Antineoplastic Agents Flashcards
Conventional chemotherapeutic agents
- inhibit metabolic processes necessary for cell replication (synth of RNA/DNA/PRO)
*damage DNA in replicating cells
*interfere with mitotic machinery
Downside: difficult or impossible to destroy tumor cells without harming normal host cells; low TI
M Phase of Cell cycle
mitotic splindles pull DNA apart
G0 phase
resting
G1/G2 phase
restriction point (checkpoint)
S phase
macromolecules synth for cell division; DNA precursors
tumor cell growth fraction
- fraction not in G0
- dividing tumor cells are responsive to conventional chemo
- differentiated tumor cells (g0) are not
- tumor stem cells are often not responsive
micrometastases
- presumably derived from tumor stem cells, generally the ultimate cause of lethality
- may be present but undetectable at diagnosis
- often susceptible to chemo
normal cells susceptible to toxic side effects
- bone marrow precursors of blood cells
- intestinal epithelial cells
- oral mucosa
- hair follicles
- gonadal cells (spermatogonial stem cells and oocytes/follicular cells)
bischloroethyl amines
class of anti-tumor alkylating agents; chloroethyl groups are electrophilic and interact with nucleotides
mechlorethamine (nitrogen mustard)
*prototype of alkylating agents; bischloroethyl amine highly reactive DNA alkylating agent (IV-reacts with H20), can cause necrosis
cyclophosphamide
less reactive (po) bischloroethyl amine; DNA alkylating activity after activation in liver or tumor tissues (prodrug)
nitrosoureas
class of alkylating agents; little cross-resistance with other alkylating agents; cross BBB (useful for brain cancers)
procarbazine
metabolized to alkylating and free radical intermediates; effective against Hodgkin’s in MOPP regimen; little cross-resistance with antineoplastic agents; leukemogenic (5-10% risk with MOPP); mutagen
MOPP
chemo regimen for Hodgkin’s : mechlorethamine, vincristine (Oncovin), procarbazine, prednisone
methotrexate
folic acid analog
DHFR inhibitor: blocks synthesis of DNA/RNA/PRO precursors; stops dihydrofolate from becoming tetrahydrofolate–which inhibits thymiylate synthetase; accumulates in cells as a polyglutamate derivative; S phase specific
resistance to methotrexate
cells: -amplify DHFR gene
- mutate DHFR gene
- decreased uptake
- increased efflux (MRP 2/4)
- leucovorin “rescue:” source of tetrahydrofolate, bypasses block of DHFR, sometimse used in intervals of recovery
6-mercaptopurine
- purine antagonists
- metabolites that inhibit de novo purine synth
- interfere with DNA/RNA synthesis
- S phase specific
- metabolically inactivated by xanthine oxidase (in milk)
- interacts with allopurinol (xanthine oxidase inhibitor, often used in conjunction with chemo to reduce uric acid accumulation/kidney toxicity associated with tumor cell death)
How do cells develop resistance to purine antagonists
-activated by conversion to NMPs/NTPs via HGPRT; cells down-regulate HGPRT enzyme
6-thioguanine
- purine antagonists
- metabolites that inhibit de novo purine synth
- interfere with DNA/RNA synthesis
- S phase specific
fluorouracil (5-FU)
- pyrimidine antagonist
- metabolite fdUMP inhibits thymidylate synthetase, causes thymineless death
- metabolites incorporated into newly synth. DNA/RNA
- S phase specific
- synergistic toxicity when admin with leucovorin (binds thymidylate synthetase even more strongly)
- variable abs orally, generally IV
capecitabine
-oral prodrug of fluorouracil
-contains hydrophobic chain, helps enter cells. MUST BE CONVERTED to 5FU via thymidine phosphorylase
-may be preferentially activated in tumor tissues
Use: colon ca, refractory breast ca
cytarabine
- sub to ribose ring
- araC converted to araCMP then araCTP , with inhibits DNA synthesis, incorporated into DNA causing mutations and breaks
- metabolic activation requires deoxycytidine kinase
resistance to cytarabine
mutational loss of deoxycytidine kinase
daunorubicin/doxorubicin
-antitumor antibiotics:anthracyclines
-3 member ring
-widely used with broad spectrum
-DNA intercalation, interferes with DNA topoisomerase II binding, DNA scission
dose limiting: irreversible cardiac toxicity at high doses
bleomycin
- antitumor antibiotics
- DNA strand scission
- broad spectrum
- no sig. myelosuppression, useful in combo (ABVD in hodgkin’s lymphoma)
- causes anaphylactic reactions- small test doses
ABVD
combo used for Hodgkin’s Lymphoma; adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine
vinblastine
- mitotic spindle poison; vinca alkaloids
- M phase specific
- inhibitor of microtubule polymerization
- S.E: N/V, dose limiting bone marrow suppression
- Hodgkin’s lymphoma (ABVD) & other lymphomas
how do cells dev resistance to vinblastine
tubulin gene mutations
vincristine
- mitotic spindle poison; vinca alkaloid
- also arrests mitosis via binding to microtubules
- no acute SE, milder non-dose limiting BM suppression, dose limiting neurotoxicity.
- acute childhood leukemia
- part of MOPP for hodgkin’s
resistance to vincristine
tubulin gene mutations
paclitaxel
- mitotic splindle poison
- plant alkaloid
- enhances tubulin polymerization
- M phase specific
- ovarian/ adv
Topotecan
- Topoisomerase I inhibitor
- bind to cleavable complex of DNA topoisomerase I and DNA, block religation of single-strang break
- Double strand breaks occur with DNA replication
- S phase specific
- ovarian/lung ca.
- dose limiting tox: myelosuppression
irinotecan
- Topoisomerase I inhibitor
- bind to cleavable complex of DNA topoisomerase I and DNA, block religation of single-strang break
- Double strand breaks occur with DNA replication
- S phase specific
- colon ca
- dose limiting tox: diarrhea
etoposide
DNA topoisomerase II inhibitor
- forms ternary complex with topoisomerase II and DNA
- interferes with religation of double-strand break
- DNA stand scission
- anthracycline antibiotics can do this as well
Cisplatin
- platinum coordination complex
- non cell-cycle specific
- may fxn by inhibiting DNA synthesis
- useful in combo
- ovarian/testicular ca.
toxicity: nephrotoxicty, acoustic nerve dysfunction
tamoxifen
- competitive inhibitor of estrogen binding to receptor, technically a selective estrogen response modulator (SERM)
- partial agonist of estrogen receptor
- efficacy varies in different tissues due to multiple receptor forms
- low toxicity, SE (hot flashes)
- employed effectively in cancers of estrogen-responsive tissues: breast, uterine, endometrium
- increased risk of thrombosis and endometrial cancer
Estrogen receptor status
presence of estrogen receptors in breast ca tissues predicts benefit from tamoxifen rx. (40 percent are ER positive)
prophylactic tamoxifen
has been suggested as an effective means of prevention for high risk women (50% risk reduction) but not increased lifespan
Tamoxifen postmenopausal
reduces risks of bone fractures
raloxifene
SERM given for prevention of breast ca in patients with osteoporosis
letrozole
-aromatase inhibitor
-inhibit conversion of androgens to estrogen
-effectively block estrogen production in postmenopausal women
-not used in pre-menopausal women because of compensatory gonadotropin/ovarian estrogen production
-more effective than tamoxifen in treatment of ER+ breast ca. in post-menopausal women
-no increased incidence of uterine ca. or thrombosis
SE: joint pain, loss of bone density (rx with biphosphonates)
anastrazole
-aromatase inhibitor
-inhibit conversion of androgens to estrogen
-effectively block estrogen production in postmenopausal women
-not used in pre-menopausal women because of compensatory gonadotropin/ovarian estrogen production
-more effective than tamoxifen in treatment of ER+ breast ca. in post-menopausal women
-no increased incidence of uterine ca. or thrombosis
SE: joint pain, loss of bone density (rx with biphosphonates)
exemestane
-aromatase inhibitor
-inhibit conversion of androgens to estrogen
-effectively block estrogen production in postmenopausal women
-not used in pre-menopausal women because of compensatory gonadotropin/ovarian estrogen production
-more effective than tamoxifen in treatment of ER+ breast ca. in post-menopausal women
-greatly reduces risk of breast ca. in high risk post menopausal women
-no increased incidence of uterine ca. or thrombosis
SE: joint pain, loss of bone density (rx with biphosphonates)
leuprolide
- synth peptide analog of GnRH, GnRH agonist
- cont., high dose rx (vs. physiological:pulsatile) lowers androgen level in men and estrogen levels in pre-menopausal women (androgen ablation)
- as effective as estrogen therapy or orchiectomy in rx of prostate ca. with fewer side effects
flutamide
- androgen receptor antagonist
- alone ineffective against prostate ca due to rapid androgen receptor mutation
- used in conjunction with leuprolide to block effects of the initial pulse of androgen levels and associated “flare” of prostate ca. at start of therapy
prednisone
- induces apoptosis in leukemia cells
- used in several multidrug regimens for leukemia, lymphoma, and myeloma
- does not cure leukemia, but useful for inducing remission in ALL or undifferentiated childhood leukemia
- palliative agen in other cancers (reduce inflammation/nausea)
targeted agents
- include kinase inhibitors and antibodies
- inhibit function of activated oncogenes or PRO necessary for tumor cell proliferation
kinase inhibitors
-small molecule inhibitors of oncogenic PRO kinases that are activated and drive tumor cell proliferation/survival
chimeric antibodies
- target tumor cell-specific cell surface receptors of angiogenic factors
- kill cells by direct and immune system-mediated mechanisms (some with conjugated toxins)
- leads to the activation of proteolytic cascade of complement and formation of a membrane attack complex (MAC). Cell is phagocytosed/cytolyzed
erlotinib
- target: EGF receptor protein tyrosine kinase that is overexpressed in cancers (lung/brain/head & neck)
- small molecule EGFR kinase inhibitor approved for NSCLC and head and neck cancers
cetuximab
- target: EGF receptor protein tyrosine kinase that is overexpressed in cancers (lung/brain/head & neck)
- chimeric EGFR antibody approved for use in colon cancer and head/neck ca.
resistance to erlotinib
once cell has mutated EGFR, develops resistance
iapatinib
target: HER2 protein tyrosine kinase (EGF-receptor related) that is overexpressed in various cancers
- smalll molecule EGFR and HER2 kinase inhibitor used in breast ca
trastuzumab
target: HER2 protein tyrosine kinase (EGF-receptor related) that is overexpressed in various cancers
- humanized HER2 antibody in HER+ refractory metastatic breast ca.
- recognizes the cell surface antigen HER2 which is dramatically elevated in 25% of breast tumors
- direct tumor cell effects and immune system-mediated effects
pertuzumab
target: HER2 protein tyrosine kinase (EGF-receptor related) that is overexpressed in various cancers
- humanized HER2 antibody approved for use in combination with tratuzumab and docetaxel to treat HER2+ metastatic breast ca.
imatinib
target: activated bcr/abl protein tyrosine kinase arising from gene rearrangement/fusion in CML
- small molecule inhibitor of abl PRO tyrosine kinase and activated bcr/abl fusion
- approved for CML with bcr/abl mutation
resistance to imatinib
-works well unless dev. an abl mutation, decreased drug binding
brentuximab vedotin
target: CD30 surface antigen on some hodgkin/non-hodkin lymphoma cells
- chimeric IgG conjugated to highly toxic mitotic spindle poison vedotin with cleavable linker
- accelerated FDA approval for HL and anaplastic large cell lymphoma
- -upon binding to CD 30 positive tumor cells, the antibody conjugated vedotin is internalized and proteolytically cleaved to release toxin
