Presentation on theme: "CANCER CHEMOTHERAPY & PHARMACOLOGY"— Presentation transcript:
1 CANCER CHEMOTHERAPY & PHARMACOLOGY HeaderCANCER CHEMOTHERAPY & PHARMACOLOGYSubheadLeo Mascarenhas, MD MS
2 Disclosure Information No financial disclosuresNo discussion of unlabeled uses
3 Outline Syllabus- ABP Outline V.A.5 (pages 54-66) Principles of chemotherapyClassification/Mechanism of actionToxicity essentials and drug interactionsOdds and ends
4 Principles of Chemotherapy CureLow therapeutic indexClinical TrialsPhase 1- Toxicity and determine MTDPhase 2- Response rate and toxicityPhase 3- Efficacy vs. standard
5 Principles of Chemotherapy Multi-drug therapyOvercome drug resistance to individual agentsNeo-adjuvant vs. adjuvant chemotherapyGoldie-Coldman hypothesisDose intensityMaximum tolerated dose rateSupportive careMicroscopic tumor has a larger number of proliferating cells and smaller burden implies that there is a lower chance of drug resistant cells being present.Curable tumor is one with no drug resistant cells. Chance of cure is maximized if all active agents are used simultaneously in the adjuvant setting when there is minimal residual disease and the probability of drug resistance is low.
6 Definitions Pharmacokinetics Pharmacodynamics Pharmacogenomics Drug disposition in the body- ADMEClearance, half life, AUC, volume of distribution, bioavailability and biotransformationAge, organ function, drug interactionsPharmacodynamicsEffects of drug on the body, relationship between drug concentration and effectPharmacogenomicsGenetic variations on spectrum of drug actionCytochrome P-450 enzymes catalyze oxidation and demethylation (Phase 1 enzymes) TPMT, UGTA1A ( Phase 2 enzymes). Methylation of MGMT gene promoter modulates response of gliomas to carmustine.
7 Definitions (continued) Cell CycleG0- resting phase, cell has left the cell cycleG1- cells increase in size, ready for DNA synthesisS - DNA replicationG2- cells increase in size, ready for mitosisM - mitosisG0- Chemo resistant. S phase antimetabolites, G2, M- mitotic inhibitors, no cell cycle specific alkylators.
8 Drugs- Cell Cycle Drug class Cell Cycle Phase Alkylating agents G0 Antitumor AntibioticsCell cycle non-specificAntimetabolitesSPlant alkaloidsMHormones
9 Drug Resistance- mostly genetic Drug specific mechanismsDecreased drug uptake by cellscorticosteroids, methotrexateDecreased intracellular drug activationcytarabine, methotrexateIncreased intracellular drug catabolismcyclophosphamideIncreased or altered affinity of targetmethotrexate, vincristineIncreased production of competitive substratecytarabine, l-asparaginaseAbnormal glucocorticoid receptors, decreased folate transporterDecreased Deoxycytidine kinase, Decreased Folylpolyglutamate synthaseIncreased aldehyde oxidaseIncreased DHFR,Increase asparagine synthase in lymphoblasts
10 Drug Resistance (continued) Multidrug resistance mechanismsDecreased drug accumulationIncreased P-glycoproteinIncreased drug detoxicficationIncreased Glutathione-S-transferaseDecreased or altered affinity of targetDecreased Topoisomerase IIIncreased DNA repairIncreased Alkylguanine-DNA-alkyltransferaseDecreased apoptosisIncreased Bcl-2 expressionPGP- Anthracyclines, epipodophylotoxins, vinca alkaloids, taxanesMGMT- Temozolomide. Nitrosoureas and dacarbazineAlkylating agents and anthracylines
12 CNS Pharmacology (continued) Strategies to enhance CNS penetrationHigh-dose systemic chemotherapyMethotrexate, cytarabineDrugs that penetrate the BBBnitrosoureas, thiotepa, camptothecinsDisrupting the BBBmannitolAdministration of drug into the intrathecal spacemethotrexate, cytarabine
13 CNS Pharmacology (continued) Age based intra-thecal dosingAge (years)Methotrexate (mg)Cytarabine (mg)< 1615183021050>/=3*1270
14 Classification/Mechanism of Action Alkylating AgentsAntimetabolitesAntibioticsPlant ProductsMiscellaneousKinase InhibitorsOther small molecule targeted agentsMonoclonal antibodies
15 Mechanism of Action DNA RNA Protein EtoposideTeniposideTopotecanIrinotecanActinomycin-DDoxorubicinDaunomycinIdarubicinMitoxantroneTopo InhibitorsIntercalatorsAra-CDoxorubicinDaunomycinIdarubicinBleomycinFH2FH4dUMPdTMPCMPdCMPDNAFree Radical DamageRNA5-FUNelarabineCladrabineMechlorethamineCyclophosphamideIfosfamideMelphalanCarboplatinCisplatinOxaliplatinNitrosureasBusulfanDacarbazineProcarbazineTemozolomideAlkylatorPurinesDe novo SynthesisSalvage PathwayMP, TGMTXProteinAsparaginaseTubulinVincristineVinblastinePaclitaxelCourtesy of Peter Adamson, MD- modified
31 Toxicity (continued) Chronic Toxicity Drug Cardiac Anthracyclines PulmonaryBleomycin, Busulfan, CarmustineInfertilityAlkylating agentsOsteonecrosisCorticosteroidsSecondary Leukemia/MDS11q23Monosomy 7, del 5qTopoisomerase II inhibitorsHearing lossCisplatinNephrotoxicityCisplatin, IfosfamideRadiation recall injuryAnthracyclines, dactinomycin
32 Oxazaphosphorines Cyclophosphamide (C) and Ifosfamide (I) Prodrugs Metabolized to phospho/iphosphoramide mustard and acrolein (hemorrhagic cystitis)Dechlorethylation I>C (neurotoxicity)Busulfan blocks activation of cyclophosphamide
33 Busulfan Oral busulfan PK is age dependent and highly variable IV busulfan decreases interpatient variabilityMetabolized by Glutathione-S- transferaseGood CSF penetrationHigh dose used for myeloablation in BMT conditioning regimens
34 Platinum compounds Cisplatin- nephrotoxicity, ototoxicity Carboplatin- myelotoxicityOxaliplatin- neurotoxicityCarboplatin clearance highly correlated with GFRTargeted dosing of carboplatin using AUC (usually 6-10mg X min/mL)
35 Thiopurines MP and TG are prodrugs MP- TGMP ( 3 steps); TG- TGMP (1 step)TGMP is phosphorylated to TGTP which is then converted by ribonucleotide reductase to dTGTP which is incorporated into DNA.Thiopurine methyl transferase (TPMT)- S-methylation of thiopurines (active metabolites)Homozygous TPMT deficiency- severe toxicity (5-10% dosing)- 1 in 300Heterozygotes TPMT- more frequent dose reductionsMm- TIMP- TXMP- TGMPHypoxanthine guanine phosphoribosyl transferase (HGPRT)
36 Thiopurines MP catabolized to thiouric acid by xanthine oxidase Allopurinol increases MP toxicityTG catabolized to thiouric acid by aldehyde oxidase via 8-OH-thioguanineAllopurinol has no effect on TG toxicity
37 TemozolomideProdrugSpontaneous change to MTIC in solution at physiological pHDelayed myelosuppression- nadir 21 daysO6-methylguanine-DNA methyltransferase (MGMT)- DNA repair protein- removes methyl adduct from O6 position of guanineIncreased expression of MGMT causes temozolomide resistance
38 MethotrexateInhibits DHFR and prevents conversion of folates to active tetrahydrofolateSingle carbon donor for purine synthesisTetrahydrofolate pools depletedIntracellular methotrexate is polyglutamated and accumulates within the cell leading to apoptosisAsparaginase depletes glutamine (Capizzi I) rescuing cells from methotrexate toxicity
39 Leucovorin rescueDoes not require DHFR and can be metabolized to tetrahydrofolateCancer cells lack transporter for leucovorinUsually initiated hours after end of methotrexate infusion and continues till serum levels are < 0.1 microM ( some cases 0.5 microM)
41 Methotrexate Toxicity Salicylates, NSAIDS, penicillins, probenicid, sulfasoxazole, iodinated radiographic contrast, proton pump inhibitorsGlucarpidase hydrolyzes methotrexate to DAMPA and glutamic acidIndicated when serum creatinine X 2 times baseline, 24 hour level > 50 microM, 48 hour level > 5 microM OR 42 hour level > 10 microM and serum creatinine X1.5 times baselineLeucovorin should not be given 2 hours before & after
42 Irinotecan Prodrug- converted in liver and GI tract to SN-38 fold more potentMyelosuppression and diarrhea are dose limitingSN-38 conjugated in liver to SN-38G by UGT1A1UGT1A1 deficiency (Gilbert, Crigler Najjar) or drugs that inhibit UGT1A1 (valproate, sorafenib) can increase irinotecan toxicityBacterial beta-glucoronidase convert SN-38G to SN38 causing delayed diarrheaCefexime/Cefpodoxime eliminate gut bacteria decreasing the incidence of irinotecan induced diarrhea
43 Retinoic acid APML and high risk neuroblastoma Teratogenic Retinoic acid syndrome-weight gain, respiratory distress, serous effusions, cardiac and renal toxicityProphylaxis with dexamethasoneBoth ATRA and cis-RA can cause pseudotumor cerebri
44 Rituximab First FDA approved monoclonal antibody Used in the treatment of NHLReactivation of hepatitis B infection leading to fulminant hepatitis, liver failure and death.
45 Gemtuzumab Ozogamicin Monclonal antibody against CD33 that is expressed on AML cellsLinked to calicheamicin, a cell cytotoxinIncreased risk of veno-occlusive disease of liver independent of BMTIncreased risk of mortality in phase 4 studies.
46 Interferon-aHuman protein (9p) developed with recombinant DNA technologyAntitumor activityHairy cell leukemia, CML, multiple myeloma, follicular lymphoma, renal cell carcinoma, Kaposi sarcoma and melanomaBind to specific plasma membrane receptors and stimulates various genesAntiangiogenic, activation of immune cells and increased immunogenicity of tumor cells, directing gene stimulation
51 Mechanisms of Drug Resistance (2) AntibioticsMultidrug resistance, decreased topoisomerase II, increased intracellular catabolism, increased DNA repairVinca alkaloidsMultidrug resistance, altered tubulin subunitCorticosteroidsLoss or defect in glucocorticoid receptor
52 Mechanisms of Drug Resistance (3) Asparaginaseincreased intracellular asparagine synthase, neutralizing antibodiesRetinoids and ArsenicMutations in PML/RAR-alphaImatinibAbl-kinase domain mutations, MDR overexpression
53 Mechanism of Resistance DrugPharmacologic DefectDecreased uptakeMethotrexateexpression of folate receptorDecreased activationAra-C, Fludarabine, Cladribinedeoxycytidine kinasefolylpolyglutamyl synthetaseIncreased drug targetMethotrexate, 5-FU, ImatinibAmplified DHFR, TS, bcr-abl kinaseAltered drug targetVP-16, Doxorubicin, ImatinibAltered topo II, DHFR, bcr-abl kinaseIncreased detoxificationAlkylatorsglutathione or glutathione transferaseEnhanced DNA repairAlkylators, platinum analogsNitrosoureas, procarbazine, temozolomidenucleotide excision repairO6-alkyl-guanine alkyl transferaseDefective recognition of DNA adductsCisplatinMismatch repair defectIncreased drug effluxDoxorubicin, VP-16, vinca alkaloids, paclitaxel, topotecanMDR expression or MDR gene amplificationDefective checkpoint function and apoptosisMost anticancer drugsp53 mutations