Chemotherapeu+cs  

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Chemotherapeu+cs  

Michael  Policastro,  MD  Director,  Medical  Toxicology,  QESI  

Clinical  Assistant  Professor,  WSU  

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Cancer  treatment  strategy  

•  Cell  surface  receptor  •  Intracellular  signal  pathway  

•  Cell  maintenance    process  

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Chemotherapeu+cs  

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Classifica+on  Chemotherapeu+cs  

•  Alkyla@ng  Agents:    Busulfan,Dacarbazine,  Melphalan,    Mustards  (Chloramphenical  Cyclophosphamide,  ifosfamide,  Mechlorethamine)    

               Nitrosureas  (  carmus+ne)    

             Pla+noids  (cispla+n,carbopla+n),  Procarbazine  (  hydrazine)  

•  An@bio@c:                            Anthracyclin  (Danorubicin,  Doxorubicin,  Idarubicin,)    

               Mitoxantrone,  Bleomycin,  Mithramycin,Mitomycin,  Mitoxantrone  

•  An@metabolite:-­‐  Methotrexate,  fludarabine,  mercaptopurine,  pentostain,thioguanine,  cyctaarabine,  Fluorouracil  (  5-­‐FU)  

•  An@mito@c:Vinblas+ne,  Vincrisi+ne,Paclitaxel,  etoposide,  teniposide  

•  Biologics  •  Radionuclides  

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Targeted  Sites  Of  Ac+on  

DNA  duplica@on  

Interphase:  All  phases  except  mitosis  

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Adverse  effects  

•  Alkyla@ng  Agents:  Transamani+s,  pulm  fibrosis,  renal  failure,  sz  

 *Cylophosphamide-­‐  hemorrhagic  cys++s  due  

to  ACROLEIN  *carmus+ne-­‐toxic  encephalopathy,  

*Cispla+n-­‐  ototoxicity,re+nal  tox,  renal  failure,  ↓  lytes  

•  An@bio@c:Mucosi+s,  myelosuppression,  dysrhythmias,  cardimyopathy  

*Bleomycin-­‐  Pulm  fibrosis,  BOOP  

*  Mitomycin  C-­‐  Hemoly+c  uremic  syndrome  

•  An@metabolites:  mucosi+s,  n,v,  transamini+s,  pancrea++s,  hyperuricemia,myelosuppression,  renal  failure  

 *  5  FU  –Cardiomyopathy,  CHF  

 *carmus+ne-­‐hypersensa+vity,  skin  reac+ons,  BM  suppression  

•  An@mito@cs:  Autonomic  dysfunc+on,  dysrhythmias,  myelosupression,  SZ,  Peripheral  neuropathy,  SIADH  

*  Taxol-­‐  GI  perfora+on  

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Chemotherapeu+cs  

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Methotrexate  (MTX)  

MTX  Inhibits    *Dihydro  folate  reductase  (DHFR)  *  Thymidylate  synthetase  (TYMS)  

N5-­‐formyl  FH4    (Leucovorin)  

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Methotrexate  

•  Inhibits  DHFR,  TYMS  

•  Tri-­‐phasic  clearance,  (  2nd  phase-­‐  renal  clearance,  3rd  phase  +ssue  redistribu+on  into  plasma)  

•  Acidosis,  renal  failure,  doses  100-­‐1000mg/m2    associated  with  toxicity,  folate  deficiency  

•  Toxicity  primarily  dependent  on  DURATION  of  exposure  •  Toxicity:  Mucosi+s,hepa++s,renal  failure,  pancytopenia,  

seizures,  hemiparesis,alopecia,olgiospermia,hypersensa+vity  pneumoni+s  

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Treatment  of  MTX  Toxicity  

•  Leucovorin  15mg/m2  

•   q  6  hrs  x  2-­‐  3  days  un+l  MTX  <5  x  10-­‐8    

•  IVFS  •  Urinary  Alkaliniza+on  •  Hemodialysis  

•  Thymidylate  IV,  carboxypep+dase  

•  Intrathecal  MTX:  CSF  drainage/exchange  

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Chemotherapeu+cs  

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Neurologic  Adverse  Effects  

•  AMS/SZ:  MTX,  Vincris+ne,  Mustards  (Chloramphenical  Cyclophosphamide,  ifosfamide,  mechlorethamine,carmus+ne)  

•  SZ:  Chlorambucil/Ifosfamide-­‐  toxin  (chloroacetaldehyde)  •  Cerebellar  ataxia:    5-­‐FU    •  Peripheral  Neuropathies:  vinca  alkaloids  ,  cispla+n        -­‐(  vincris+ne>vinblas+ne;  sensory  +  motor  and  ascending)  

     -­‐  taxol-­‐  primarily  sensory  •  Cranial  N  (  3-­‐7,  10):    vinca  alkaloids  •  Tinnitus,  hearing  loss,  re@nopathy:  cispla+n  

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An+-­‐Microtubules  

•  Colchicine:  Colchicum  autumnale,  Gloriosa  superba  

-­‐  Meta-­‐phase  (  M)    arrest  -­‐  3  phases  tox:  GI,  Muli-­‐organ  failure,  

alopecia,  Diabetes  insipidus  -­‐  TX:  MDAC,  G-­‐  CSF  

•  Vinca  Alkaloids:  Catharanus  roseus        -­‐  Vincris+ne  most  reported  chemo  OD  in  

lit.  ,  -­‐  Severity:  Vincris+ne>vinblas+ne    -­‐      Vincris+ne:  Cri+cal  Neuro  ,  SIADH              (  sensory/motor,  ascending)  -­‐  Vinblas+ne:  bone  marrow  -­‐  TX:  Glutamic  acid-­‐  neuro,  

Hyaluronidase-­‐  extravasa+on  injuries  

•  Paclitaxel:    Taxus  brevifola  •  Podophyllotoxin  :  Podophyllum  

peltatum  -­‐        derivates:  etoposide,  teniposide  -­‐  Podophyllin  more  tox  than  

derivates,  similar  tox  colchicine  -­‐  Podophyllin-­‐  M-­‐  phase  -­‐  Etoposide-­‐  inter-­‐phase,  

topoisomerase  II  inhibitor  -­‐  No  specific  an+dote  

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Renal/Electrolyte  Adverse  Effects  

•  SIADH:  Vincris+ne  •  Diabetes  Insipidus(DI)  :  Colchicine  •  Hemorrhagic  cys@@s:  Cyclophosphamide,Ifosfamide    

               **toxin=  acrolein  

•  Renal  Failure,  Distal  tubular  necrosis:  Cispla+n  •  Hypomagnesium,Hypocalcemia:  Cispla+n  

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Chemotherapeu+cs  

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Cardiac  Adverse  Effects  

•  Athracycline  abx  (Danorubicin,  Doxorubicin,  Idarubicin)              —irreversible  conges+ve  cardiomyopathy              —immediate  :  dysrhythmia,  pericardi+s,myocardi+s  

•  Cyclophosphamide              —CHF,  hemorrhagic  pericardi+s,  myocardial  necrosis  

•  5-­‐FU                  —vasospasm,  myocardial  ischemia,  cardiogenic  shock  •  Vinca  Alkaloids            ̶      Platelet  aggrega+on,  coronary  spasm  

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Pulmonary  Adverse  Effects  

•  Bleomycin:  pulm  fibrosis,  BOOP,  nodular  lesions  

•  Methotrexate  (  MTX):  hypersensa+vity  pneumoni+s,  Hilar  adenopathy  

•  Cytosine  arabinoside:  non-­‐cardiogenic  pulmonary  edema  

•  Busulfan:  alveolar-­‐inters+al  proteinosis  •  Nitrosureas  :Upper  lobe  pulmonary  fibrosis  

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Mucosi+s  

•  MTX  •  5FU  •  Bleomycin  

•  Doxorubicin  

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Chemotherapeu+cs  

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An+dotes  •  Dexaroxane  :  Anthracycline  ABX  (  Doxurubicin)  cardiomyopathy  :  Iron  chelator  •  NA  Thiosulfate:  Cispla+n  •  MESNA  (  2-­‐mercaptoethane  sulfonate  sodium):  cyclophosphamaide-­‐  inac+vates  

acrolein  to  thioether  •  Methylene  Blue:  Ifosfamide  encephalopathy  •  Amifos@ne:  Cispla+n;  ac+vated  intracellular  by  alkaline  phosphatase,  scavages  free  radicals  •  Folinic  Acid:  MTX  •  Glutamic  Acid:  Vincrisi+ne  –  preven+on  neuropathy  •  DDTC  (diethyldithiocarbamate)  /Disulfuram:    Cispla@n,  also  recall  Ni,  Ni  Carbonyl  •  KI:  131    Iodine  •  Prussian  Blue:  Thallium  •  DTPA:  Plutonium  •  G-­‐CSF:  colchicine,  most  chemo  agents  •  Pyridoxine:  Procarbazine  (  hydrazine)  

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Occupa+onal  Disulfuram  Agents  

Clinical  Environmental  Health  and  Toxic  Exposures  .Sullivan  and  Kreiger.2001  .  Table  18-­‐4.  P.238  

Goldfrank’s  Toxicologic  Emergencies.  6th  edi+on.  2006.  Figure  77.1  p.1177  

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 Decontamina+on/Elimina+on  

AC:  MTX,  busulfan,  melphalan,  chlorambucil  

MDAC:  colchicine  Urinary  Alkaliniza@on:  MTX  

Plasmapharesis:  Cispla+n,Vincrisi+ne  

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Chemotherapeu+cs  

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Biologics  (  MAB)  

An@-­‐Inflammatories  

•  TNF  inhibitors  •  T  cell  inhibitors  •  IL  inhibitors  •  Leukocyte  Integrin  Blockers  

An@-­‐cancer  •  GF/  Tyrosine  Kinases          (  VEGF,  PDGF,  EGF)  •  Serine/threonine  kinase              (  ATK)  •  Intracellular  protein  kinases              (  RAS,  RAF,  APC)  •  Transcrip+on  factors/genes  •  G  proteins  •  Phospholipases  

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Extravasa+on  An+dotes  

•  Dimethyl  sulfoxide  (DMSO):  topical:  Antracyclines,Mitomycin:  limits  free  radicals;  compress-­‐  ICE  

•  Dexrazoxane:  IV:  Anthracyclines:  limits  free  radicals  •  Sodium  thiosulfate:  IV:  Mechlorethamine:  prevents  +ssue  

alkyla+on  

•  Hyaluronidase:  SubQ  :  Vinca  alkaloids,epipodophyllotoxins:  degrades  hyaluronic  acid;  compress-­‐  WARM  

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Regulatory  Laws  

EPA  Resource  Conserva@on  and  Recovery  Act  40  CFR  

Regulates  9  an+-­‐neoplas+cs:  arsenic  trioxide,  chlorambucil,  cyclophosphamide,  daunomycin,  melphalan,  mitomycin  c,  napthylamine  mustasrd,  streptozocin,  uracil  mustard  

**  Review  Regulatory  Laws  and  Programs    

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Chemotherapeu+cs  

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Chemotherapeu+cs  

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Transplant  Immunosuppressive  Agents  

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Transplant  Biologics  

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Chemotherapeu+cs  

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Calcineurin  Inhibitors:  cyclosproin/tacrolimus  Side  effects  

•  Hypertension,  Hyperlipidemia  •  Nephrotoxicity  (  inhibi@on  pep@dyl,  prolyl-­‐cis  transisomerase)  

•  Cardiovascular  death  increase  •  CSA:  hirsui+sm,  gingival  hyperplasia  

•  Tacrolimus:DM  

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Calcineurin  inhibitors  :  cyp3A4    drug  interac+ons    

Increased  levels  •  CCB  •  Emycin  •  Fluconazole  •  Allopurinol  •  Bromocrip+ne  •  Colchicine  •  Metoclopramide  •  Protease  inhibitors  •  Grape  fruit  juice  

Decreased  levels  

•  Rifampin  

•  CBZ,  Phenobarb,  Phenytoin  •  Octreo+de  •  St.  John’s  Wort  

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Sirolimus  (Rapamycin)    

•  Macrolide  compound,  3A4  •  Inhibits  IL-­‐2/5,  binds  to  kinase  MTOR  also  known  as  FRAP,  RAFT  

•  MTOR:  signal  transduc+on  of  GF,  PI3  kinase,  AKT/  protein  kinase  B  pathway  

•  Side  effects:Hyperlipidemia,  cytopenia,  arthalgias,  apthous  ulcers,  inters++al  pneumonia,  hepa@c  artery  thrombosis,  wound  dehiscence  (  liver  transplant)  

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Chemotherapeu+cs  

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Mycophenolate  Mofe+l  (  MMF)  (Cellcept)  

•  Blocks  purine  nucleo+de  synthesis  inhibits  type  2  IMPDH  (  inosine  monophosphate  dehydrogenase)  =  inhibits  conversion  of  IMP  to  GMP  

•  No  effect  on  cytokines  •  Side  effects:  GI,  heme  

•  Do  not  give  with  Azathioprine  or  other  an@-­‐metabolites  

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MMF  drug  interac+ons  

Increased  levels  

•  Acyclovir,ganciclovir  •  Probenicid  •  Salicyaltes  •  Sirolimus  

Decreased  levels  

•  Antacids:  Al/Mg  

•  Iron  •  Metronidazole  

•  Norfloxacin  •  rifampin  

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TNF-­‐alpha  contraindica+ons  

•  Latent  TB  or  Hep  B  •  Chronic  Heart  failure  •  Vaccina+ons  with  live  organisms  

•  Other  possible  side  effects:  infx,  autoimmune  disorders,  uvei+s,  mul+ple  sclerosis,  psoriasis,  lymphoma  

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Chemotherapeu+cs  

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TNF-­‐alpha  

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Pregnancy  And  Immune  Modulators  

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Pregnancy  and  Biologicals  

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Chemotherapeu+cs  

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SERMs  (  Selec+ve  estrogen  receptor  modifying  drugs)  

Side  effects  •  Tamoxifen  ,  toremifene  (  Fareston),  fulvestrant(Faslodex)  

•  Hot  flushes,  decreased  bone  mineral  density  premenopause  

•  Thrombosis  (  DVT,  PE,  Stroke)  

•  Increased  endometrial  thickness,  vaginal  bleeding,  ovarian  cyst  

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Aromatase  Inhibitors  

•  Anstrazole  (Arimadex),  exemestane  (Aromasin),letrozole  (Femara)  

•  Side  effects:  menopause  symptoms,  muscle  cramps  

•  NO  increase  in  endometrial  cancer  

•  Less  effects  than  SERMS  

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Signal  Transduc+on  Inhibitors:    Tyrosine  Kinase  Inhibitors,  side  effec  

ts  •  EGFR:gefi+nib(Iressa),erlo+nib(Tarceva),cetuximab(erbitu

x),panitumumab(Vec+bix),(  RASH-­‐papulopustular,  inters@@al  lung  disease,  diarrhea)  

•  VEGF:Vandetanib(Zac+ma),Sorafenib(nexavar),  suni+nib(sutent),  pazopanib  (Votrient)    

       (  coagulopathy,  thrombosis)  •  Her-­‐2:tratuzamab(Hercep+n),lapa+nib(Tykerb),  

pertuzumab  (Omnitarg),  fever,  chills  (  Anthracycline  +  her-­‐2  =  ventricular  dysrhythmias,  CHF)  

•  BCR-­‐ABL:ima+nib  mesylate  (  Gleevac)  (  edema)  •  Fusion  protein  EML4-­‐ALK:  Crizo+nib(Xalkori)  

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Chemotherapeu+cs  

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Signal  Transduc+on  Inhibitors:  mTOR  

•  Temsirolimus  (Torisel)  •  Everolimus  (Afinitor)  •  Hypersensi+vity  reac+ons,  hyperglycemia  •  Opportunis+c  infec+on  •  Bowel  Perfora+on  •  Coagulopathy  •  Avoid  Live  vaccines  •  CYP  3A4  interac+ons  

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Signal  transduc+on:    serine/threonine  kinase  BRAF  

•  Vemurafenib  (Zalboraf)  •  Rash,  LFTS  

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Gene  Expression/Cell  Func+on  Inhibi+on  

•  HDAC(  Histone  Deacytylase):Vorinostat  (Zolinza),  Romidespsin  (Istodax)    

 Thrombocytopenias,  rash  

•  Re+noids:  Bexarotene  (Targre+n),Alitre+noin  (Panre+n),  Tres+noin(Vesanoid)  

Pregnancy  X,  cataracts,  rash/photosensi@vity,  LFTS  

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Chemotherapeu+cs  

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Angiogenesis  Inhibitor  Bevacizumab  (Avas@n)  

•  Endothelial  VEGF  •  HTN,  Thromboembolism,  Bleeding  

•  Proteinuria,  impaired  wound  healing  

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Apoptosis  Inducer  

•  Proteosome:Bortezomib  (Velcade)  •  An@folate:  Pralatrexate  (like  MTX):accumulates  in  cells  express  RFC-­‐1  protein  

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Immune  Cell  Modulators  

•  CD3:  orthoclone  OKT3  •  CD20:  Rituximab  (  Rituxan),  ofatumumab  (Arzerra),  

ibritumomab  (Zevalin),tositumomab  HSV  ,  dyspnea,  inters@@al  pneumoni@s  •  CD30:Brentuximab  (Adcentris)  •  CD33:Gemtuzumab  •  CD52:  Alemtuzamab  (  Campath)  (ITP,  autoimmune  

thyroid)  •  CTLA-­‐4:  Ipilimumav  (Yervoy)  •  IL-­‐2:  Denileukin  (Ontak),  daclizumab  (Zenapax)  (CD25  ,  

alpha  chain  IL-­‐2)  

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Chemotherapeu+cs  

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Rituximab(  Rituxan)  Side  effects  

•  Monoclonal/chimeric  an+-­‐  CD  20  •  HSV  ,  dyspnea,  inters++al  pneumoni+s  

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Natalizumab  (Tysabri)  Side  effects  

•  MAB  against  integrin  •  progressive  mul+focal  leukoencephalopathy  (PML)  caused  by  reac+va+on  of  the  JC  virus,  

•  hepatotoxicity  

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