PRINCIPLES OF CHEMOTHERAPY

Dr. R. RAJKUMAR M.D; D.M.Dr. R. RAJKUMAR M.D; D.M.ASSISTANT PROF.& CONSULTANT MEDICAL ASSISTANT PROF.& CONSULTANT MEDICAL

ONCOLOGISTONCOLOGIST

ETIOLOGY OF CANCER CarcinogenesisCarcinogenesis

A cancer, is thought to develop A cancer, is thought to develop from a cell in which the normal from a cell in which the normal mechanisms for control of growth mechanisms for control of growth and proliferation are altered. and proliferation are altered.

Current evidence supports the Current evidence supports the concept of carcinogenesis as a concept of carcinogenesis as a multistage process that is multistage process that is genetically regulatedgenetically regulated

ETIOLOGY OF CANCERGenetic and Molecular Basis of CancerGenetic and Molecular Basis of Cancer

Two major classes of genes are involved in Two major classes of genes are involved in carcinogenesis: oncogenes and tumor carcinogenesis: oncogenes and tumor suppressor genessuppressor genes

InvasivityMotility

Aneuploidy

AngiogenesisImune Defense

Evasion

DeregulatedProliferation

Altered EnergyMetabolism

Immortalization(Anti-Apoptosis)

Hallmarks Hallmarks oof Cancerf Cancer Target Areas for Therapeutic InterventionsTarget Areas for Therapeutic Interventions

MODALITIES OF TREATMENT

1-local therapy:1-local therapy: -surgery.-surgery. -radiation therapy.-radiation therapy.

2-systemic treatment:2-systemic treatment: chemotherapy.chemotherapy. Hormonal therapyHormonal therapy.. Monoclonal antibodies.Monoclonal antibodies. Radioactive material.Radioactive material.

3-supportive care.3-supportive care. 4-non-conventional therapy4-non-conventional therapy..

SURGERY

Surgery was the first modality used Surgery was the first modality used successfully in the treatment of cancer.successfully in the treatment of cancer.

It is the only curative therapy for some It is the only curative therapy for some common solid tumors.common solid tumors.

The most important determinant of a The most important determinant of a successful surgical therapy are the successful surgical therapy are the absence of distant metastases and no absence of distant metastases and no local infiltrationlocal infiltration..

Cont: Microscopic invasion of surrounding Microscopic invasion of surrounding

normal tissue will necessitate multiple normal tissue will necessitate multiple frozen section.frozen section.

Resection or sampling of regional lymph Resection or sampling of regional lymph node is usually indicated.node is usually indicated.

Surgery may be used for palliation in Surgery may be used for palliation in patients for whom cure is not possible.patients for whom cure is not possible.

Has significant role in cancer preventionHas significant role in cancer prevention.. E.gE.g familial polyposis coli.familial polyposis coli.

RADIATION THERAPY

RADIATION THERAPY

Radiation therapy: is a local modality Radiation therapy: is a local modality used in the treatment of cancer .used in the treatment of cancer .

Success depend in the difference in the Success depend in the difference in the sensitivity between the tumor and sensitivity between the tumor and normal tissue.normal tissue.

It involves the administration of ionizing It involves the administration of ionizing radiation in the form of x-ray or gamma radiation in the form of x-ray or gamma rays to the tumor site.rays to the tumor site.

Method of delivery: External Method of delivery: External beam(teletherapy). Internal beam beam(teletherapy). Internal beam therapy(Brachytherapytherapy(Brachytherapy). ).

Cont: Radiation therapy is planned and Radiation therapy is planned and

performed by a team of nurses, performed by a team of nurses, dosimetrists,physician and radiation dosimetrists,physician and radiation oncologist.oncologist.

A course of radiation therapy is preceded A course of radiation therapy is preceded by a simulation session in which low-by a simulation session in which low-energy beam are used to produce energy beam are used to produce radiograghic images that indicate the radiograghic images that indicate the exact beam locationexact beam location. .

Cont: Radiation therapy is usually delivered in Radiation therapy is usually delivered in

fractionated doses such as 180 to 300 fractionated doses such as 180 to 300 cGy per day,five times a week for a total cGy per day,five times a week for a total course of 5-8 weeks. course of 5-8 weeks.

Radiation therapy with curative intent is Radiation therapy with curative intent is the main treatment in limited stage the main treatment in limited stage Hodgkin’s disease , some NHL, limited Hodgkin’s disease , some NHL, limited stage CA prostate, gynecologic tumors & stage CA prostate, gynecologic tumors & CNS tumor CNS tumor ..

Also can be used in palliative & Also can be used in palliative & emergency setting.emergency setting.

COMPLICATION OF RADIATION

There are two types of toxicities - acute and long There are two types of toxicities - acute and long term toxicity.term toxicity.

Systemic symptoms such as Fatigue , local skin Systemic symptoms such as Fatigue , local skin reaction , GI toxicity , oropharyngeal mucositis , reaction , GI toxicity , oropharyngeal mucositis , xerostomia & myelosuppression.xerostomia & myelosuppression.

Long-term sequelae: may occur many months or Long-term sequelae: may occur many months or years after radiation therapy.years after radiation therapy.

Radiation therapy is known to be mutagenic, Radiation therapy is known to be mutagenic, carcinogenic ,and teratogenic ,and having carcinogenic ,and teratogenic ,and having increased risk of developing both secondary increased risk of developing both secondary leukemia and solid tumorleukemia and solid tumor..

NUCLEAR MEDICINE

RADIONUCLIDES For decades have been used systemically For decades have been used systemically

to treat malignant disorders.to treat malignant disorders. They are administer by specialists in They are administer by specialists in

nuclear medicine or radiation oncologist.nuclear medicine or radiation oncologist. Radioactive iodine in the from of Radioactive iodine in the from of 131131I is I is

effective therapy for well differentiated effective therapy for well differentiated thyroid ca thyroid ca

Strontium-89. Is used for the treatment of Strontium-89. Is used for the treatment of bony metastasis .It is an alkaline earth bony metastasis .It is an alkaline earth element in the same family as calcium element in the same family as calcium

CHEMOTHERAPY

Paul Ehrlich 1854 - 1915

• Father of Chemotherapy

• Salvarsan for Treatment of Syphilis

• Nobel Prize 1908

• “Magic Bullet Concept”

HISTORICAL PERSPECTIVE

Nitrogen mustards were a product of the Nitrogen mustards were a product of the secret war gas programs in both world secret war gas programs in both world warswars

In WWII, an explosion at Bar Harbor In WWII, an explosion at Bar Harbor exposed seamen to mustard gas - they exposed seamen to mustard gas - they developed severe marrow and lymphoid developed severe marrow and lymphoid hypoplasiahypoplasia

Led to the use Led to the use of these of these agents to treat agents to treat Hodgkins and non-Hodgkins lymphomas Hodgkins and non-Hodgkins lymphomas at Yale in 1943at Yale in 1943

HISTORICAL PERSPECTIVE

In the 1950’s, folic acid was shown In the 1950’s, folic acid was shown to accelerate the progression of to accelerate the progression of childhood leukemias; led to childhood leukemias; led to development of folic acid development of folic acid antagonistsantagonists

In the 1960’s, combination In the 1960’s, combination chemotherapy for childhood chemotherapy for childhood leukemias and Hodgkins lymphoma leukemias and Hodgkins lymphoma began to be usedbegan to be used

CHEMOTHERAPY

Systemic chemotherapy is the main Systemic chemotherapy is the main treatment available for disseminated treatment available for disseminated malignant diseases.malignant diseases.

Progress in chemotherapy resulted in Progress in chemotherapy resulted in cure for several tumors.cure for several tumors.

Chemotherapy usually require multiple Chemotherapy usually require multiple cycles.cycles.

MODES OF CHEMOTHERAPY PRIMARY CHEMOTHERAPY PRIMARY CHEMOTHERAPY - chemotherapy is - chemotherapy is

used as the sole anti-cancer treatment in a used as the sole anti-cancer treatment in a highly sensitive tumor typeshighly sensitive tumor types Example – CHOP for Non-Hodgkins lymphomaExample – CHOP for Non-Hodgkins lymphoma

ADJUVANT CHEMOTHERAPY ADJUVANT CHEMOTHERAPY – treatment is given – treatment is given after surgery to “mop up” microscopic residual after surgery to “mop up” microscopic residual diseasedisease Example – Adriamycin, cyclophosphamide for Example – Adriamycin, cyclophosphamide for

breast cancerbreast cancer NEOADJUVANT CHEMOTHERAPYNEOADJUVANT CHEMOTHERAPY – treatment is – treatment is

given before surgery to shrink tumor and given before surgery to shrink tumor and increase chance of successful resectionincrease chance of successful resection Example – Adriamycin, ifosfamide for Example – Adriamycin, ifosfamide for

osteosarcomaosteosarcoma

MODES OF CHEMOTHERAPY

CONCURRENT CHEMOTHERAPY CONCURRENT CHEMOTHERAPY – – treatment is given simultaneous to treatment is given simultaneous to radiation to increase sensitivity of cancer radiation to increase sensitivity of cancer cells to radiationcells to radiation Example – Cisplatin, 5-fluourouracil, Example – Cisplatin, 5-fluourouracil,

XRT for head and neck tumorsXRT for head and neck tumors

There is a wide variation in sensitivity of various cancers to chemotherapy

HighHigh IntermediateIntermediate LowLow

LymphomaLymphoma BreastBreast Head and neckHead and neck

LeukemiaLeukemia ColonColon ProstateProstate

Small Cell Lung Small Cell Lung cancercancer

Non-small cell lung Non-small cell lung cancercancer

GastricGastric

Testicular cancerTesticular cancer PancreaticPancreatic

CANCER CHEMOTHERAPY: PRINCIPLES

1. The “Silver Bullet” isn’t out there1. The “Silver Bullet” isn’t out there..

2. 2. Conventional chemotherapy targets Conventional chemotherapy targets have been the cell cycle, microtubules have been the cell cycle, microtubules and DNAand DNA

3. Combination chemotherapy improves 3. Combination chemotherapy improves responses over single agent, but dose responses over single agent, but dose intensity must be maintained.intensity must be maintained.

CANCER CHEMOTHERAPY: PRINCIPLES

44. . It is better to treat It is better to treat micrometastatic diseasemicrometastatic disease

5. Phase I trials define an MTD --a 5. Phase I trials define an MTD --a Maximum Tolerated Dose - this Maximum Tolerated Dose - this may not equate to the may not equate to the Maximum TherapeuticMaximum Therapeutic

CANCER CHEMOTHERAPY: PRINCIPLES

6.6. For classical chemotherapy to be For classical chemotherapy to be effective, cell proliferation is effective, cell proliferation is required. Indolent (slowly growing) required. Indolent (slowly growing) cancers are typically resistant. If cancers are typically resistant. If therapy is ineffective, tumor therapy is ineffective, tumor indolence determines survival.indolence determines survival.

7.Almost 7.Almost all who die with cancer have all who die with cancer have been treated with chemotherapy been treated with chemotherapy -- -- thus drug resistance is a major cause thus drug resistance is a major cause of death. Drug resistance can stem of death. Drug resistance can stem from host, tumor and cellular factors.from host, tumor and cellular factors.

GOMPERTZIAN GROWTH Growth rates are exponential at Growth rates are exponential at

early stages early stages of development andof development and slowerslower at later stages of at later stages of developmentdevelopment

Biological growth follows this characteristic curve.Biological growth follows this characteristic curve.

GOMPERTZIAN GROWTH MODEL

Initial tumour growth is first order, with later growth being much slower

Smaller tumour grows slowly but large % of cell dividing

Medium size tumour grows more quickly but with smaller growth fraction

Large tumour has small growth rate and growth fraction

AIM OF COMBINATION CHEMOTHERAPYAIM OF COMBINATION CHEMOTHERAPY

INCREASED EFFICACYINCREASED EFFICACY

Different mechanisms of action Compatible side effects

Different mechanisms of resistance

ACTIVITYACTIVITY SAFETYSAFETY

PRINCIPLES OF CHEMOTHERAPY

Rationale for combination Rationale for combination chemotherapychemotherapy

Different drugs exert their effect Different drugs exert their effect through different mechanisms and through different mechanisms and at different stages of the cell cycle, at different stages of the cell cycle, thus maximize cell killthus maximize cell kill

Decease the chance of drug Decease the chance of drug resistanceresistance

Combination chemotherapy:Metastatic Breast Cancer

Agents Dose Intensity PR (%)* CR (%)*

Cyclophosphamide 1 1 35 0

Methotrexate 1 1 25 0

Fluorouracil 1 1 25 0

Doxorubicin (A) 1 1 50 5

CMF 0.5+0.33+0.33 1.17 50 5

CAF 0.5+0.7+0.33 1.53 75 10

* Patients with overt metastases and no prior chemotherapy except in the

adjuvant setting

PR = partial response

CR = complete response

(“Cancer Medicine”, Holland and Frey (eds.), 5th Ed., 2002)

CANCER CHEMOTHERAPY: PRINCIPLES More is better, to a point!

ABVD

FFP: 81%

MOPP/ABV

FFP: 67%

ABVD

FFP: 65%

MOPP

FFP: 63%

SINGLE

AGENT

FFP: 20%

Advanced Hodgkin’s Disease

Careful Sequencing is CriticalDocetaxel Doxorubicin

Doc Dox

40 mg/m2 50 mg/m2

Dox Doc

50 mg/m2 70 mg/m2

Itoh et al. Study of Sequence Switching of AdministrationClin. Cancer Res 6:4082-4090, 2000

CANCER CHEMOTHERAPY: Adjuvant Chemotherapy Improves SurvivalOsteosarcoma: Sarcoma of the bone

1970’s: Surgery if no evidence of metastatic disease

One-half developed metastatic disease, Usually within 6 mos of surgery

20% 5 year survival.

Thus:80% had micrometastatic disease.

With adjuvant chemotherapy:

60-70% long-term survival

CANCER CHEMOTHERAPY: adjuvant chemotherapy improves survival

Breast Cancer C CMF ∆ Odds

1970’s: 3 yr RFS 1 -3 Nodes+ 64% 78% 39%

>3 Nodes+ 44% 49% 9%

CAF vs. CMF: 2% - 12% improvement reported

Widely adopted: Adriamycin + Cytoxan

Increasingly, followed by Taxol

Interphase Prophase Metaphase

Anaphase Interphase Cytokinesis

STAGES OF MITOSIS:

Cancer Chemotherapy After completion of mitosis, the resulting daughter After completion of mitosis, the resulting daughter

cells have two options: cells have two options: (1) they can either enter G1 & repeat the cycle or (1) they can either enter G1 & repeat the cycle or (2) they can go into G0 and not participate in the cell (2) they can go into G0 and not participate in the cell

cycle.cycle. Growth fraction - at any particular time some cells Growth fraction - at any particular time some cells

are going through the cell cycle whereas other cells are going through the cell cycle whereas other cells are resting. are resting.

The ratio of proliferating cells to cells in G0, is The ratio of proliferating cells to cells in G0, is called the growth fraction. called the growth fraction.

A tissue with a A tissue with a large percentage of proliferating large percentage of proliferating cellscells & few cells in & few cells in G0G0 has a has a high growth fraction. high growth fraction.

Conversely, a tissue composed of Conversely, a tissue composed of mostly of cells in mostly of cells in G0G0 has a has a low growth fractionlow growth fraction..

MECHANISMS OF CHEMOTHERAPY

Damage the DNADamage the DNA of the affected cancer cells. of the affected cancer cells. It is not always possible to be selective, but selectivity is It is not always possible to be selective, but selectivity is the ultimate goal of any drug. the ultimate goal of any drug. e.g.e.g., cisplatin (Platinol®), , cisplatin (Platinol®), daunorubicin (Cerubidine®), doxorubicin daunorubicin (Cerubidine®), doxorubicin (Adriamycin®), and etoposide (VePesid®). (Adriamycin®), and etoposide (VePesid®).

Inhibit the synthesis of new DNAInhibit the synthesis of new DNA strands to strands to stop the cell from replicating, because the replication of stop the cell from replicating, because the replication of the cell is what allows the tumor to grow. the cell is what allows the tumor to grow. e.ge.g.., , methotrexate (Abitrexate®), mercaptopurine methotrexate (Abitrexate®), mercaptopurine (Purinethol®), fluorouracil (Adrucil®), and hydroxyurea (Purinethol®), fluorouracil (Adrucil®), and hydroxyurea (Hydrea®). (Hydrea®).

Stop the mitotic processesStop the mitotic processes of a cell. of a cell. Stopping mitosis stops cell division (replication) of the Stopping mitosis stops cell division (replication) of the cancer and may ultimately halt the progression of the cancer and may ultimately halt the progression of the cancer. cancer. e.g.e.g., Vinblastine (Velban®), Vincristine , Vinblastine (Velban®), Vincristine (Oncovin®) (Oncovin®) and Pacitaxel (Taxol®).and Pacitaxel (Taxol®).

CLASSIFICATION OF CYTOTOXIC DRUG Cytotoxic agent can be roughly Cytotoxic agent can be roughly

categorized based on their activity categorized based on their activity in relation to the cell cycle.in relation to the cell cycle.

phase nonspecific. phase specific

cyto toxic drug

Cont : What is the difference between phase What is the difference between phase

specific & phase non specific?…..specific & phase non specific?….. Phase non-specific: Phase non-specific:

The drugs generally have a linear dose-The drugs generally have a linear dose-response curve(response curve( the drug the drug administration ,the administration ,the the fraction of cell the fraction of cell killed).killed).

Phase specific:Phase specific: Above a certain dosage level,further Above a certain dosage level,further

increase in drug doesn’t result in more increase in drug doesn’t result in more cell killing.but you can play with cell killing.but you can play with duration of infusion. duration of infusion.

Two Broad Classes of Chemotherapy Drugs: Cytotoxic agentsCytotoxic agents

Cisplatin – causes DNA damageCisplatin – causes DNA damage 5-Fluourouracil – blocks enzymes necessary 5-Fluourouracil – blocks enzymes necessary

for RNA and DNA synthesisfor RNA and DNA synthesis Docetaxel – inhibits microtubule formationDocetaxel – inhibits microtubule formation

Targeted therapiesTargeted therapies Erlotinib – small molecule inhibitor the EGFR Erlotinib – small molecule inhibitor the EGFR

tyrosine kinasetyrosine kinase Cetuximab – antibody that binds to EGFRCetuximab – antibody that binds to EGFR

CHEMOTHERAPEUTIC AGENTS Alkylating agents:Alkylating agents: Antimetabolites:Antimetabolites: Antitumor antibiotic:Antitumor antibiotic: Plant alkaloidsPlant alkaloids:: Other agentsOther agents Hormonal agent:Hormonal agent: Immunotherapy: Immunotherapy:

Chemotherapy – routes of administration oral oral

intravenousintravenous

intramuscularintramuscular

intrathecalintrathecal

intraperitonealintraperitoneal

intrapleuralintrapleural

► isolated organ isolated organ

perfusionperfusion

► intrapericardialintrapericardial portal veinportal vein

LimbLimb

intraarterialintraarterial

PLANNING DRUG DOSES AND SCHEDULES Doses Doses - based on body surface area- based on body surface area

- differ between children and adults- differ between children and adults

- adjusted for people who are elderly, have poor- adjusted for people who are elderly, have poor

nutritional status, have already taken or taking nutritional status, have already taken or taking other medications, have already received or other medications, have already received or are currently receiving radiation therapy, have low are currently receiving radiation therapy, have low blood cell counts, or have liver or kidney diseasesblood cell counts, or have liver or kidney diseases

PLANNING DRUG DOSES AND SCHEDULES

Schedule (Cycles)Schedule (Cycles)

- A cycle = one dose followed by several - A cycle = one dose followed by several days or weeks without treatment for normal days or weeks without treatment for normal tissues to recover from the drug’s side effectstissues to recover from the drug’s side effects

The number of cycles = based on the type and The number of cycles = based on the type and stage of cancer, and side effectsstage of cancer, and side effects

HEMATOLOGICAL CONSIDERATIONS FOR DOSE SCHEDULING LifespanLifespan

Platelet - 7-10 daysPlatelet - 7-10 days Red blood cell - 120 daysRed blood cell - 120 days Neutrophils - 6-12 hoursNeutrophils - 6-12 hours

Time from Stem Cell to Mature NeutrophilTime from Stem Cell to Mature Neutrophil ~7-10 days~7-10 days

DECIDING ON TREATMENT INTERVALS

As short as possibleAs short as possible

Recovery of bone marrowRecovery of bone marrow

Supplies mature cells for 8-10 days Supplies mature cells for 8-10 days

Onset 9-10th daysOnset 9-10th days

Lowest (nadir) 14-18Lowest (nadir) 14-18thth days days

Recovery by day 21-28.Recovery by day 21-28. Usual schedule is q21-28 days.Usual schedule is q21-28 days.

COMPLICATION OF CHEMOTHERAPY

Every chemotherapeutic will have some Every chemotherapeutic will have some deleterious side effect on normal tissue .deleterious side effect on normal tissue .

E.G; Myelosuppression,nausea&vomiting,E.G; Myelosuppression,nausea&vomiting,

Stomatitis,and alopecia are the most Stomatitis,and alopecia are the most frequently observed side effects.frequently observed side effects.

MucositisMucositis

Nausea/vomitingNausea/vomiting

DiarrheaDiarrhea

CystitisCystitis

SterilitySterility

MyalgiaMyalgia

NeuropathyNeuropathy

Alopecia

Pulmonary fibrosis

Cardiotoxicity

Local reaction

Renal failure

Myelosuppression

Phlebitis

SIDE EFFECTS OF CHEMOTHERAPYSIDE EFFECTS OF CHEMOTHERAPY

CRITERIA USED TO DESCRIBE RESPONSE ARE: Complete response (complete remission)is the (complete remission)is the

disappearance of all detectable malignant disappearance of all detectable malignant disease.disease.

Partial response : is decrease by more than 50% : is decrease by more than 50% in the sum of the products of the perpendicular in the sum of the products of the perpendicular diameters of all measurable lesions.diameters of all measurable lesions.

Stable disease : no increase in size of any lesion : no increase in size of any lesion nor the appearance of any new lesionsnor the appearance of any new lesions..

Progressive disease : means an increase by at : means an increase by at least 25% in the sum of the products of the least 25% in the sum of the products of the perpendicular diameters of measurable lesion or perpendicular diameters of measurable lesion or the appearance of new the appearance of new lesions.lesions.

Methods to increase the efficacy of chemotherapy standard dosingstandard dosing

high dosehigh dose

dose-densedose-dense

ENDOCRINE THERAPY

ENDOCRINE THERAPY

Many hormonal antitumor agents are functional agonist or Many hormonal antitumor agents are functional agonist or antagonist of the steroid hormone family.antagonist of the steroid hormone family.

Adrenocorticoids:Adrenocorticoids: Antiandrogen:Antiandrogen: Estrogen:Estrogen: Antiestrogen:Antiestrogen: ProgestinsProgestins Aromatase inhibitor:Aromatase inhibitor: Gonadotropin-releasing hormone agonists:Gonadotropin-releasing hormone agonists: Somatostatin analogues: Somatostatin analogues:

ADRENOCORTICOSTEROID

Are frequently used in combination regimen for Are frequently used in combination regimen for the treatment of lymphocytic leukemia and the treatment of lymphocytic leukemia and lymphoma.lymphoma.

They function by binding to glucocorticoid-They function by binding to glucocorticoid-specific receptors present in lymphoid cells and specific receptors present in lymphoid cells and initiate programmed cell deathinitiate programmed cell death

They most commonly used agent are They most commonly used agent are prednisone,methylprednisone,dexamethosone. prednisone,methylprednisone,dexamethosone.

ANTIANDROGENS

Flutamide :Flutamide :

Effectively blocks the binding of androgen to Effectively blocks the binding of androgen to its receptor in the periphral tissue .its receptor in the periphral tissue .

It is used in the treatment of disseminated It is used in the treatment of disseminated prostate caprostate ca

BIOLOGIC THERAPY

Immunotherapy:Immunotherapy: CytokinesCytokines Cellular therapy.Cellular therapy. Tumor vaccine:Tumor vaccine:

Hematopoietic growth factors. Hematopoietic growth factors.

DefinitionNew technology and drugs that allow the cancer treatment to “target” a certain cancer cell by interfering with the natural functions of tumor growth

How they workThey “target” specific parts of a cancer cell or its actions; hand in a glove analogy

What it means in cancer treatment Potentially fewer side effects

“TARGETED” THERAPIES

Targeted Therapies

SIGNALLING PATHWAYS

TARGETED THERAPIES Monoclonal antibodiesMonoclonal antibodies: proteins that trigger the : proteins that trigger the

body’s pathways involved in cancer growth to body’s pathways involved in cancer growth to fight cancer more effectively. fight cancer more effectively.

EGFREGFR: family of receptors found on surface of : family of receptors found on surface of normal and cancer cells that bind with an normal and cancer cells that bind with an epidermal growth factor (EGF) causing cells to epidermal growth factor (EGF) causing cells to divide.divide.

Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitors: Part of the cell that : Part of the cell that signals it to divide and multiply; enhances cell signals it to divide and multiply; enhances cell growth. Still investigationalgrowth. Still investigational

TK TKATP ATP

Cell Cell ProliferationProliferation

AntiapoptosiAntiapoptosiss

AngiogenesisAngiogenesis

Gene Transcription

Cell Cycle Progression

+

MetastasesMetastasesSurvivalSurvival

Tumor Cell StimulationTumor Cell Stimulation

TK TK TK

Strategies to Inhibit Signaling

---- --

tyrosine tyrosine kinase kinase

inhibitorsinhibitors

““-ibs”-ibs”

Anti- mAbsAnti- mAbs

““-mab”-mab”

Anti-ligand Anti-ligand mAbsmAbs

““-mab”-mab”

ATP

CONCLUSIONS People with cancer are living longerPeople with cancer are living longer The focus is on quality of life in addition to The focus is on quality of life in addition to

quantityquantity People surviving cancer want to live normal livesPeople surviving cancer want to live normal lives New treatments of various kinds are available and New treatments of various kinds are available and

there is no need to sufferthere is no need to suffer