cinétique de croissance des tumeurs
DESCRIPTION
Cinétique de croissance des tumeurs Une tumeur de 1cm de diamètre contient de 10 9 ~ 10 10 cellules (30 temps de doublement) Peut être cliniquement silencieuse dans une masse tissulaire (masse abdominale ou thoracique) - PowerPoint PPT PresentationTRANSCRIPT
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
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1950
1960
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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)
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Alkylating agents
• Cyclophosphamide • Cisplatin• Procarbazine • Busulfan• Mechlorethamine
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Utilisation clinique
• Non-Hodgkin’s lymphoma• Breast Ca• Ovarian Ca• Neuroblastoma
Toxicités associées aux alkylants
Nausées vomissementsMyélosuppressionAlopécieStérilité infertilitéSecond cancerCystite hémorragiqueNeurotoxNephrotoxDéficit immunitaireSIADH
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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
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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
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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
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NH3 CISPLATINE
CARBOPLATINE
Oxalato 1,2-trans-L-diaminocyclohexane platinium(OXALIPLATINE)
NH2
NH2
PtO O
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Cibles et toxicité- mécanismes d’action- différents
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Anticancer Antibiotics
• Anthracyclines:– Doxorubicin (Adriamycin)– Daunorubicin
• Bleomysin• Dactinomycin• Mitomycin
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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
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LegendDrug ClassSub-class
Prototype Drug
TrimetrexatePemetrexed
ThioguanineFludarabine Phosphate
Cladribine
Cytarabine GemcitabineCapecitabine
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Antimetabolits: sites of drug action
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Methotrexate
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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.
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Mechanism of Resistance
1. Decreased drug transport
2. Altered DHFR3. Decreased polyglutamate
formation4. Increased levels of
DHFR
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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
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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.
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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
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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??
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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.
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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
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Eniluracile
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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
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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
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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
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Topoisomerase inhibitors
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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
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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
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Sex hormone antagonists
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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
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MOA of drugs
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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
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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.
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Contd..
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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