Principles of Chemotherapy

and Chemotherapy

Complications

Özlem Sönmez, MDYeditepe University HospitalSection of Medical Oncology

Malignant cells

Malignant Transformation

• Fundamental lesion:– Changes in DNA-> Alterations in proteins->

Cellular transformation

• >1 genetic defect: almost certainly required

• Accumulation of changesMalignant transformation

50.2 Rang

Malignant transformation

Biological basis of cancer chemotherapeutics

• Anticancer drugs interfere cellular processes that are altered in malignancy.

• Antineoplastic effects– Cell death– Cell growth inhibited– Cell differentiation

• Cancer treatment usually involves one or more of surgery, radiotherapy and systemic therapy.

• In early-stage disease, low-risk patients are often cured with surgery alone, but in many other cases a combination of treatments is required.

• In metastatic disease, systemic therapy is the principal therapeutic modality, as delivery through the blood stream facilitates access to disseminated cancer sites.

• Systemic therapies include hormonal therapy, targeted therapy, and chemotherapy.

Population kinetics• Tumor size: Size of proliferating pool of cells + # of cells dying

spontaneously,

• Growth rate (doubling time): rapid during early and exponential stages of growth

• Growth fraction: The ratio of proliferating cells to cells in G0

– High % of proliferating cells & few cells in G0 high growth fraction

– Mostly of cells in G0 ->Low groth fraction

• When tm is small-> growth fraction is high

• When tm gets larger ->growth fraction is low (restriction of space, nutrients, blood supply)

• Larger the tumor mass, greater the % of nondividing, dying cells and longer it takes for average cell to divide (prolonged doubling time).

• Tumors with greater growth fraction, benefit more from chemotherapy

Chemotherapy response

• Solid tumors – Generally have a low growth fraction thus

respond poorly to chemotherapy – In most cases need to be removed by surgery

• Hematological tumors– Generally have a high growth fraction &

generally respond well to chemotherapy

Population kinetics

• 1x109 cells = 1 gr (1 cm)

• 1 cell to 109 cells: 30 doubling times

• Doubling time: 24 hours to years

• 1012-1013 cells: Damage to vital organs, death

Gompertzian Growth

Chemotherapy kineticsLog kill hypothesis

• Chemotherapy: kills fixed proportion of cells, not fixed number of cells. This is independent of tumor mass (2-5 log)

• Repeated cycles of chemotherapy are neeeded for tumor eradication.

• Dose administered within a certain period (mg/m2/week) determines success (not total dose).

Targets of Anticancer Drugs

Targets of Anticancer Drugs

• All drugs have a target.

• Traditional drug targets– DNA

• Nucleotide bases• Enzymes of DNA synthesis• Degradation• Repair

– Microtubules– GF receptors

• Steroid hormone receptors

New targets• GFs (VEGF)

• Mutated or overexpressed oncogene products– EGFR– Her-2/neu (c-erb-B2)– Bcr:abl– cKit– bRaf

• Cell surface antigens– CD33, CD22, CD20, CD30, IL2-R

• The machinery of protein synthesis (L-asparaginase)

• Protein degradation (ubiquitin proteasomal degradation)

Targets

• Drugs that affect these newer targets: “Targetted therapy”

• Classic chemotherapeutics : Also have targets

Targets in Cancer Treatment

Classic chemotherapeutics

Drugs that alter nucleic acid synthesis and function

• DNA synthesis• DNA replication• Transcription Inhibitors• DNA methylation• Topoisomerases• Microtubules• Protein Synthesis• Protein degradation

Classification of classic cytotoxic agents

Alkylating Anti- metabolite

Mitotic spindle inhi.

Antitumor antibiotics

Topoisomerase

inhibitors

Other

Alkylates DNA nucleotides prevent replication &RNA transcription

Inhibit purine &pyrimidine synthesis

Affect structure of microtubule-> prevent cell division

Intercalation with DNA (inserts itself bet. DNA base pairs),Topoisomerase II inhi.

Topoisomerase I or II inhibition

Busulfan

Carmustine

Chlorambusil

Cisplatin

Carboplatin

Cyclophosphamide

Melphalan

Ifosfamide

Procarbazine

Dacarbazine

CCNU, BCNU

Antifolate

Metotrexate

Pyrimidine

Ara-C, 5-FU,

Gemsitabine

Floksuridine

Purine

6-MP

6-TG

Pentostatin

Cladribine

Vinca alkoloid

Vinblastine

Vincristine

Vindesine

Taxane

Docetaxel

Paclitaxel

Bleomycin

D-actinomicin

Mitomisin-C

Plikamicin

Mitoxantrone

Antracyclin

Daonurubicin

Doxorubicin

Epirubicin

Idarubicin

Podophyllotoxin

(Topoiso. II)

Etoposide

Teniposide

Camptotecin

(Topoiso.I)

Topotecan

Irinotecan

L-asparaginase

Hydroxyurea

Mitotane

Alkylating agents

• Nitrogen mustards– Mechloroethamine– Cyclophosphamide– Ifosfamide– Chlorambucil– Melphalan

• Alkylsulfonates– Busulfan

• Nitrosoureas– Carmustine (BCNU)– Lomustine (CCNU)– Streptozocin– Semustine

• Triazenes– Dacarbazine (DTIC)– Temozolamide

• Hydrazines– Procarbazine

• Platinum– Cisplatin– Carboplatin– Oxaliplatin

Alkylating agentsMechanism of action

• Transfer alkyl groups to DNA

• Alkylates nucleophilic groups on DNA bases, particularly at the N-7 position of guanine

Consequences of alkylation1. Cross-linkage: Interstand and intrastrand cross-linkages

2. Mispairing of bases:Alkylation of N7 of guanine base pairing with thymidine, instead of

cytosine Gene miscoding AT base pairs replacing GC base pairs Defective proteins

3. DNA strand breaksN7 alkylation –> Cleavage of imidazole ring excision of guanine residue

Inhibition of DNA replication and

transcription

Cyclophosphamide

Toxic to bladder Antitumor activity

Ifosfamide

• Analogue of cyclophosphamide• Metabolic activation to forn 4-hydroxyifosfamide• More toxic to bladder Hemorrhagic cystitis

Side effectsIfosfamide-Cyclophosphamide

• Side effect: – Hemorrhagic cystitis

• Prevention:– Hydration– Mesna Detoxification

Side effectsPlatinums (cisplatin, carboplatin,

oxaliplatin)Cisplatin• Renal insufficiency

– Prevention• Hydration: If adequate->5%, if inadequate-> 25-45%• Forced diuresis: Mannitol• Avoid nephrotoxic agents

• Ototoxicity: Tinnitus, hearing loss• Constipation• Periferal sensorial neuropathy• Severe nausea and vomiting

Side effectsPlatinums (cisplatin, carboplatin,

oxaliplatin)Oxaliplatin• Acute dysesthesia (hands, foot, peroral, throat)

– During administration –upto 2 days– Can be induced or augmented by cold– Resolves in 2 weeks – Prevention: Prolong administration period (6 hours)

• Periferal sensorial neuropathy– Cumulative toxicity– Usually reversible (within 1 year)

Nitrosoureas

• Carmustine (BCNU)

• Lomustine (CCNU)

• Highly lipid soluble Cross BBB

Antimetabolites

Folic Acid Analogs Purine (A, G) Analogs Pyrimidine (C, T,U) Analogs

Methotrexate Mercaptoguanine Fluorouracil

ThioguanineFludarabineCladribinePentostatin

TrimetrexatePemetrexed

Cytarabine GemcitabineCapecitabine

Antimetabolites

• They are structurally similar to endogenous compounds• Compete with natural metabolites blocking one or more of the

metabolic pathways involved in DNA synthesis.

• Mostly active in S phase

• They act as antagonists of:– Folic acid (methotrexate)– Purines (Mercaptopurine and thioguanine)– Pyrimidine (fluorouracil, cytarabine)

Purines and pyrimidines

Purines Pyrimidines

C, T: DNA

C, U: RNA

Antimetabolites: sites of drug action

Methotrexate (MTX)• Folic acid analog • Binds with high affinity to the active

catalytic site of dihydrofolate reductase (DHFR)

• Thus it interferes with the synthesis of tetrahydrofolate (THF)

• THF serves as the key one-carbon carrier for enzymatic processes involved in de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine.

• Result: Interferes with the formation of DNA, RNA, and key cellular proteins

Methotrexate side effects

• Bone marrow suppression • Mucositis• Folic acid deficiency

• The toxic effects of MTX on normal cells is reduced by administering folinic acid (leucovorin)– This is called leucovorin rescue– Higher the dose of MTX: more the

leucovorin you give

Side effects: Methotrexate

• Prevention: – Hydration– Alkalinization of urine– Leukovorin rescue: 24 hours after treatment (calcium

folinate)

6-Mercaptopurine (6-MP) & Thioguanine

• Inhibit several enzymes involved in purine metabolism

6-MP & Allopurinol

• 6-MP: metabolized in the liver by xanthine oxidase and the inactive metabolites are excreted in the urine

• Allopurinol (Ürikoliz)– Xanthine oxidase inhibitor – used to treat/prevent hyperuricemia

• Do not use 6-MP and allopurinol in combination.– If Allopurinol have to be used with 6-MP, then the

dose of 6-MP is reduced by more than 75%

Cytarabine (Ara-C)

• Cytarabine arabinoside is a pyrimidine antimetabolite

• Inhibits conversion of cytidine to deoxycytidine

• The drug is activated by kinases to AraCTP– This acts as an inhibitor of

DNA polymerase

• Side effect: At high doses cause neurotoxicity (cerebellar dysfunction and peripheral neuritis)– Hand-foot syndrome

5-FU• 5-FU is converted to 5-FdUMP, which

competes with deoxyuridine monophosphate (dUMP) for the enzyme thymidylate synthetase

• 5-FU causes, “thymidineless death” of cells• Imbalance DNA and RNA synthesis

• Side effects: Mucositis, diarrhea, hand and foot syndrome, hyperpigmentation

• Activity increased if given with folinic acid.

5-FU = 5-fluorouracil5-FUR = 5-fluorouridine5-FUMP = 5-fluorouridine monophosphate5-FUDP = 5-fluorouridine diphosphate5-FUTP = 5-fluorouridine triphosphatedUMP = deoxyuridine monophosphatedTMP = deoxythymidine monophosphate5-FdUMP = 5-fluorodeoxyuridine monophosphate.

Topoisomerase inhibitors

• These drugs are most active in late S and early G2 phase

• Epipodophyllotoxins: Inhibit topoisomerase II– Etoposide– Teniposide

• Camptothecins: Inhibit topoisomerase I– Irinotecan– Topotecan

Topoisomerase inhibitors

Irinotekan (Campto)

• Diarrhea :2 mechanisms

– Early (first 24 hour)• Cause: Cholinergic response (concomitant symptoms: tearing, abdominal

crampsterleme)• Treatment/prevention: Atropine

– Late (>24 hour): life-threatening• Cause: Secretory, toxic effect to mucosa • Treatment: High dose loperamide

Mitotic spindle inhibitors

• Primarily on the M phase of cancer cell cycle

• Vinca alkaloids– Vinblastine– Vincristine– Vinorelbine

• Taxanes– Paclitaxel– Docetaxel

Vinka alkaloids (Vinblastine, vincristine)

• Block the formation of mitotic spindle by preventing the assembly of tubulin dimers into microtubules

• Side effects– Severe neurotoxicity

• Paresthesias (Periferal sensorial neuropathy)

• Loss of reflexes• Foot drop• Ataxia• Cortical blindness

Paclitaxel & Docetaxel

• Prevent microtubule disassembly into tubulin monomers

Side effects• Peripheral neuropathy• Allergic reactions

Anticancer Antibiotics

• Anthracyclines– Doxorubicin (Adriamycin)– Daunorubicin– Idarubicin– Epirubicin

• Bleomycin• Dactinomycin• Mitomycin-C

Antracyclines

• Intercalate between base pairs, inhibit topoisomerase II and also generate free radicals (damage DNA)

• Block RNA and DNA synthesis and cause strand scission

Antracyclines-Side effects

• Cardiac toxicity – due to generation of free radicals– Acute form: arrthythmias, ECG changes,

pericarditis, myocarditis– Chronic form: ***Dilated cardiomyopathy, heart

failure– Prevention: Dexrazoxane

• This is an inhibitor of iron mediated free radical generation

• Adriamycin:If dose>300 mg/m2

• Radiation recall reaction

Maximum total dose during lifetime

• Adriamycin (Doxorubisin) 450 mg/m2

• Epirubicine 900 mg/ m2

• Mitoxantrone 160 mg/m2

• Bleomycin 200 mg/m2

Bleomycin • Reacts with oxygen and iron to form free

radicals

• Binds DNA Single and double strand breaks following free radical formation inhibition of DNA synthesis

• DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations

• Causes accumulation of cells in G2

Side effect:• Pulmonary fibrosis• Anaphylaxis: 1-7%

Target Examples

DNA SynthesisDihydrofolate reductase

Thymidylate synthase

Adenosine deaminase

Methotrexate, trimetrexate

5-fluorouracil, capecitabine, pemetrexed

Pentostatin, Cladribine

DNA ReplicationAlkylating

Platinating

Transcription inhibitors

Nitrogen mustard (mechlorethamine, cyclophos)

Nitrosureas (BCNU)

Ethyenimines (Thiotepa)

Alky sulfonates (Busulfan)

Triazenes(Dacarbazine, temozolamide)

Cis-, carbo-, oxaliplatin

Actinomycin-D

DNA Methylation 5’azacytidine

TopoisomerasesTopoisomerase-I

Topoisoerase-II

Topotecan, irinotecan

Doxorubicin, epirubicin, etoposide, mitoxantrone

MicrotubulesVinca alkaloids

Taxanes

Vincristine, vinblastine, vinorelbine

Paclitaxel, docetaxel

Protein Synthesis L-asparaginase

Protein degradation60S proteasome Bortezomib

Extravasation

• Vesicant agents: Causes tissue necrosis– Antracyclins (rubicin): Doxorubicin (adriamisin), Daunorubicine,

idarubicin

– Vinka alkaloids: Vinciristine, vinblastine, vinorelbine, vindesine

– Actinomisin-D

– Mitomisin

– Cisplatin

– Nitrojen mustard

Extravasation

• İrritant agents: Causes pain, mild inflammation at the injection site or anfd all through vein

– Mitoxantrone– Bleomisin– Dacarbazine– Carmustine– Streptozosin– 5-FU, Etoposide ->seldom

• Nonvesicant agents: – L-asparaginaz– Cytarabine– Carboplatin– Cyclophosphamide– Ifosfamide

Side effects of cytotoxic drugs

• Anticancer drugs kill fast growing cells– blood cells progenitors– cells in the digestive tract– reproductive system– hair follicles

• Other tissues affected– heart and lungs– kidney and bladder– nerve system

Common toxicities

– Neutropenia– Anemia, nausea/vomiting– Diarrhea– Alopecia– Peripheral Neuropathies– Mucositits– Arthralgia/myalgia

Specific toxicitiesof some chemotherapeutic agents

• Hemorrhagic cystitis• Ifosfamide• Cyclophosphamide

• Nephrotoxicity, ototoxicity• Cisplatin

• Pulmonary fibrosis• Bleomycin• Busulphan

• Allergic reactions• L-asparaginase

• Peripheral neuropathy• Cisplatin, Oxaliplatin• Vincristine

• Cerebellar dysfunction• Cytarabine

• Cardiotoxicity• Antracylines (adriamycim, epirubicine, idarubicin, mitoxantrone)

Specific toxicitiesof some chemotherapeutic agents

Cyclophosphamide Hemorrhagic cystitis, SIADH syndrome

Ifosfamide Hemorrhagic cystitis, encephalopathy

Cisplatin Nephrotoxicity, ototoxicity, peripheral neuropathy, SIADH syndrome

Methotrexate Mucositis, GI ulcers, pulmonary fibrosis, nephrotoxicity, diarrhea

5-Fluorouracil Stomatitis, GI ulcers, diarrhea, cerebellarataxia, angina

Capecitabine Stomatitis, GI ulcers, diarrhea, hand and foot syndrome

Cytarabine Conjuctivitis, cerebellar dysfunction

Antracyclines Cardiotoxicity

Bleomycin Pulmonary fibrosis, allergic reactions, anaphylaxis, fever

Specific toxicitiesof some chemotherapeutic agents

Docetaxel Hypersensitivity, fluid retension

Paclitaxel Anaphylaxis, peripheral neuropathy

İrinotecan Diarrhea

L-asparaginase Allergic reactions,Coagulopathy, hyperglycemia

Vincristine Peripheral neuropathy, SIADH syndrome, ileus

Mitomycin-C Hemolytic uremic syndrome

Late toxicities

• Late organ toxicities– Heart: Heart failure, MI– Lung: Fibrosis– Nephrotoxicity– Neurotoxicity– Immune insufficiency

• Secondary malignancies• Early menapouse• Gonadal insufficiency

Principles of combination chemotherapy

• Provides maximum cell kill within the range of

toxicity tolerated by the host for each drug

• Offers a broader range of coverage of resistant

cell lines in a heterogeneous tumor population

• Prevents or slows the development of new drug resistant cell lines.

Combination chemotherapyAdvantages

1. Suppression of drug resistance• less chance of a cell developing resistance to 2 drugs

than to 1 drug.

2. Increased cancer cell kill • administration of drugs with different mechanisms of

action.

3. Reduced injury to normal cells• by using a combination of drugs that do not have

overlapping toxicities, we can achieve a greater anticancer effect than we could by using any one agent alone.

Combination chemotherapy

• Agents with single agent activity

• Different mechanism of actions

• Different toxicities

INCREASED EFFICACYINCREASED EFFICACY

Different mechanisms of action Compatible side effects

Different mechanisms of resistance

ACTIVITYACTIVITY SAFETYSAFETY

Aim of combination therapy

Drug resistance

• Primary resistance

• Acquired resistance• Decreased intracellular uptake• Increased efflux• Change in target of drug• Increased DNA repair• Metabolic changes• Gen amplification in target zone

Multidrug resistance

Drugs that reverse MDR:verapamil, quinidine, cyclosporine

MDR increases resistance to natural drug products including the anthracyclines, vinca alkaloids, and epipodophyllotoxins

Drugs that affect the interaction between GF and receptors

• Growth factors

• Nuclear receptors• Gonadotrophin receptors• Plasma membrane receptors

• Multiple kinases• Miscellanous

Target Monoclonal antibody Tyrosine kinase inhibitor

Angiogenesis

VEGF

VEGFR

Bevacizumab

-

-

Sunitinib

Sorafenib

EGFR Cetuximab Erlotinib

Gefitinib

Her2 Trastuzumab Lapatinib

Bcr-abl İmatinib

CD20 Rituximab

Targeted Therapies

ErlotinibGefitinib

Bevacizumab

SunitinibSorafenib

Sorafenib

Chemotherapy

Temsirolimus

Inhibition of programmed cell death (apoptosis)

Tumor cell proliferation

Tumor cell invasion

metastasis

Development of tumor vasculature

(angiogenesis)

Cetuximab

PDGFR

Imatinib

PI3K

Monoclonal antibodies

• Large molecules

• Targets GF’s or extracellular part of receptors

• Longer half life

• IV administration

• Allergic reactions

Tyrosine kinase inhibitors

• Small molecules

• Targets intracellular part of receptors

• Shorter half life

• Oral

Characteristics

Specific side effects of targetted agents

Rituximab Immunosuppression-infections

Trastuzumab Heart failure

Bevacizumab Hypercoagulability (arterial and venous trombosis)

Bleeding

GI perforation

Hypertension

Proteinuria

Cetuximab Skin reactions, diarrhea, mucositis

Erlotinib Skin reactions, diarrhea, mucositis

Thank you