Cancer chemotherapy

Cancer

The term cancer refers to the heterogeneous

group of diseases caused by an impairment of

the normal functioning genes which lead to

genetic damage.

objective of chemotherapy

1. Cure may be solve with aggressive therapy

for a prolonged period of time to eradicate all

disease.Leukemia's is curative approach may

consist of remission , induction, attempting

the maximum cell kill , followed by

consolidation therapy to eradicate all clinically

undetectable disease and to lower tumor cell

burden below 103 ,at which level host

immunological defense may keep the cell in

control

2- if the goal is palliation , chemotherapy may

be given to decrease a tumor size , control

growth ,and reduce symptoms .palliative

therapy is usually given when complete

eradication of the tumor is considered unlikely

the patient reduces aggressive therapy

3-adjuvant.

4-neoadjuvnt.

5-salvage.

dosing

May be based on body weight ,body surface

area(BSA) or area under the concentration

versus time cure (AUC).

BSA is the most frequently used because an

accurate comparison of activity and toxicity

Across species . In addition BSA correlate with

cardiac output which determine renal hepatic

blood flow and thus affect drug elimination

combination

Usually effective than single agent

Factors consider in combination:

1. Antitumor activity.

2. Different mechanism of action.

3. Minimally overlapping toxicities.

The reasons for administering

chemotherapy:

1. Overcoming or preventing resistance.

2. Cytotoxicity to resting and dividing cells.

3. Biochemical enhancement of effect.

4. Rescue of normal cells.

adminsteration

Routes of administration vary ,although

intravenous adminsteration is employed most

commonly.

Other technique include oral, subcutaneous

s, intrathecal, intra-arterial intraperitoneal

,intravesical, continuous iv infusion, bolus iv

infusion, and hepatic artery infusion.

Response to chemotherapy

1. Complete response.

2. Partial response.

3. Response rate.

4. Stable response.

5. Progression or no response

Factors affecting response to

chemotherapy

1. Tumor cell heterogenetiy.

2. Drug resistance

3. Dose intensity

4. Patient specific factors.

Classification of chemotherapeutic

agents

1.

Cytotoxic agents

Alkylating agents, platinums, tumor antibiotics, anti-mitotic agents, anti-metabolites

Hormonal treatment

Anti-Estrogens, GnRH agonists, Androgen receptor blockers

Biologic response modifiers

Interleukin, G-CSF

Targeted agents

Monoclonal antibodies

Tyrosine kinase inhibitors

• Alkylating Agents:

– Nitrogen Mustards: Mechlorethamine, Cyclophosphamide, Ifosfamide, Melphalan Chlorambucil

– Ethylinimines and Methilinimines: Hexamethylamine, Thiotepa

– Alkyl Sulfonates: Busulfan

– Nitrosoureas: Carmustine, Lomustine, Streptozocin

– Triazines: Dacarbazine, Temozolomide

• Antimetabolites:

– Folic acid analogs: Methotrexate

– Pyrimidine analogs: 5-FU, Floxuridine, Cytarabine

– Purine analogs: Mercaptopurine, Thioguanine, Cladribine, Fludarabine

• Anti-Mitotic Agents:– Vinca Alkaloids: Vincristine, Vinblastine, Vinorelbine

– Taxanes: Paclitaxel, Docetaxel

• Topoisomerase-interactive agents:– Topoisomerase I Poison: Camptothecins: Topotecan, Irinotecan

– Topoisomerase II Poison:

• Epipodophyllotoxins: Etoposide, Teniposide

• Anthracyclines: Doxorubicin, Epirubicin, Daunorubicin, Idarubicin (Also classified as tumor antibiotics

• Tumor antibiotics:– Anthracyclines

– Mitomycin

– Bleomycin

– Dactinomycin

• Platinum compounds:– Cisplatin, Carboplatin, Oxaliplatin

• Miscellaneous:– Mitoxantrone

– Hydroxyurea

– Procarbazine

– Mitotane

Phase Non-specific:

Alkylating Agents

Tumor antibiotics

Platinum Compounds

Phase Specific:

Cytarabine, Hydroxyurea (S)

Methotrexate, 6-Mercap

Vinca’s and Taxanes (M)

1-akalyating agent:

The first group of antineoplastic agent

Cause cross linking and abnormal base

pairing of DNA strands which lead to

replication failure.

Examples:

Alteretamine,busulfan,carmustine,chlorabucil,c

isplatin,cyclophosphamide.

2-Antitumor antibiotics

Most of these antibiotics are obtained from

streptomyces genus.

These agents may act by alkalyation or

intercalation .intercalation is the process by

which the drug slides betweenDNA base pairs

and inhibits synthesis

Examples:

Bleomycin, dactinomycin ,daunorubicin ,

mitomycin C,doxorubicin.

Ant metabolites:

Are structural analogs of naturally occurring substrates for biochemical reactions

They inhibit DNA synthesis by acting as false substitutions in the production of nucleic acids .these are s-phase specific agents.

They are three main group:

Folate analogs.(e.g. methotrexate)

Pyrimidine analogs(5-flurouracil)

Purine analog (6-mercaptopurine,pentostatin,fludarabine)

Mitotic inhibitors

The vinca alkloids aresset cell division by

preventing microtubule formation.

The taxanes promote microtubule assembly

and stablization ,thus preventing cell division .

These are M-phase specific.

Examples:

Vinca alkaloids eg vincristine,vinbalstin

Taxanes:pacetaxel,docetaxel.

Topoisomerase inhibitors:

Inhibits the enzymes topoisomerase 1 or2.

The topoisomerases are necessary for DNA

replication and RNA tranacription.

These are G2 phase specific agents.

Examples :

etopside ,topotecan, teniposide.

enzymes

Asparginase is an enzyme that cause the

degradtion of essential amino acid

asparagines to aspartic acid and ammonia

,unlike normal cells tumor cells lack the ability

to synthesize asparagines

These agent are G1 –phase specific agent.

examples :Asparginase and

pegaasparginase.

Protein tyrosine kinase

inhibitors

Imatinib mesylate is aselective tyrosine kinase

inhibitors that causes apoptosis or arrest of

growth in cells expressing the Bcr-Abi

oncoprotein bcr-abi is the product of a specific

chromosomal abnormality(peldilpheia

chromosome)

miscellaneous

1. Tretinoid

2. Arsenic trioxide.

3. Bexarotene

4. Bortezomib

5. thalidomide

hormones

• Steroids

• Aromatase Inhibitors

• Anti-Estrogens

• GnRH analogues

• Anti-Androgens

steroids

• Most commonly used:– Prednisone

– Dexamethasone

• Able to induce remissions in hematologic cancers and responses in solid tumors

• Valuable component in NHL, HL, CLL, ALL

• MOA?- promote apoptosis

• Side effects:– Immunosuppression, glucose intolerance, osteoporosis, water

retention, GI ulcers

Aromatase inhibitors

• Most commonly used:– Letrozole (Femara)

– Anastrozole (Arimidex)

– Exemestane (Aromasin)

• Inhibits aromatase enzyme that converts androgens to estrogens

• Aromatase enzyme in adrenal glands and adipose tissue.

• Indicated for post-menopausal ER/PR+ breast cancer patients in adjuvant, neoadjuvant, and metastatic setting.

• Side effect: Bone mineral density, bone pains, increased fracture rates.

Anti-Estrogens

• Tamoxifen: binds to ER receptors preventing binding to DNA

• Eventually decresaes autocrine stimulation of breast cancer cells.

• Has an agonist effect on endometrial cells and increases thrombotic risk

• breast cancer treatment (adjuvant or metastatic) • Side effect: thrombosis risk, endometrial CA, hot

flashes, nausea, vomiting, menstrual irregularities.

antiandrogen

• Bicalutamide

• Flutamide

• Nilutamide

• Binds to Androgen receptors and causes complete androgen blockade

• Usually given with GnRH analogs

• Side effects: decreased libido, hot flashes, gynecomastia, mastodynia, paradoxical stimulation of androgen receptors

GnRH analogs:

• Prototypes: Goserelin, Leuprolide

• Administered intramuscularly or subcutaneously

• Initially stimulate FSH and LH production by the pituitary, then later cause negative feedback inhibition.

• Estrogen levels fall to post-menopausal values

• Androgen levels fall to castrate values.

• Used in breast cancer and prostate cancer

• Can have initial ‘flare’ reaction which can be controlled by concomitant anti-androgens or anti-estrogens

Biological cell response

1. Cytokines

2. Monoclonal antibodies

Target extracellular receptors or

Ligands

1. Immunotoxins

• Interleukin-2:– Not directly cytotoxic

– Expands a T-cell response that is cytolytic for tumor cells

– Uses: Melanoma, Renal cell carcinoma, AML

Bone Marrow Suppression Neutropenia – Low WBC G-CSF (filgrastim) & GM-CSF (sargramostim)

Thrombocytopenia – Low platelete count Oprelvekin (Neumega)

Anemia – Low RBC Erythropoetin

Digestive Tract Problems Stomatitis – inflammation of oral mucosa Diarrhea – impaired nutrient absorption

Nausea & Vomiting (N/V) Occurs 17 – 98% (Psych factors) Ondansetron (Zofran) and others (handout

Other

Alopecia – hair loss

Reproductive – sterility in males

Hyperuricemia – increased urination (DNA)

Extravasation of vesicants

Drug-specific (hepatic, coronary, etc)

Carcinogenesis – some patients sensitive