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
![Page 1: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/1.jpg)
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)
![Page 2: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/2.jpg)
Cinétique de croissance tumorale:• une fois détectable la tumeur croit rapidement
![Page 3: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/3.jpg)
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
![Page 4: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/4.jpg)
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
![Page 5: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/5.jpg)
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
![Page 6: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/6.jpg)
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
![Page 7: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/7.jpg)
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
![Page 8: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/8.jpg)
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.
![Page 9: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/9.jpg)
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
![Page 10: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/10.jpg)
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
![Page 11: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/11.jpg)
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
![Page 12: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/12.jpg)
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
![Page 13: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/13.jpg)
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)
![Page 14: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/14.jpg)
14
Alkylating agents
• Cyclophosphamide • Cisplatin• Procarbazine • Busulfan• Mechlorethamine
![Page 15: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/15.jpg)
15
Utilisation clinique
• Non-Hodgkin’s lymphoma• Breast Ca• Ovarian Ca• Neuroblastoma
![Page 16: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/16.jpg)
Toxicités associées aux alkylants
Nausées vomissementsMyélosuppressionAlopécieStérilité infertilitéSecond cancerCystite hémorragiqueNeurotoxNephrotoxDéficit immunitaireSIADH
![Page 17: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/17.jpg)
17
![Page 18: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/18.jpg)
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
![Page 19: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/19.jpg)
![Page 20: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/20.jpg)
![Page 21: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/21.jpg)
![Page 22: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/22.jpg)
![Page 23: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/23.jpg)
![Page 24: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/24.jpg)
![Page 25: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/25.jpg)
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
![Page 26: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/26.jpg)
Autres alkylants: les dérivés du PlatineLe Cis Platine
![Page 27: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/27.jpg)
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
![Page 28: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/28.jpg)
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
![Page 29: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/29.jpg)
![Page 30: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/30.jpg)
30
Anticancer Antibiotics
• Anthracyclines:– Doxorubicin (Adriamycin)– Daunorubicin
• Bleomysin• Dactinomycin• Mitomycin
![Page 31: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/31.jpg)
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
![Page 32: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/32.jpg)
32
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
![Page 33: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/33.jpg)
Toxicités les plus communes avec les antibiotiques anticancéreuxMyélosuppressionMuciteNausées vomissementsAlopécieCausticité
Toxicités plus spécifiquesPulmonairesCutanéesRappel de radiationFièvreToxicité cardiaque
![Page 34: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/34.jpg)
![Page 35: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/35.jpg)
![Page 36: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/36.jpg)
![Page 37: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/37.jpg)
![Page 38: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/38.jpg)
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
![Page 39: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/39.jpg)
39
LegendDrug ClassSub-class
Prototype Drug
TrimetrexatePemetrexed
ThioguanineFludarabine Phosphate
Cladribine
Cytarabine GemcitabineCapecitabine
![Page 40: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/40.jpg)
40
Antimetabolits: sites of drug action
![Page 41: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/41.jpg)
41
Methotrexate
![Page 42: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/42.jpg)
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.
![Page 43: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/43.jpg)
43
Mechanism of Resistance
1. Decreased drug transport
2. Altered DHFR3. Decreased polyglutamate
formation4. Increased levels of
DHFR
![Page 44: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/44.jpg)
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
![Page 45: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/45.jpg)
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**
![Page 46: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/46.jpg)
46
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.
![Page 47: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/47.jpg)
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
![Page 48: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/48.jpg)
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??
![Page 49: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/49.jpg)
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***
![Page 50: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/50.jpg)
50
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.
![Page 51: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/51.jpg)
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
![Page 52: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/52.jpg)
HN
N
FO
OH
H
HN
NOH
HO
HH
H
HN
N
C CH
HH
O
O
1
FU FUH25 _
Eniluracile
A
B
O
HO OH
N
NO
N O
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…
![Page 53: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/53.jpg)
![Page 54: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/54.jpg)
![Page 55: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/55.jpg)
55
VinblastineVincristineVinorelbine
Teniposide Irinotecan Docetaxel
![Page 56: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/56.jpg)
![Page 57: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/57.jpg)
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
![Page 58: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/58.jpg)
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
![Page 59: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/59.jpg)
59
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
![Page 60: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/60.jpg)
60
Topoisomerase inhibitors
![Page 61: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/61.jpg)
![Page 62: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/62.jpg)
62
Paclitaxel & Docetaxel• These drugs act by interfering with
mitotic spindle• They prevent micotubule
disassembly into tubulin monomers• Taxanes animationADR• Neutropenia• Peripheral neuropathy
![Page 63: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/63.jpg)
Etoposide (VP16 et teniposide VM26
![Page 64: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/64.jpg)
![Page 65: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/65.jpg)
![Page 66: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/66.jpg)
![Page 67: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/67.jpg)
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.
![Page 68: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/68.jpg)
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)
![Page 69: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/69.jpg)
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”
![Page 70: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/70.jpg)
• 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.
![Page 71: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/71.jpg)
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
![Page 72: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/72.jpg)
72
Hormonal agents
• Glucocorticoids• Sex hormone antagonists• GnRH analogs• Aromatase inhibitors
![Page 73: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/73.jpg)
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
![Page 74: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/74.jpg)
74
Sex hormone antagonists
![Page 75: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/75.jpg)
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
![Page 76: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/76.jpg)
76
MOA of drugs
![Page 77: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/77.jpg)
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
![Page 78: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/78.jpg)
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.
![Page 79: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/79.jpg)
79
Contd..
![Page 80: Cinétique de croissance des tumeurs](https://reader035.vdocuments.fr/reader035/viewer/2022062812/56816449550346895dd611f5/html5/thumbnails/80.jpg)
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