Lecture 12: Antineoplastic drugs Flashcards
hyperplasia
increased capacity for proliferation
6 hallmarks of cancer
- sell-sufficiency in growth signals
- insensitivity to growth inhibitory signals
- evasion of programmed cell death (apoptosis)
- limitless replication potential
- sustained angiogenesis
- tissue invasion and metastasis
What type of disease is cancer?
Genetic disease
all cancer caused by abnormalities in DNA sequence composition
Gompertzian Growth
tumor grow faster early and slower later
effect of early intervention great than latter intervention
small tumor more responsive
Advantage of intermittent dosing
can allow for recovery of normal tissue between drug cycles
Nitrogen mustards
cause alkylation of DNA
form DNA crosslink by sequential N7-guanine alkylation
generate DNA adducts
Clastogen
any agent that induce sugar-phosphate backbone cleavage
Cyclophosphamide
Most useful alkylating agent
PRODRUG
activated by hepatic cytochrome P450
cytotoxic products: phosphoramide mustard and acrolein
Nitrosoureas
highly lipid-soluble, can cross BBB
useful in brain tumors
alkylating agent
Platinum complexes (Cisplatin)
NOT an alkylating agent
cause DNA crosslinking
1, 2 intrastrand adducts
cause severe distortion of DNA helix
covalent bonds to N7 positions of purine bases
Methotrexate
folic acid analogues
competitive inhibitor of dihydrofolate reductase
inhibit dTMP synthesis
normal cells can be rescued from toxicity by administering leucovorin
Leucovorin (folinic acid)
folic acid analogues
less metabolically active folic acid coenzyme
preferred uptake into normal cells
5-FU
pyrimidine analogues
5-FU converts into F-dUMP (active)
irreversible inhibitor of thymidylate synthetase
block DNA synthesis
major use in acute lymphoblastic leukemia (ALL), colon cancer
6-mercaptopurine, 6-thioguanine
purine analogues
counterfeit incorporation
interfere with purine biosynthesis
Anthracyclines (Daunorubicin, Doxorubicin)
antibiotics
one of the most useful class
inhibit topoisomerase II
DNA intercalation
produce ROS
Etoposide, Teniposide
derivatives of podophyllotoxin
no effect on microtubular structure at normal dose
stabilize “cleavable complex”
inhibit topoisomerase II
block cells in late S-G2 phase (prevent initiation of mitosis)
Topoisomerase II action
helps to segregate DNA before mitosis
drugs inhibit religation of the cleavable complex
Vincristine, Vinblastine (vinca alkaloids)
spindle poisons
depolymerization of microtubules
mitotic arrest at metaphase
Paclitaxel
significant activity in ovarian and advanced breast cancer
mitotic spindle poison
cause stabilization of microtubules and formation of abnormal bundles of microtubules
Tamoxifen
antiestrogen
competitive antagonist at the estrogen receptor
extremely useful in breast cancer
Traztuzumab (Herceptin)
humanized monoclonal antibody
targets HER2
inhibit proliferation of tumor that overexpress HER2
dont attach to other protein, few side effects
Bevacizumab (Avastin)
humanized monoclonal antibody
attach to circulating VEGF, prevents activation of VEGF receptors
used with 5-FU to treat metastatic colorectal cancer
Imatinib mesylate (Gleevec)
RTK inhibitor
used in chronic myelogenous leukemia
Acquired resistance
most common reason for drug resistance
initially sensitive tumor cell
selects for resistant cells in a tumor
New way to view MOA by antineoplastic drugs
no longer considered to kill cells
instead trigger DNA damage response in cell
p53
over 50% of tumor contains p53 mutation
“guardian of the genome”
increase p53 activity can sensitize tumor to apoptotic signal
