Cinétique de croissance des tumeurs

• Une tumeur de 1cm de diamètre contient de 109~ 1010 cellules (30 temps de doublement)

• Peut être cliniquement silencieuse dans une masse tissulaire (masse abdominale ou thoracique)

• Les 10 temps de doublement suivants amènent la tumeur à une masse de 1kg (1012 cellules)

Cinétique de croissance tumorale:• une fois détectable la tumeur croit rapidement

Thérapeutique

• Les buts des traitements anticancéreux:• curatifs (adjuvant, néoadjuvant, métastatique)• maintient de la qualité et de la durée de vie• soulagement des symptômes (traitement palliatif)

• essais cliniques de nouveaux traitementsA discuter avec le patient et sa famille

Evaluation de la réponse thérapeutique individuelle

1. Réponse complète (CR): disparition complète de toutes les manifestations tumorales2. Réponse partielle (PR) . Diminution >50% de la taille tumorale sans progression d’autre localisationni nouvelle tumeur3. Maladie stable: pas d’augmentation de la masse tumorale ou diminution < 25% 4. Progression- Augmentation de la masse tumorale >25%, nouvelles lésions ou décès lié à la maladie

Efficacité globale du traitement dans des groupes de patients

• Durée de survie –semaines mois années • Taux de réponse (% de CR+PR) • Durée de réponse jusqu’à la progression• Toxicités- grading du NCI • Qualité de vie- requis par la FDA pour toutes les nouvelles molécules

1945

1950

1960

1970

1980

1990

2000

Nitrogen mustardMercaptopurineMethotrexateBusulfanCyclophosphamideChlorambucil5FluoruracilVinblastin-VincristinActinomycin DL-PAMAraCMOPPBleomycinDoxorubicinDTIC-CCNUCis PlatinVP16Mitoxantrone

Taxol-TaxotereOxaliplatine- G-CSF- ErythropoiétineHerceptin-RituximabGlivecGefitinib- crizotinib- Vemurafenib

Premières rémissions complètes en hématologie

Rechutes et résistance

Associations médicamenteuses

Multi- drug- resistance (MDR)Oncogenes- facteurs de croissance et récepteursAnticorps monoclonaux

P glycoprotéine et efflux des médicamentsAntioncogènes

Cycle cellulaire et signalisation Facteurs de croissance hématopoiétiques (HuR)Génétique des tumeurs familialesCiblage thérapeutique

D’après Hanahan and Weinberg – Cell 2000

Invasion tissulaire et métastase

Potentiel réplicatif illimité

Angiogenèse active

Insensibilité aux régulateurs négatifs

Autosuffisance des signaux de croissance

Résistance à l’apoptose

Complexité du ciblage thérapeutique des cancers

LOG kill hypothesis• The example shows the effects

of tumor burden, scheduling, initiation/duration of treatment on patient survival.

• The tumor burden in an untreated patient would progress along the path described by the RED LINE –

• The tumor is detected (using conventional techniques) when the tumor burden reaches 109 cells

• The patient is symptomatic at 1010-1011 cells

• Dies at 1012 cells.

Dommages cellulaires provoqués par la chimithérapie cytotoxique

1- blocage de la synthèse des précurseurs de l’ADN

2- Interaction directe avec l’ADN3- Inhibition de la synthèse de l’ADN4- Interférence avec la transcription5- Inhibition de la synthèse des protéines 6- L’effet global est la mort cellulaire par

apopotose ou nécrose

Spécificités des traitements anticancéreux

- Les cytotoxiques ne distinguent pas les cellules cancéreuses des cellules normales

- Les cellules cancéreuses sont plus fréquemment impliquées dans la multiplication cellulaire et sont plus sensibles aux effets toxiques des cytotoxiques

- La moelle osseuse, l’épithélium digestif et les follicules pileux sont les plus sensibles aux effets toxiques

Resistance to Cytotoxic Drugs Increased expression of MDR-1 gene for a cell surface P-glycoprotein

MDR-1 gene is involved with drug efflux

Drugs that reverse MDR :verapamil, quinidine,

cyclosporine MDR increases resistance

to natural drug products including the anthracyclines,

vinca alkaloids, and epipodophyllotoxins

Modes of Resistance to Anticancer Drugs

Mechanism Drugs or Drug GroupsChange in sensitivity (or ↑ level) or ↓ binding affinity of target enzymes or receptors

Etoposide, methotrexate, vinca alkaloids, estrogen & androgen receptors

Decreased drug accumulation via ↑ expression of glycoprotein transporters, or ↓ permeability

Methotrexate, alkylating agents, dactinomycin

Formation of drug-inactivating enzymes

Purine & pyrimidine antimetabolites

Production of reactive chemicals that “trap” the anticancer drug

Alkylators, bleomycin, cisplatin. doxorubicin

Increased nucleic acid repair mechanisms

Alkylating agents, cisplatin

Reduced activation of pro-drugs Purine & pyrimidine antimetabolites

Les agents alkylants

- Sont responsables de la production d’ions très réactifs chargés positivement

- Ces ions forment des liaisons covalentes avec des régions electrophiles sur des molécules biologiques (Nucléotides, protéines AA)

- La liaison de ces alkylants fonctionnels au DNA est la cause de la mort (mutagenese, apoptose)

14

Alkylating agents

• Cyclophosphamide • Cisplatin• Procarbazine • Busulfan• Mechlorethamine

15

Utilisation clinique

• Non-Hodgkin’s lymphoma• Breast Ca• Ovarian Ca• Neuroblastoma

Toxicités associées aux alkylants

Nausées vomissementsMyélosuppressionAlopécieStérilité infertilitéSecond cancerCystite hémorragiqueNeurotoxNephrotoxDéficit immunitaireSIADH

17

18

ADR• Acrolein is the metabolite• Responsible for causing hemorrhagic cystitis

– Suprapubic pain– Hematuria– Cyctoscopic findings

• ***This is prevented/treated by MESNA (mercaptoethanesulfonate)

• Rarely cyclophosphamide can cause SIADH and pulmonary toxicity

25

Procarbazine

• MOA: forms hydrogen peroxide, which generates free radicals that cause DNA damage

• Important component of regimens especially for Hodgkin’s lymphoma

ADR• ***Disulfiram like reactions

Autres alkylants: les dérivés du PlatineLe Cis Platine

27

Cisplatin • Platinum analog• Same MOA as cyclophosphamide• **Used in testicular carcinoma• Also used for Ca of bladder, lung and ovary• Carboplatin is new drug with better safety profileADR• Nephrotoxicity (prevented by Amifostine***)• ***Ototoxicity (acoustic nerve damage)• Peripheral neuritis• Severe nausea and vomiting

Strategies pour améliorer les thérapeutiques

PtNH3Cl

Cl NH3

O

O

O

OPt

NH3

NH3    CISPLATINE

  

CARBOPLATINE

  

Oxalato 1,2-trans-L-diaminocyclohexane platinium(OXALIPLATINE)

NH2

NH2

PtO O

OO

Cibles et toxicité- mécanismes d’action- différents

30

Anticancer Antibiotics

• Anthracyclines:– Doxorubicin (Adriamycin)– Daunorubicin

• Bleomysin• Dactinomycin• Mitomycin

31

Doxorubicin & Daunorubicin • These drugs intercalate

between base pairs, inhibit topoisomerase II and also generate free radicals

• They block RNA and DNA synthesis and cause strand scission

• *These are CCNS drugs• Used as a component in

ABVD regimen in Hodgkin’s lymphoma

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ADR• Cardiac toxicity (due to generation of free radicals)• Acute form: arrthythmias, ECG changes, pericarditis,

myocarditis• Chronic form: ***Dilated cardiomyopathy, heart

failure• ****Rx with dexrazoxane

– This is an inhibitor of iron mediated free radical generation • Bone marrow depression, Total alopecia• Radiation recall reaction

Toxicités les plus communes avec les antibiotiques anticancéreuxMyélosuppressionMuciteNausées vomissementsAlopécieCausticité

Toxicités plus spécifiquesPulmonairesCutanéesRappel de radiationFièvreToxicité cardiaque

Les antimétabolites sont des analogues structuraux de substances biologiquement impliquées dans la fonction cellulaire

Ils vont interférer avec la synthèse des acides nucléiques en s’incorporant frauduleusement

ouEn inhibant de manière spécifique des enzymes critiques de la synthèse des acides nucléiques

Ils sont cycle spécifique – Phase S

39

LegendDrug ClassSub-class

Prototype Drug

TrimetrexatePemetrexed

ThioguanineFludarabine Phosphate

Cladribine

Cytarabine GemcitabineCapecitabine

40

Antimetabolits: sites of drug action

41

Methotrexate

42

Methotrexate (MTX)• MTX is a folic acid analog that 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.

• Inhibition of these various metabolic processes thereby interferes with the formation of DNA, RNA, and key cellular proteins.

43

Mechanism of Resistance

1. Decreased drug transport

2. Altered DHFR3. Decreased polyglutamate

formation4. Increased levels of

DHFR

44

Contd..• Most commonly used anticancer drug. • Cell cycle specific (CCS) drug and acts during S phase of the

cell cycle. • Antineoplastic, immunosuppressant and antiinflammatory• Used in RA, psoriasis • Well absorbed orally; can also be given IM, IV or intrathecally**. • It is bound to plasma proteins, does not cross the BBB and most

of the drug is excreted unchanged in urine.• It is a weak acid and so is excreted better at high urine pH.

Appropriate hydration and alkalinizing the urine is important to prevent renal tox with MTX

45

ADR• Bone marrow suppression (BMS)• 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**

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Leucovorin Rescue

Mechanism of action of methotrexate and the effect of administration of leucovorin.

• FH2 = dihydrofolate• FH4 = tetrahydrofolate• dTMP = deoxythymidine

monophosphate• dUMP = deoxyuridine mono

phosphate.

47

6-Mercaptopurine (6-MP) & Thioguanine

• Both 6-MP and Thioguanine are activated by HGPRT to toxic nucleotides that inhibit several enzymes involved in purine metabolism

• ***Resistance is due to cancer cells having d activity of HGPRT

• Cancer cells also es alkaline phosphatase that inactivate toxic nucleotides

48

6-MP & Allopurinol• 6-MP is metabolized in the liver by xanthine oxidase

and the inactive metabolites are excreted in the urine• ***Allopurinol is used frequently to treat/prevent

hyperuricemia caused by many anticancer drugs.• If Allopurinol is used with 6-MP then the dose of 6-MP

is reduced by more than 75%– Why??

49

Cytarabine (Ara-C)• Cytarabine arabinoside is a pyrimidine antimetabolite • The drug is activated by kinases to AraCTP

– This acts as an inhibitor of DNA polymerase• ***of all antimetabolites, this is the most specific for S

phase of tumor cell cycle• It is an important component in acute lukemia regimens• ADR: at high doses cause neurotoxicity (cerebellar

dysfunction and peripheral neuritis)– Hand-foot syndrome***

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5-FUMechanism of the cytotoxic action of 5-FU• 5-FU is converted to 5-FdUMP, which

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

• 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.

51

Contd..• 5-FU causes, “thymidineless death” of cells• Resistance is due to d activation of 5-FU and d thymidylate

synthase activityUses and ADR• Metastatic carcinomas of the breast and the GI tract, hepatoma• Carcinomas of the ovary, cervix, urinary bladder, prostate,

pancreas, and oropharyngeal areas• Combined with levamisole for Rx of colon cancer • ADR: nausea, mucositis, diarrhea, ***hand and foot syndrome,

Alopecia, hyperpigmentation, neurologic deficits, bone marrow depression

HN

N

FO

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H

HN

NOH

HO

HH

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HN

N

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HH

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FU FUH25 _

Eniluracile

A  

B

O

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N

NO

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FH

O

HO OH

HN

NO

FO

HN

NO

FO

H

5-FU (4)

5'-DFUR (3)

5'-DFCR (2)

dThdPase

TUMEUR

CAPECITABINE 

Stratégies pour améliorer les thérapeutiques

Nombreux médicaments adaptés à la forme orale:Taxanes, Vinorelbine, Inhibiteurs de TOPO-1…

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VinblastineVincristineVinorelbine

Teniposide Irinotecan Docetaxel

57

Vinka alkaloids (Vinblastine, vincristine)

• These drugs block the formation of mitotic spindle by preventing the assembly of tubulin dimers into microtubules

• ***They act primarily on the M phase of cancer cell cycle

• Resistance is due to d efflux of drugs from tumor cells

58

VinBlastine VinCristine (oncovan)Uses ; (ABVD)Hodgkin’s disease LymphomasCarcinoma BreastTesticular tumorsToxicity:Bone marrow suppression, anorexia, nausea, vomiting & Diarrhea, Alopecia

Uses: (MOPP)Childhood leukemiasChildhood tumors-Wilm’s tumor, Neuroblastoma, Hodgkin’s diseaseToxicity:Peripheral neuritis with Paresthesia, Muscle weakness***Vincristine has marrow sparing effect

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Etoposide & Teniposide• Acts by inhibiting topoisomerase II• These drugs are most active in late S and early

G2 phase• Used in combination Tx of small cell carcinoma

of lung, prostrate and testicular carcinomasOther topoisomerase inhibitors:• Topotecan, Irinotecan

– Both act by inhibiting topoisomerase-I

60

Topoisomerase inhibitors

62

Paclitaxel & Docetaxel• These drugs act by interfering with

mitotic spindle• They prevent micotubule

disassembly into tubulin monomers• Taxanes animationADR• Neutropenia• Peripheral neuropathy

Etoposide (VP16 et teniposide VM26

General problems with anticancer drugs

• Most of them are antiproliferative, i.e. they damage DNA and so initiate apoptosis.

• They also affect rapidly dividing normal cells.• This leads to toxicity which are usually severe.• To greater or lesser extent the following

toxicities are exhibits by all anticancer drugs.

ADR of Antineoplastic Drugs in Humans Tissue Undesirable Effects

Bone marrow Leukopenia and resulting infections

Immunosuppression

Thrombocytopenia

Anemia

GI tract Oral or intestinal ulceration

Diarrhea

Hair follicles Alopecia

Gonads Menstrual irregularities, including premature

menarche; impaired spermatogenesis

Wounds Impaired healing

Fetus Teratogenesis (especially during first trimester)

Distinctive Toxicities of Some Anticancer DrugsToxicity Drug(s)

Renal Cisplatin,* methotrexate

Hepatic 6-MP, busulfan, cyclophosphamide

Pulmonary Bleomycin,* busulfan, procarbazine

Cardiac Doxorubicin, daunorubicin

Neurologic Vincristine,* cisplatin, paclitaxel

Immunosuppressive Cyclophosphamide, cytarabine, dactinomycin, methotrexate

Other Cyclophosphamide (hemorrhagic cystitis); procarbazine (leukemia); asparaginase* (pancreatitis)

*Less Bone marrow suppression – “marrow sparing”

• Proliferating cells are especially sensitive to chemotherapy because cytotoxic drugs usually act by disrupting DNA synthesis or mitosis, cellular activities that only proliferating cells carry out.

• Unfortunately, toxicity to the anticancer agents is to any rapidly dividing cells. (e.g. bone marrow, hair follicles, sperm forming cells).

Chemotherapeutic agents are much more toxic to tissues that have a high growth fraction than to tissues that have a low

growth fraction.

Prevention or Management of Drug Induced toxicities

• The toxicities of some anticancer drugs can be well anticipated and hence be prevented by giving proper medications

• E.g. mesna is given to prevent hemorrhagic cystitis by cyclophosphamide

• Dexrazoxane, is used to reduce the risk of anthracycline-induced cardiomyopathy

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Hormonal agents

• Glucocorticoids• Sex hormone antagonists• GnRH analogs• Aromatase inhibitors

73

Glucocorticoids (Prednisone)• Because of their marked lympholytic action, they are

used in acute leukemias and lymphomas.• Have anti-inflammatory effect• Increase appetite• Produce euphoria (feeling of well being)• Increase body weight• Suppress hypersensitivity reaction due to certain

anticancer drugs• Control hypercalcemia• Control bleeding• Have non-specific antipyretic effect• Increase the antiemetic effect of

ondansetron/granisetron/ metoclopramide

74

Sex hormone antagonists

75

Tamoxifen • It is a SERM• Blocks the binding of estrogen to receptors of estrogen

sensitive cancer cells in bresat tissue• It is used in receptor positive breast carcinoma• Also useful in progestin resistant endometrial

carcinomaADR:• Hot flushes, vaginal bleeding and venous thrombosisOther drugs• Flutamide: androgen receptor antagonist used in

prostatic carconima • ADR for flutamide includes: gynecomastia, hot flushes

76

MOA of drugs

77

GnRH analogs • Leuprolide, gosarelin and naferelin• Effective in management of Prostatic carcinomas• When given in constant doses they inhibit release of

pituitary LH and FSH• These drugs suppress gonadal function due to down

regulation and desensitization of Gn-RH receptorsADR• Leuprolide may cause gynecomastia, hematuria,

impotence and testicular atrophy

78

Aromatase inhibitors • The aromatase reaction is responsible for the extra-

adrenal synthesis of estrogen from androstenedione• This takes place in liver, fat, muscle, skin, and breast

tissue, including breast malignancies. • Peripheral aromatization is an important source of

estrogen in postmenopausal women. • Aromatase inhibitors decrease the production of

estrogen in these women.

79

Contd..

80

Contd..

• Anastrozole and Letrozole• These drugs inhibit the aromatase enzyme • ****Used in Tx of postmenopausal women with

metastatic breast ca (1st line drug)• ADR includes: bone pain and peripheral edema