Cancer• Cancer accounted for 7.1 million deaths world-wide (12.5%).

• Ranks as 3 of the top 10 leading causes of death world wide.

• 11 million are diagnosed with cancer each year and by 2020 the World health organisation expects this rise to 16 million.

• Second cause of death in the West (after cardiovascular diseases).

Sources: WHO and Cancer Research UK

Pathogenesis of cancer • DNA mutations

– Inborn mutations of cancer susceptibility genes– Acquired mutations

• Other epigenetic factors– Chemical carcinogens– Virus-induced cancer– X-rays– Other risk factors (tobacco, alcohol, Asbestos, diet)

Cancer

• Genetic mutations within a single affected cell leads to monoclonal development. Genes affected can be those controlling cell cycle, DNA repair and/or differentiation, This leads to uncontrolled proliferation and tumour formation.

Cancer Types

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

– Carcinoma: a tumor derived from epithelial cells, those cells that line the surface of our skin and organs (80-90% of all cancer cases reported)

– Sarcoma: a tumor derived from muscle, bone, cartilage, fat or connective tissues.

– Leukemia: a cancer derived from white blood cells or their precursors.

– Lymphoma: a cancer of bone marrow derived cells that affects the lymphatic system.

– Myelomas: a cancer involving the white blood cells responsible for the production of antibodies (B lymphocytes).

Causes of cancer

• 30% of cancer is due to smoking.• 30% of cancer cases is diet related.• 15% of cases are viral related infections:

– Papilloma virus… sexually transmitted… cause cervical cancer.

– Hepatitis-B is the cause of 80% of liver cancer.• Some are bacteria related:

– H.pylori…. Leads to stomach cancer.

The Classification of Anticancer Drugs

According to chemical structure and resource of the drug:

– Alkylating Agents

– Anti-metabolite

– Antibiotics

– Plant Extracts

– Hormones

Problems with chemotherapy• Treatments are non-specific, attack healthy cells as well as normal cells since cancer cells are derived from normal cells.• Cancers can develop resistance: for example with platinum-drugs, cancer cells became resistant by many ways:

– Decreased drug uptake/increased efflux– Enhanced tolerance of DNA adducts– Enhanced repair of DNA adducts– Increased drug deactivation by intracellular glutathione

Ideal cytotoxic drugs should:

• Selectively target cancer cells without causing damage to normal cells.

• Reduce size of tumors + minimize risks of metastases.

unfortunately, most of the available agents are not selective, they also affect rapidly-proliferating normal tissues (bone marrow, gastro intestinal epithelium, hair cells, …), causing serious side-effects (bone marrow suppression, nausea, vomiting, …).

alkylating agents

• Nitrogen mustard• Nitrosourea• Busulfan• Cisplatin and Cisplatin Analogues• Dacarbazine and Procarbazine• Mitomycin C

Chemical Warfare – circa 1914

• Two most common agents:• Chlorine gas• Mustard gas

Cl

Cl

NR

Cl

Cl

S

Sulfur Mustard

(chemical weapon) not used clinically

Nitrogen Analog

Alkylating Agents

Mechanism of Action

• Nitrogen mustards inhibit cell reproduction by binding irreversibly with the nucleic acids (DNA). The specific type of chemical bonding involved is alkylation. After alkylation, DNA is unable to replicate and therefore can no longer synthesize proteins and other essential cell metabolites. Consequently, cell reproduction is inhibited and the cell eventually dies from the inability to maintain its metabolic functions.

Alkylating Agents

• Alkylating agents are reactive compounds that act on DNA, RNA or enzymes.

• Cells are killed by the alkylation of DNA– Formation of a covalent bond between drug and DNA (usually

N7 on G) to form crosslinks– Methylation at N7

• Procarbazine, streptozocin, dacarbazine, temozolomide• Drug resistance is common

• Alkylating agents are reactive compounds that act on DNA, RNA or enzymes.

• Cells are killed by the alkylation of DNA– Formation of a covalent bond between drug and DNA (usually

N7 on G) to form crosslinks– Methylation at N7

• Procarbazine, streptozocin, dacarbazine, temozolomide• Drug resistance is common

• nitrogen mustard • amino acid, nucleic base or hormone uptake by carrier protien

N

Cl

Cl

H2N

COOHH

L-phenylalanine(amino acid)

Melphalan

CH3

H

H

H

OH

H

O

O

NCl

Cl

Estradiol(sex hormone)

NH

HN

O

O

N

CH3

CH3

Uracil Mustard

Uracil(nucleic base)

Estramustine

nitrogen mustard

Nitrogen Mustard

Mechlorethamine (or Chlormethine)

chloroethylamino structure (N-CH2CH2-Cl)

H3C N

Cl

Cl

+

-

nucleophile

electrophileN

Cl

Cl

-system

structureElectrophilic carbon

MOA: Nitrogen Mustards

Generation of highly reactive “aziridinium ions” that act as alkylating agents to cross-link DNA producing defective DNA and abnormal cellular function and eventually cell death

H3C N

Cl

Cl

Cl-

H3C N

Cl

HNN

NN

O

NH2

NHN

N N

O

H2N

HNN

NN

O

NH2

NHN

N N

O

H2N

N

Cl

H3C

HNN

NN

O

NH2

NHN

N

N O

NH2

NH3C

HNN

NN

O

NH2

HN N

NN

O

NH2

N

H3C

Nitrogen Mustards

Mechlorethamine HCl - Mustargen®

NCl

ClCH3 HCl

N,N-bis(2-chloroethyl)methylamine

Extravasation a problem – 0.16 M sodium thiosulfate and ice packs, {antidote for extravasation} highly reactive aziridinium ion

Injection only, monitor renal, hepatic and bone marrow

MOST reactive of the mustards

Theoretical rationales used to improve nitrogen mustards-Substituting an aromatic ring for methyl group can be predicted to increase chemical stability and thereby decrease the rate of alkylation because of electron-withdrawing effect. This also, will lead to good oral bioavailability, tissue distribution, before alkylation is widespread.

E.g. Chlorambucil, and melphalan.

Nitrogen Mustards

4(-p-bis(2-Chloroethylamino)phenyl) butyric acid.

(CH2)3-COOH

Cl

Cl

N

Chlorambucil

Synthesis

(CH2)3-COO-

Cl

Cl

N(CH2)3-COO-

OH

OH

N

CH3

CH3

CH3

CH3

(CH2)3-COO-NH2

CH3

CH3

(CH2)3-COO-O2N

(CH2)3-COOHO2N(CH2)3-COOH

CH3

CH3

O

CH3

CH3

OH

Nitration

4-Phenylbutyric acid

2

Hydrolysis

POCl3

Chlorambucil(CH2)3-COOH

Cl

Cl

N

Ethylene oxide (oxirane)

Phosphoryl chloride

Melphalan - Alkeran®

NCl

ClNH2

HO2C

Oral or IV, severe bone marrow suppression resulting in infection and bleeding

Dosage reduction may be necessary in renal failure as measured by BUN

Known to cause chromosome abnormalities

Nitrogen Mustards

ClS

Cl ClS

NuH

ClS

Nu

+ HCl

Slow

less stable than N-aanalog

Moderate

ClN

Cl ClN

NuH

ClN

Nu

+ HCl

Fast

Moderate

R

R2- order kinetics

1. order kinetics(1. step rat lim)

R=Alkyl

R

ClN

Cl ClN

NuH

ClN

Nu

+ HCl

Slow

ModeratePh

Lone pair delocalizedLess nucleophilic

Ph1. order kinetics(1. step rat lim)

To increase selectivity, nitrogen mustards was bonded with natural carrier e.g. estramustine which is active against prostate cancer, another examples is the bonding with antimetabolites e.g. uracil mustard.

Nitrogen Mustards

Estramustine phosphateEstracyt®

Pro-drug

O

O P

O

O

O

Na

Na

N

O

Cl

Cl

Water solubility

1) Oral absorb2) Fast metabol.

O

OH

N

O

Cl

Cl

Main comp. plasma

EstradiolCarry to cells with estrogenic receptors

Estrogenic (Anti-androgenic) effect protate cancerCleaved to active alkylating agent?

Ideal cytotoxic drugs should:

• Selectively target cancer cells without causing damage to normal cells.

• Reduce size of tumors + minimize risks of metastases.

unfortunately, most of the available agents are not selective, they also affect rapidly-proliferating normal tissues (bone marrow, gastro intestinal epithelium, hair cells, …), causing serious side-effects (bone marrow suppression, nausea, vomiting, …).