TY  - CHAP
M1  - Book, Section
TI  - Pharmacology and Toxicity of Antineoplastic Drugs
A1  - Chabner, Bruce A.
A1  - Fathi, Amir T.
A1  - Raje, Noopur S.
A1  - Hobbs, Gabriela S.
A1  - How, Chi-Joan
A1  - Johnson, Patrick Connor
A1  - Nabel, Christopher S.
A1  - Lei, Matthew M.
A1  - Leblebjian, Houry
A1  - Richardson, Paul G.
A2  - Kaushansky, Kenneth
A2  - Prchal, Josef T.
A2  - Burns, Linda J.
A2  - Lichtman, Marshall A.
A2  - Levi, Marcel
A2  - Linch, David C.
PY  - 2021
T2  - Williams Hematology, 10e
AB  - SUMMARYThe  discovery  and  development  of  curative  treatments  for  hemologic  malignancies  have  created  a  paradigm  for  effective  combination  therapy  now  adopted  in  treating  common  solid  tumors.  The  safe  and  effective  use  of  anticancer  drugs  in  the  treatment  of  hematologic  malignancies  requires  an  in-depth  knowledge  of  the  pharmacology  of  these  agents.  In  this  field  of  medicine,  the  margin  of  safety  is  narrow  and  the  potential  for  serious  toxicity  is  real.  At  the  same  time,  anticancer  drugs  cure  many  hematologic  malignancies  and  provide  palliation  for  others.The  intelligent  use  of  these  drugs  begins  with  an  understanding  of  their  mechanism  of  action.  Cytotoxic  anticancer  drugs  inhibit  the  synthesis  of  DNA  or  directly  attack  its  integrity  through  the  formation  of  DNA  adducts  or  enzyme-mediated  breaks.  These  DNA-directed  actions  are  recognized  by  repair  processes  and  by  the  checkpoints  that  monitor  DNA  integrity,  including  most  prominently  p53.  If  DNA  damage  cannot  be  repaired,  and  if  the  DNA  damage  reaches  thresholds  for  activating  programmed  cell  death,  then  DNA  damage  is  translated  into  tumor  regression.  In  the  past  2  decades,  attention  has  turned  to  the  possibility  of  identifying  molecular  targets  unique  to  tumor  cells,  or  dramatically  overexpressed  in  those  cells,  including  molecules  involved  in  cell  signaling  and  cell-cycle  control,  but  the  principles  of  drug  action  and  resistance  to  these  compounds  remain  the  same  as  for  cytotoxic  drugs.  The  underlying  mutability  of  tumors  leads  to  the  selection  of  tumor  cell  with  mutations  that  affect  drug  uptake,  activation  or  inactivation,  and  target  binding.  These  resistant  tumors  emerge  as  the  dominant  tumor  population.  Combination  chemotherapy  overcomes  resistance  to  single  agents,  but  multidrug  resistance  mechanisms,  such  as  amplification  of  the  multidrug  resistant  transporter,  or  loss  of  the  apoptotic  response,  can  result  in  broad-based  resistance.In  addition  to  the  molecular  determinants  of  drug  action,  pharmacokinetics  (the  disposition  of  drugs  in  humans)  plays  a  critical  role  in  determining  drug  effectiveness  and  toxicity.  Drug  regimens  are  designed  to  achieve  a  maximally  effective  concentration  in  plasma  and  tumor  cells  for  an  effective  duration  of  exposure.  Because  of  interindividual  variability  in  pharmacokinetics,  and  the  potential  of  these  agents  for  toxicity,  it  is  critical  for  hematologists  and  oncologists  to  understand  the  pathways  of  drug  clearance  and  to  adjust  dose  in  the  presence  of  compromised  hepatic  or  renal  function.  In  addition,  clinicians  must  be  alert  to  the  potential  for  drug  interactions,  particularly  the  ability  of  drugs  that  induce  or  inhibit  cytochrome  P450  metabolism  to  alter  patterns  of  drug  elimination.  Pharmacokinetic  monitoring  has  a  standard  role  in  the  use  of  certain  therapies,  particularly  high-dose  methotrexate,  and  in  the  evaluation  of  new  drugs  or  new  drug  combinations.Inherited  genetic  variations  in  drug-metabolizing  enzymes  may  lead  to  an  increased  risk  of  drug  toxicity  and  may  alter  the  antitumor  response.  The  most  important  of  these  familial  syndromes  affecting  treatment  of  leukemia  is  the  deficiency  of  thiopurine  methyltransferase,  which  slows  the  elimination  of  6-mercaptopurine  and  leads  to  unanticipated  toxicity  during  maintenance  chemotherapy  for  acute  lymphocytic  leukemia.  To  ensure  appropriate  dosing,  and  management  of  toxicity,  there  is  no  substitute  for  therapy  based  on  standard  protocols  and  peer-reviewed  clinical  trials.  Adherence  to  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/16
UR  - hemonc.mhmedical.com/content.aspx?aid=1180478576
ER  -