Chemotherapy Pharm Flashcards
class 1 agents class 2 agents class 3 agents
• Class 1: all cells killed
; ex: nonspecific alkylating agents, nitrogen mustard
• Class 2: cell cycle specific; plateaus
ex: vinblastine, methotrexate
• Class 3 agents: non-cycle specific but slower rate of kill than class 1; example: daunorubicin
survival curves are ____
what does that mean?
logarithmic
-a given dose kills a constant fraction of cells
MDR
multidrug resistance
over production of glycoproteins that pump drugs out of cells
nitrogen mustards def and mechanism (4 are?)
Mech: DNA is alkylated –> causes misreading and strand breaks
MICC - melphalan, ifosfamide, chlorambucil, cyclophasphamide
melphalan and chlorambucil
nitrogen mustards; phenylalanine derivatives
orally; 1.5-2 hr half life
clyclophosphamide
nitrogen mustard –>activated to aldophosphamide by hepatic cyt p450 –> hydrolized to active phosphoramide mustard in target cells
-inactivated by aldehyde dehydrogenase
reduced hepatotoxicity BUT --> o Toxicities (different than the others) – immunosuppression, pulmonary fibrosis, cystitis, water retention, alopecia, carcinogenesis
ifosfamide
Cyclophosphamide derivative for testicular cancer
2 chloroethyl nitrosureas
carmustine
lomustine
nitrosureas
carmustine and lomustine
Mech: Alkylation, DNA crosslinking, and carbamoylation of proteins
o lipid soluble –> disappear rapidly from plasma into lipids/CNS = long half-life
toxicities: delayed/severe hematopoietic depression;
which nitrosurea can be implantable wafer for treatment of malignant glioma.
carmustine
cisplatin
platinum coordinate; only the cis-dichloro form is active. Used for testicular/ovarian cancer, and head/neck cancers.
• Mechanism: alkylation by dissociation of Cl- ions leaving a + charged complex –> crosslinks are formed.
3 platinum coordination complex drugs
cisplatin
oxaliplatin
carboplatin
which form of cisplatin is active?
inactive?
cis-dichloro is active
plasma bound drug is inactive
oxaliplatin
cisplatin analogue used to treat colorectal cancer.
toxicity of platinum coordinator complexes
myelosuppression, nephrotoxicity, ototoxicity; nephrotoxicity can be attenuated by administration of the free radical scavenger amifostine.
carboplatin
platinum coordinator complex with less renal toxicity; dose is limited by leukopenia and thrombocytopenia
procarbazine
nonspecific alkylator (DNA, RNA, protein) • treat Hodgkin's lymphoma.
classes of alkylating agents
nitrosureas
platinum coordinators
nitrogen mustards
procarbazine
vinca alkaloids
Vincristine and vinblastine
potent plant-derived antitumor agents
• Mechanism: INHIBITS microtubule formation
vincristine - class? toxicity?
vinca alkaloid
neurotoxicity and stimulates ADH release
vinblastine - class? toxicity?
vinca alkaloid
myelosuppression and mucositis
2 taxanes?
paclitaxel and docetaxel
paclitaxel
taxane from yew tree Taxus; inhibits microtubule reorganization
which taxane is natural? which is semisynthetic?
docetaxel is semisynthetic
paclitaxel is natural
ixabepilone
binds directly to β-tubulin and, in contrast to the vinca alkaloids, promotes polymerization/stabilizes microtubules, arresting cells in G2/M.
o Used for treatment of taxane- and anthracycline-resistant breast cancer.
2 Epipodophylotoxins
Etoposide and teniposide
etoposide and teniposide
from mandrake plant podophyllotoxin
• Uses: Hodgkin’s lymphoma, diffuse histiocytic lymphoma and lung small cell carcinoma
• Mechanism: Inhibit topoisomerase II
• Toxicities: leukopenia, thrombocytopenia
2 derivatives from the plant alkaloid camptothecin
their mechanism?
irinotecan and topotecan
inhibit topoisomerase 1
irinotecan
derivative of plant alkaloid camptothecin
inhibits topoisomerase 1
treatment of metastatic colorectal cancer.
topotecan
derivative of the plant alkaloid camptothecin
inhibits topoisomerase 1
Effective for treatment of ovarian and small cell lung carcinoma.
2 anthracyclines
Daunorubicin and doxorubicin
Daunorubicin and doxorubicin
anthracyclines
o Free radical and strand breaks formation
o Inhibition of DNA topoisomerase II
• CARDIOTOXICITY
dexrazoxane
a protectant, iron chelator that inhibits free radical formation
can reduce cardiac damage from anthracyclines
what drug do you pair with anthracyclines (daunorubicin and doxorubicin) to prevent ROS and reduce cardiac damage?
dexrazoxane
bleomycin
antibiotic
• causes depurination and depyrimidation–> strand breaks
• NOT a substrate for MDR
• Toxicity: sub-acute or chronic pneumonitis, lesions of the skin
what is NOT a substrate for MDR?
bleomycin
an anti-metabolite?
its antidote if there is toxicity?
methotrexate
leucovorin
methotrexate
- folic acid analogue; inhibits dihydrofolate reductase
folic acid analogue that is a competitive inhibitor of the enzyme dihydrofolate reductase?
methotrexate
leucovorin
treats MTX toxicity
by supplying reduced folate to cells
pyrimidine analogues
analogues of uridine or cytidine –> synthesis of defective DNA and chain termination
5GACC –> 5 fluorouracil, gemcitabine, azacitidine, capecitabine, cytosine arabinoside
5GACC
the pyrimidine analogues –> synthesis of defective DNA and chain termination
5 fluorouracil, gemcitabine, azacitidine, capecitabine, cytosine arabinoside
capecitabine
a 5-FU prodrug whose final step of activation is catalyzed by thymidine phosphorylase; used in metastatic breast and colon cancer.
azacitidine
pyrimidine analogue
o Used to treat myelodysplastic syndrome.
purine analogues
6 mercaptopurine and 6 thioguanine
converted by HPRT
S phase of cell cycle is most sensitive
asparaginase
catalyzes conversion of asparagine to aspartate –> inhibition of protein synthesis.
o Toxicities: Reduction in concentration of secreted proteins (clotting factors, insulin, albumin, etc.), hypersensitivity reactions, hepatotoxicity.
kinase inhibitors
GIVES gefitinib imatinib mesylate vemurafenib erlotinib sorafenib
Imatinib mesylate
treats CML
—blocks the ATP-binding site of the c-abl tyrosine kinase
vorinostat
• Histone deacetylase inhibitor; Used to treat cutaneous T cell lymphoma
all trans retinoic acid
(vitamin A) - First line therapy for promyelocytic leukemia
cetuximab
directed against EGF receptor
trastuzumab
cell-mediated cytotoxicity;
.
bevacizumab
• Ab against VEGF; Designed to inhibit angiogenesis;
o risk of thromboembolic events;
rituximab
anti-CD20 monoclonal antibody
o Toxicity: can result in HBV reactivation.
ipilimumab?
gemtuzumab ozogamicin?
pembrolizumab?
TARGETs:
- -CTLA-4 –myeloid surface antigen CD33.
- -PD-1 receptor (programmed cell death 1)
intrathecal methotrexate
CNS prophylactic into CSF - dihydrofolate reductase inhibitor that targets CNS since chemo doesn’t cross into there but cancer can
toxicity: meningitis
