Principles of Chemotherapy and Chemotherapy Complications Özlem Sönmez, MD Yeditepe University Hospital Section 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 changes  Malignant 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 1x10 9 cells = 1 gr (1 cm) 1 cell to 10 9 cells: 30 doubling times Doubling time: 24 hours to years cells: Damage to vital organs, death

Gompertzian Growth

Chemotherapy kinetics Log 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/m 2 /week) determines success (not total dose).

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 AlkylatingAnti- 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),Topoiso merase II inhi. Topoisomerase I or II inhibition Busulfan Carmustine Chlorambusil Cisplatin Carboplatin Cyclophosphami de 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 agents Mechanism of action Transfer alkyl groups to DNA Alkylates nucleophilic groups on DNA bases, particularly at the N-7 position of guanine

Consequences of alkylation 1.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 breaks N7 alkylation –> Cleavage of imidazole ring  excision of guanine residue Inhibition of DNA replication and transcription

Cyclophosphamide Toxic to bladderAntitumor activity

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

Side effects Ifosfamide-Cyclophosphamide Side effect: –Hemorrhagic cystitis Prevention: –Hydration –Mesna  Detoxification

Side effects Platinums (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 effects Platinums (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 MethotrexateMercaptoguanineFluorouracil Thioguanine Fludarabine Cladribine Pentostatin Trimetrexate Pemetrexed Cytarabine Gemcitabine Capecitabine

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 PurinesPyrimidines 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-fluorouracil 5-FUR = 5-fluorouridine 5-FUMP = 5-fluorouridine monophosphate 5-FUDP = 5-fluorouridine diphosphate 5-FUTP = 5-fluorouridine triphosphate dUMP = deoxyuridine monophosphate dTMP = deoxythymidine monophosphate 5-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) D iarrhea :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/m 2 Radiation recall reaction

Maximum total dose during lifetime Adriamycin (Doxorubisin)450 mg/m 2 Epirubicine900 mg/ m 2 Mitoxantrone160 mg/m 2 Bleomycin200 mg/m 2

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 G 2 Side effect: Pulmonary fibrosis Anaphylaxis: 1-7%

TargetExamples DNA Synthesis Dihydrofolate reductase Thymidylate synthase Adenosine deaminase Methotrexate, trimetrexate 5-fluorouracil, capecitabine, pemetrexed Pentostatin, Cladribine DNA Replication Alkylating 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 Topoisomerases Topoisomerase-I Topoisoerase-II Topotecan, irinotecan Doxorubicin, epirubicin, etoposide, mitoxantrone Microtubules Vinca alkaloids Taxanes Vincristine, vinblastine, vinorelbine Paclitaxel, docetaxel Protein Synthesis L-asparaginase Protein degradation 60S 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 toxicities of 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 toxicities of some chemotherapeutic agents CyclophosphamideHemorrhagic cystitis, SIADH syndrome IfosfamideHemorrhagic cystitis, encephalopathy CisplatinNephrotoxicity, ototoxicity, peripheral neuropathy, SIADH syndrome MethotrexateMucositis, GI ulcers, pulmonary fibrosis, nephrotoxicity, diarrhea 5-FluorouracilStomatitis, GI ulcers, diarrhea, cerebellarataxia, angina CapecitabineStomatitis, GI ulcers, diarrhea, hand and foot syndrome CytarabineConjuctivitis, cerebellar dysfunction AntracyclinesCardiotoxicity Bleomycin Pulmonary fibrosis, allergic reactions, anaphylaxis, fever

Specific toxicities of some chemotherapeutic agents DocetaxelHypersensitivity, fluid retension Paclitaxel Anaphylaxis, peripheral neuropathy İrinotecanDiarrhea L-asparaginase Allergic reactions,Coagulopathy, hyperglycemia VincristinePeripheral neuropathy, SIADH syndrome, ileus Mitomycin-CHemolytic 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 chemotherapy Advantages 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 EFFICACY Different mechanisms of action Compatible side effects Different mechanisms of resistance ACTIVITY SAFETY 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

TargetMonoclonal antibodyTyrosine kinase inhibitor Angiogenesis VEGF VEGFR Bevacizumab - Sunitinib Sorafenib EGFRCetuximabErlotinib Gefitinib Her2TrastuzumabLapatinib Bcr-ablİmatinib CD20Rituximab

Targeted Therapies Erlotinib Gefitinib Bevacizumab Sunitinib 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 RituximabImmunosuppression-infections TrastuzumabHeart failure BevacizumabHypercoagulability (arterial and venous trombosis) Bleeding GI perforation Hypertension Proteinuria CetuximabSkin reactions, diarrhea, mucositis ErlotinibSkin reactions, diarrhea, mucositis

Thank you