Pharm- Antineoplastic Agents 10/25 Flashcards
Nitrogen mustards, prototype
cyclophosphamide
ifosfamide
alkyl sulfonate, prototype
busulfan
platinum coordination complexes, prototype
cisplatin
vinca alkaloids, prototype
vinblastine
vincristine
taxanes, prototype
paclitaxel
epipodophyllotoxins, prototype
etoposide
antibiotics, prototype
bleomycin, doxorubicin
enzymes, prototype
L-asparaginase
folic acid analogs, prototype
methotrexate (MTX)
pyrimidine analogs, prototype
fluorouracil (5-fluorouracil, 5-FU)
purine analogs, prototype
mercaptopurine
differentiating agents, prototype
tretinoin
biological response modifiers, prototype
interferon-alfa
interleukin-2
immunomodulators, prototype
thalidomide
rescue agents, prototype
leucovorin
mesna
protein tyrosine kinase inhibitors, prototype
dasatinib
erlotinib
imatinib
lapatinib
proteasome inhibitor, prototype
bortezomib
monocolonal antibodies, prototype
bevacizumab
cetuximab
rituximab
trastuzumab
agents used to minimize adverse effects, prototype
erythropoietin serotonin antagonists (ondansetron)
primary induction therapy
main treatment that provides the best possible outcome, also called first-line therapy
neoadjuvant therapy
treatment given BEFORE primary induction therapy in order to improve outcome
adjuvant therapy
additional therapy given CONCOMITANTLY or AFTER primary induction therapy in order to reduce the probability of relapse
cell cycle specific agents, definition
cytotoxic for cells during specific phases of the cell cycle
cell cycle non-specific agents, definition
cytotoxic regardless of whether the cells are cycling or resting in G0 compartment (although cycling cells are more sensitive)
growth fraction
the ratio of proliferating cells to resting cells (G0). It is a determinant of responsiveness to chemotherapy
cells with high growth fraction
bone marrow
GI tract
hair follicles
sperm-forming cells
log cell kill hypothesis
a fraction (not an absolute number) of cells are killed. A three-log cell kill eliminates 99.9% of cells
primary resistance
an absence of response on the first drug exposure, thought to be d/t genomic instability
acquired resistance
develops in response to exposure to a given antineoplastic agent; often highly specific to a single drug, or class of drugs, and is usually d/t an increased expression of 1+ genes
Multi-drug resistance
P-glycoprotein: ATP-dependent efflux pump that actively pumps antineoplastic agents out of cells, confers resistance to a broad range of agents
Anthracyclines, vinca alkaloids, etoposide, paclitaxel, and dactinomycin
purpose of hematopoietic agents in treatment
for treating neutropenia
thrombocytopenia
anemia
purpose of administering ondansetron
serotonin receptor antagonists for emetogenic effects
purpose of administering bisphosphonates
delay skeletal complications
five major types of alkylating agents
- nitrogen mustards
- nitrosoureas
- alkyl sulfonates
- methylhydrazine derivatives
- triazines
* * Also included are platinum compounds**
Alkylating agents, MOA
form covalent linkages with DNA, both intra- and inter-strand. Prevents DNA from unwinding, therefore inhibits transcription and translation
biotransformation of cyclophosphamide
forms acrolein, which causes hemorrhagic cystitis
Mesna
inactivates acrolein and is used for prophylaxis of chemotherapy-induced cystitis
busulfan toxicity
pulmonary fibrosis
cisplatin toxicity
renal tubular damage
ototoxicity
cyclophosphamide toxicity
hemorrhagic cystitis
general toxicities of alkylating agents
direct vesicant (blistering) effects and tissue damage at injection site (consider oral administration) acute toxicity: N/V w/i 30min delayed toxicity: bone marrow depression with leukopenia, thrombocytopenia, nephrotoxicity, alopecia, mucosal ulceration, intestinal denudation
three major types of antimetabolites
- folic acid analogs
- pyrimidine analogs
- purine analogs
Antimetabolites, MOA
structural analogs to compounds necessary for cell proliferation, block or subvert pathways that are involved in (or lead to) cell replication
Antimetabolites, cell cycle specific or non-specific?
Cell cycle specific (S phase)
Alkylating agents, cell cycle specific or non-specific?
cell cycle non-specific
methotrexate, MOA
inhibits dihydrofolate reductase (DHFR), thereby inhibiting cell proliferation
indications for methotrexate
cancer
RA
psoriasis
leucovorin
reduced folate can bypass DHFR
used to rescue normal cells from high-dose MTX
antidote for accidental MTX overdose
fluorouracil, MOA
active compound (FdUMP): covalently binds thymidylate synthetase and blocks de novo synthesis of thymidylate. incorporated into both DNA and RNA (FdUTP into DNA, and FUTP into RNA).
Can leucovorin rescue 5-FU?
no, upstream of the enzyme
6-mercaptopurine, MOA
prodrug, inhibition of several enzymes of de novo purine nucleotide synthesis, incorporates into DNA and RNA
6-MP and Allopurinol
6-MP normally undergoes first pass effect in the liver by xanthine oxidase.
allopurinol inhibits xanthine oxidase. administering allopurinol with oral 6-MP results in increased levels of 6-MP and increased toxicity
anti-metabolites, cell cycle specific or non-specific?
cell cycle specific (S-phase)
common toxicities of anti-metabolites
N/V/D, myelosuppression, immunosuppression, thrombocytopenia, leukopenia, hepatotoxicity
vinca alkaloids, ADRs
alopecia
myelosuppression (vinblastine > vincristine)
vincristine exhibits neurotoxicity (numbness/tingling in extremities, loss of DTRs, motor weakness, autonomic dysfunction)
vinca alkaloids, MOA
bind to beta-tubulin and inhibit microtubule assembly
vinca alkaloids, cell cycle specific or non-specific?
cell cycle specific (M-phase)
taxanes, MOA
bind to beta-tubuline and stabilize microtubule assembly.
taxanes, cell cycle specific or non-specific?
cell cycle specific (M-phase)
taxanes, ADRs
Paclitaxel: hypersensitivity reactions in hands and toes, change in taste
Docetaxel: greater cellular uptake; retained intracellularly longer than paclitaxel permitting smaller dose, which reduces AEs, hypersensitivity, neutropenia, alopecia
topoisomerase inhibitors, cell cycle specific or non-specific?
cell cycle specific (primarily S phase, also G1 and G2). EXCEPTION: anthracyclines
anthracyclines, MOA
inhibit topoisomerase, intercalate DNA, oxygen free-radicals bind to DNA, causing single- and double-stranded DNA breaks
anthracyclines, cell cycle specific or non-specific?
cell cycle non-specific (but cycling cells are most susceptible)
anthracyclines, ADR
free radicals are linked to significant cardiotoxicity
cumulative cardiac damage can lead to arrhythmias and heart failure
bleomycin, class
anti-tumor antibiotic
bleomycin, MOA
free radicals cause single- and double-stranded DNA breaks
bleomycin, cell cycle specific or non-specific?
cell cycle specific (G2 arrest)
bleomycin, ADR
pulmonary toxicity, minimal myelosuppression
Imatinib
a small molecule inhibitor of ABL tyrosine kinase, can also inhibit the RTKs PDGFR and c-KIT.
BCR-ABL fusion protein results from t(9:22) translocation, found in 95% of CML patients
erlotinib and gefitinib, MOA
inhibit EGFR, a receptor tyrosine kinase.
erlotinib and gefitinib, ADR
dermatologic toxicities
Target for trastuzumab and lapatinib
HER2/neu (breast CA)
trastuzumab, ADR
cardiovascular complications (decreased LVEF, HF)
Pegaspargase, drug class
Natural Product- Enzyme
Teniposide, drug class
Natural Product- Epipodophyllotoxins
Daunorubicin, drug class
Natural Product- Antibiotic
Dacarbazine, drug class
Alkylating Agents- Triazenes
Streptozocin, drug class
Alkylating Agents- Nitrosoureas
Oxaliplatin, drug class
Platinum Coordination Complex
Cytarabine (Cytosine arabinoside; Ara-C), drug class
Antimetabolite, Pyrimidine analogs
Pentostatin, drug class
Antimetabolite, Purine analogs
Chlorambucil, drug class
Alkylating Agents, nitrogen mustards
