgkin’s lymphoma- Adenocarcinoma of stomach, colon, and rectal cancer- Hepatocarcinoma

I-Alkylating Agents (CCNS)

Carmustine Lomustine

Synthesis of Carmustine

3) Alkyl Sulfonates (Busulfan)

Clinical usesGreat effect on for Chronic granulocytic Leukemia

Toxicity/ Side Effects- Dose limiting toxicity is bone marrow depression.- Pulmonary infiltrates and pulmonary fibrosis-- Nausea and vomiting- Alopecia- Sterility- Skin hyper pigmentation- Cataracts- Hepatitis

I-Alkylating Agents

4) Ethylenimines and methyl melamines (Thiotepa, Hexamethyl melamine)

Thiotepa (N, N', N''-triethylenethiophosphoramide) is an organophosphorus compound with the formula SP(NC2H4)3. This molecule features tetrahedral phosphorus and is structurally akin to phosphate. It is derived from aziridine and thiophosphoryl chloride.

Use:Adenocarcinoma of the breast, adenocarcinoma of the ovary, superficial papillary carcinoma of the urinary bladder

I-Alkylating Agents

Synthesis of Thiotepa

Aziridine Thiophosphoryl chloride.

Thiotepa

Synthesis of Mechlorethamine

Synthesis of Melphalan

Synthesis of Cyclophosphamide

Synthesis of Chlorambucil

Synthesis of Busulfan

5) Platinum Coordination CompoundsCisplatin• Forms crosslinks within DNA strands.

• Cis-platin is not really an “alkylating” agent, but since it operates

via the same mechanism as the alkylating agents, it is placed

within that group.

Carboplatin A derivative of cisplatin with less nephero- ,neuro- & ototoxicity.

Clinical Uses- Very powerful against TESTICULAR CANCER- Also good for carcinomas of ovary, bladder, head, and neck

I. Alkylating Agents

II. Antimetabolites (CCS)• An antimetabolite is a chemical with a similar structure to a metabolite

required for normal biochemical reactions, interfere with the normal functions of cells, including cell division.

• All antimetabolites are used in cancer treatment, as they interfere with DNA production and therefore cell division and the growth of tumors (mainly in S-phase specific).

• They are classified into: 1- Folic acid analogues (Methotrexate) 2- Purine analogues (6-Mercaptopurine, thiogunine) 3- Pyrimidine analogues (5-fluorouracil, Cytarabine)

• Purine and pyrimidine antagonists are phosphorelated inside the body into nucleotide form in order to be cytotoxic

Uses• leukemia. • non-Hodgkin's lymphoma• inflammatory bowel disease such as Crohn's Disease and ulcerative colitis• widely used as immunosuppressant in transplantations to control rejection

reactions.

O BaseO

RO

POO

O

R=H in DNAR=OH in RNA

HN

N

O

O

Thymin

N

N

NH2

O

Cytosin Adenine

N

N N

N

NH2

Guanine

HN

N N

N

O

H2N

DNA

RNA HN

N

O

O

Uracil

Cytosin Adenine Guanine

II. Antimetabolites (CCS)

Cytarabine (ARA-C)

N

N

NH2

O

O

HO

HO

OH

ARA-C

metabolic activation

N

N

NH2

O

O

HO

O

OH

ARA-C

PPP

Metabolic inactivation(fast)

HN

N

O

O

O

HO

HO

OH

N

N

NH2

O

O

HO

OP

OH

N

N

NH2

O

O

HO

OP

Inhib. DNA polymerase

Incorporation DNA/RNA; misreading

D-arabinose D-ribose

6-Mercaptopurine (6-MP)

N

N

SH

NH

N HN

N

S

NH

N

S-Analog hypoxanthine

Metabolic activation HN

N

S

N

N

O

OHHO

OP

6-MPMPInhib. several steps in purine biosynth

N

N

S

N

N

O

OHHO

OP

Me

HN

N

S

N

N

O

OHHO

OPPP

Incorp . DNA / RNA instead og guanine

also antimetabolite

Methotrexate: A folic acid analogue, prevents the formation of THF, essential for purine and pyrimidine synthesis,

Inhibits DHF reductase, leads to inhibition of production of DNA, RNA and proteins (as tetrahydrofolate is also involved in the synthesis of amino acids as serine and methionine).

It is actively taken up into the cells by the same transport system for folate.

1-Folic acid analogues

folic acid

Methotrxate

Methotrexate compete with folic acid for DHFR and inhibits it. Therefore, it inhibits the synthesis of DNA, RNA and proteins.

Also, DHFR catalyses the conversion of DHF to the active THF which is needed for the synthesis of the deoxynucleoside thymidine phosphate DTMP (required for DNA synthesis)

Cont: Folic acid analogues

Purines are integral components of RNA, DNA and coenzyme that are synthesized in proliferaton of cancer cells. Therefore, an agent that antagonizes the purine will certainly lead to formation of false DNA and these include analogues of natural purine bases, nucleosides and nucleotides.

A few drugs belonging to this classification are, namely : Mercaptopurine and Azathiopurine

2. Purine analogues

o-Mercapto-6-purine ; 6 MP

Mercaptopurine is found to inhibit experimental orthoimmune encephalomyletis and thyroiditis and hence used in combination with vincristine, methortrexate and prednisone in the treatment of childhood leukemia.

As such 6-MP may cause hyperuricamia but it is usually administered with allopurinol—ananalogue of hypoxanthine which blocks the conversion of 6-MP to uric acid and hence the dose of 6-MP is reduced and still the desired response is obtained.

Mercaptopurine

It may be prepared by the interaction of hypoxanthine with phosphorus pentasulphide.

Synthesis of Mercaptopurine

The main use of azathiopurine is as an adjunct for the management and prevention towards the rejection of renal homotransplants.

Azathiopurine

Synthesis of Azathiopurine

It is prepared by treating 6-mercaptopurine with 5-chloro-1-methyl-4-nitroimidazole

Pyrimidine analogues have the capacity to interfere with the synthesis of pyrimidine nucleoside and hence the DNA synthesis. Aside from their antineoplastic effects they are also found to be equally effective in psoriasis and fungal infections.

A few characteristic compounds of this category are, namely : Fluorouracil and Cytarabine.

Pyrimidine analogues

It is used in the palliative treatment of

carcinoma of the breast, pancreas, prostrate,

colon and hepatoma for which surgery or

irradiation is not possible.

It is also found to be beneficial in tropical

treatment of premalignant solar keratosis.

5-FU

Synthesis of 5-FU

This official compound is prepared by the direct fluorination of uracil with fluoroxytrifluoromethane.

It is indicated in both adult and childhood leukemia. It is

specifically useful in acute granulocytic leukemia and found

to be more effective when combined with thioguanine and

daunorubacine.

Cytarabine

Synthesis of Cytarabine

Cytarabine may be synthesized by the acetylation of uracil

arabinoside followed by treatment with phosphorus

pentasulphide and subsequent heating with ammonia.

Folic Acid analogs as antimetabolites

Metotreksat

Raltitrexed HN

N N

NO

N

O

NH

CO2H

CO2H

S

N

N N

NNH2

H2N

N

O

NH

CO2H

CO2H

• Chemotherapy• Alkylation Agents √• Antimetabolites / Nucleoside Analogs √• Antibiotics• Antimitotic Agents• Micellaneous Antineoplastic Agents• Hormonal Therapy

Metabolites from microorg., too toxic as antibiotics - anticancer comp.

• Bleomycins• Actinomycins• Mitomycins• Antracyclins• Coformycins

The recognition of antibiotics as an important class of antineoplastic agents is quite recent.

Consequently, the production of antineoplastic agents through proper strain selection and controlled microbial fermentation conditions may ultimately optimize the formation of a particular component in an antibiotic mixture.

A few important members of this category are described below, namely ; Dactinomycine; Daunorubicin ;

III. Antibiotics

Dactinomycine

It is used in the treatment or rhabdomyosarcoma in children and methotrexate-resistant choricarcinoma in women. It has also been used to inhibit immunoligical response particularly the rejectionof renal transplants.

The first antibiotic to be isolated from a species of Streptomyces was Actinomycin A and many related antibiotics including Actinomycin D were latter obtained. Actinomycin D is commercially available as Dactinomycine.

It is found to the acitve against L-1210, P-1534, P-388 and adenocarcinoma strains. It binds to DNA thereby preventing DNA transcription

Anthracyclines constitute another complex and bigger family of antibiotics. They mostly occur as glycosides of the anthracyclinones (aglycone residue). They act by intercalation with the DNA in both normal and neoplastic cells.

Anthracyclines

O

O

OH

OHO

OH

OR2

R3

R4NH2

CH3

R1

DoxorubicineR1 = OMe, R2 = OH, R3 = H; R4 = OH

Daunorubicin R1 = OMe, R2 = H, R3 = H; R4 = OH

Daunorubicin

Daunorubicin is useful in the treatment of acute

lymphoblastic leukemia in children.

It is normally employed in combination therapy, for

instance : with cytosine arabinoside in the treatment of

myclogenous leukemia ;

With cytarabine in the treatment of non-lymphoblastic

leukemia in adult.

Vinca alkaloids

Vinca alkaloids (Indols)from Vinca rosea(Catharantus roseus)

NH

N

HO

MeO2C

MeONR

N

H OCOMe

CO2MeOH

R=-Me: Vinblastin, Velbe®R=-CHO: Vinkristin, Vincristine®

Binds to microtubuli- Supression of microtubuli dynamics-Metaphase arrest

Depolymerization of microtubuli high conc.

Discovered in the 1950’s by Canadian scientists, Robert Noble and Charles Beer.

First isolated from bark of Western / Pacific yew (Taxus brevifolia)

Mecanism ≈ Vinca alkaloids, different binding sites

R1 = -Ph, R2 = -COMe: Palitaxel, Taxol®R1 = -OBut, R2 = -H: Dodetaxel, Taxotere® Semisynthetic

OO

HO

OH

R2

O OH

O

O

O

HO

NH

OR1

O

O

Taxanes

From Colchicum autumnale seeds

H3COCH3O

H3CO

OOCH3

NH

O

Colchicine

Binds to microtubuli - metaphase arrest, too toxic too be used in cancer treatment

Used to treat gout (podagra)

Podophyllotoxines

From Podophyllum peltarumMay apple

Antiviral, veneric warts

Toxic - lead for anticancer drugs

O

OO

OMeOMeMeO

OH

O

Podophyllotoxin

Affects DNA topoisomerase II (not intercalating)DNA strand breakage

CamptothecinsFirst isolated Camptotheca acuminata NIH screeningLater found in several plants N

N

O

O

OOH

Camptothecin, toxic, Lead comp.

NN

O

O

OOH

HO

N

NN

O

O

OOH

O

N O

N

TopotecanIrinotecan

Semisynth. inhib. DNA topoisomerase II, DNA strand breakage

ImatinibLeukemia types

GefitinibLung cancer

HN

HN

N

N

N

O

NN

ON O

N

N

HN

FCl

H3CO

Other agents

• Chemotherapy• Alkylation Agents √• Antimetabolites / Nucleoside Analogs √• Antibiotics √• Antimitotic Agents √• Micellaneous Antineoplastic Agents √• Hormonal Therapy

Antiestrogens

HO

H

HH

O

Estrone

in vivo

HO

H

HH

Estradiol

OH

HO

H

HH

Estriol

OH

in vivo

(Low activity)(fast metabolism)

OH

(low activity)

ON

TamoxifenNolvadex® Tamoxifen®

HO

OH

DiethylstilbestrolEstrogene agonist, used as drug before

HO

H

HH

OH

HO

OH

Overlap estradiol

Estrogens and agonists

Breast cancer(estrogen depend.)

Androgens

H

HHO

Testosterone

OH

5-reduktaseH

HHO

5-Dihydrotestosterone (5DHT)More active

OH

H

Anti-androgens

FlutamidProstate cancer

F3C

O2N

HN

O

BicalutamidProstate cancer (less tox.)

F3C

O2N

HN

O

HO O2S

F