09- Antineoplastics Flashcards
capecitabine
Pyrimidine Antagonist (anti-tumor anti-metabolite)
-Converted to 5-FU (prodrug) via thymidine phosphorylase.
+thymidine phosphorylase is found in higher concentration in tumor cells.
HER2- positive
HER2 is an epidermal growth factor over expression in breast cancer
lapatinib-HER2 kinase inhibitor
trastuzumab- humanized HER2 antibody
tumor suppressor
block or suppress development of cancer helps regulate cell division
cytosine arbinoside (cytrabine)
Pyrimidine Antagonist (anti-tumor anti-metabolite)
- resembles CTP and is incorporated into DNA leading to damage.
- Activation by deoxycytidine kinase.
oncogene addiction
tumor cells proliferation becomes dependent upon activated oncogenes
RALOXifene (Evista)
- antagonist of hormone action
- selective estrogen response modulator (SERM)
- approved for prevention of breast cancer in patients with osteoporosis
- less adverse effects noted
flutamide
- antagonist of hormone action, specifically androgen receptor
- ineffective when used alone in prostate CA d/t rapid androgen receptor mutation
- used in conjunction with leuprolide to block effects of the initial pulse androgen levels and associated “flare” of prostate CA at the start of leuprolide therapy
methchlorethamine
Anti-tumor alkylating Agent (bischlorethyl amine).
- nitrogen mustard
- highly reactive alkylating agent (must be given IV).
- chlorethyl groups are elctrophilic and react with nucleophils. Leads to DNA cross-linkage.
cyclophosphamide
Anti-tumor alkylating Agent (bischlorethyl amine).
- PO prodrug of methclorethamine; less reactive.
- chlorethyl groups are elctrophilic and react with nucleophils. Leads to DNA cross-linkage.
DHFR- dihydrofolate reductase
inhibited by methotrexate normally converts FH2 into FH4
leuprolide
- antagonist of hormone action
- synthetic analog of GnRH, a GnRH-R agonist
- continuous, high dose treatment greatly lowers androgen levels in men and estrogen levels in women
- high doses cause down regulation of receptors and system for hormone production shuts down
- as effective as estrogen therapy or orchiectomy in treatment of prostate CA with fewer s/fx
vinCRISTINE (Oncovin)
- mitotic spindle poison that is a vinca alkaloid
- M Phase specific
- DOSE LIMITING: neurotoxicity (no acute side effects and milder, non-dose limiting bone marrow suppression
- uses: acute childhood leukemia
- Hodkin’s Disease M”O”PP regimen (Oncovin= vincristine)
- resistance by tubulin gene mutations
EGF receptor protein tyrosine kinase
overexpressed/mutationally activated in various cancers (lung, brain, head and neck)
-over expression and overactivity increases tumor growth
HER2 protein tyrosine kinase
(EGF receptor related) overexpressed/activated in various cancers causing aggressive tumor growth
DAUNOrubicin
- anti-tumor antibiotic (Anthracycline) AND topoisomerase II inhibitor
- DNA intercalation (mutagenic, carcinogenic)
- DNA topoisomerase II binding (double-strand break), DNA scission
- widely used with broad spectrum of activity
- DOSE LIMITING: irreversible cardiac toxicity at high doses
bleomycin
- anti-tumor antibiotic
- cytotoxicity from DNA strand scission
- DOSE LIMITING: pulmonary toxicity (pulmonary fibrosis) at large doses (fibrosis with 100% O2)
- no significant myelosuppression so useful in combination therapies (A”B”VD, in Hodgkin Lymphoma)
- can cause anaphylaxis so give small doses at first
letrozole
- antagonist of hormone action
- AROMATASE inhibitor that inhibits conversion of androgens to estrogen
- effectively blocks estrogen production in POSTMENOPAUSAL women
- not used in premenopausal women because of compensatory gonadotropin and ovarian estrogen production
- MORE effective than tamoxifen in treatment of ER+ breast cancers in postmenopausal women
- no enhanced risk of thrombosis or uterine cancer
tumor growth fraction
fraction of cells not in G0 cells that are actually dividing responsive to conventional chemotherapy
neoadjuvant
chemotherapy is given before surgery
trastuzumab (Herceptin)
Targeted agent
- “humanized” HER2 antibody that recognizes surface antigen HER2 that is elevated in many breast tumors
- effective against in HER2+ breast cancers
- direct tumor cell effects and immune system mediated effects
Normal cells susceptible to toxic side effects
bone marrow–myelosuppression
intestinal epithelial– N/V oral mucosa
gonadal cells– infertility
hair follicles
estrogen receptor status
presence of estrogen receptors in breast cancer tissue predicts benefit of tamoxifen treatmen
nitrosoureas
- Alkylating agents -can cross BBB and useful against brain tumors.
- BCNU, CCNU, methyl-CCNU.
erlotinib (Tarceva)
Targeted agent
- EGFR KINASE INHIBITOR
- used to treat non-small cell lung cancer, head/neck cancer
deoxycytidine kinase
required to activated cytarabine (cytosine arabinoside) mutational loss is a mechanism of resistance
vinBLASTINE
- mitotic spindle poison that is a vinca alkaloid
- M Phase specific action
- inhibitor of microtubule polymerization (mitotic arrest)
- DOSE LIMITING: bone marrow suppression
- used in combination therapy (AB”V”D in Hodgkin Lymphoma)
- resistance by tubulin gene mutations which cause mitotic spindles to have less binding affinity for drug
cisplatin
Pt Coordination Complex
- Cell-cycle nonspecific, DNA cross-linking.
- nephrotoxic, acoustic nerve injury.
“targeted” agent
inhibit the function of activated oncogenes or proteins necessary for tumor cell proliferation and tumor angiogenesis
6-thioguanine
Purine Antagonist (anti-tumor anti-metabolite)
- S-Phase specific
- incorporated into DNA/RNA via DNA polymerase.
- Activated by hypoxanthine-guanine phosphoribosyl transferase (HGPRT).
- Not inactivated by xanthine oxidase.
TOPOtecan
- topoisomerase I inhibitor that is a camptothecin
- bind to “cleavable complex” of DNA topoisomerase I and DNA, block religation of single-strand break
- double strand breaks occur with DNA replication
- S Phase-specific
***(Grayed out on slide)- Uses: ovarian and lung cancers and Dose Limiting: myelosuppression
imatinib (Gleevac)
Targeted agent
- inhibitor of abl protein tyrosine kinase (and activated bcr/abl fustion)
- approved for chronic myelogenous leukemia (bcr/abl mutation) (activated bcr/abl protein tyrosine kinase arises from gene rearrangement/fusion in chronic myelogenous leukemia
procarbazine
Alkylating agent: Misc
- metabolized to alkylating free radicals.
- part of MOPP Tx for Hodgkin’s
- Leukemogenic in 5-10% of pt receiving MOPP therapy.
TAMOxifen
- antagonist of hormone action
- Selective estrogen response modulator (SERM)
- PARTIAL AGONIST of estrogen receptor (some competitive inhibition) (efficacy depends on tissue)
- low toxicity and manageable side-effects
- Uses: estrogen-responsive tissues (female/male breast; uterine endometrium)
- presence of estrogen receptor in breast cancer predicts efficacy in treatment
- prophylactic treatment has been suggested in high risk women but may not prolong life span
- reduce risk of bone fractures in postmenopausal women
- enhanced risk of thrombosis or uterine cancer
methotrexate
Anti-tumor anti-metabolite
- dihydrofolate reductase inhibitor (inhibit the synthesis of FH4 from FH2).
- S-Phase specific
- Myelosuppression
- Can be “reversed” with leucovorin (increases FH4)
cell cycle
mitosis, cell divison
microtubule
tubulin required for M phase cell divison
leukemogenic
relating to the development of leukemia side effect of procarbazine
alkylating agent
add an alkyl group to the DNA causing breakage and cell death
prednisone
Adrenocorticosteroid
- induces apoptosis in leukemia cells
- used in drug regimens for leukemia, lymphoma, myeloma
- does not cure leukemia but useful for inducing remission in childhood
- palliative agent in other cancers (reduce inflammation, N/V)
6-mercaptopurine
Purine Antagonist (anti-tumor anti-metabolite)
- S-Phase specific
- incorporated into DNA/RNA via DNA polymerase.
- Activated by hypoxanthine-guanine phosphoribosyl transferase (HGPRT).
- Inactivated by xanthine oxidase
+high xanthine oxidase in cow’s milk
+allopurinol decreases xanthine oxidase.
oncogene
gene that can convert a normal cell into a tumor cell
HGPRT- hypoxanthine-guanine phosphoribosyl transferase
converst purine antagonist to NMPs, and NTPs
-down regulation of enzyme is common mechanism of resistance
exemestane
- antagonist of hormone action
- AROMATASE inhibitor that inhibits conversion of androgens to estrogen
- effectively blocks estrogen production in POSTMENOPAUSAL women
- not used in premenopausal women because of compensatory gonadotropin and ovarian estrogen production
- MORE effective than tamoxifen in treatment of ER+ breast cancers in postmenopausal women
- great reduction in Breast CA in high risk PostM women
- no enhanced risk of thrombosis or uterine cancer
M phase-specific
Mitotic phase Cell Divison
therapeutic index
TD50/ED50 low in chemotherapeutic
etoposide
- topoisomerase II inhibitor
- form ternary complex with toposisomerase II and DNA -interfere with religation of double-strand break
- DNA strand scission
brentuximab vedotin (Adcetris)
Targeted agent
- targets CD30 surface antigen of some Hodgkin and Non-Hodgkin lymphomas
- chimeric IgG conjugated to highly toxic mitotic spindle poison vendotin with cleavable linker
- upon binding to CD30-positive tumor cells, vedotin is internalized and cleaved to release toxin
paclitaxel (Taxol)
- mitotic spindle poison
- plant alkaloid (western yew)
- enhances tubulin polymerization (blocks microtubule disassembly)
- disassembly block triggers cell death
- uses: ovarian and advanced breast cancers
xanthine oxidase
metabolically inactivates 6-mercaptopurine high in cow’s milk inhibited by allopurinol (used to reduce uric acid/kidney toxicity)
IRINOtecan
- topoisomerase I inhibitor that is a camptothecin
- bind to “cleavable complex” of DNA topoisomerase I and DNA, block religation of single-strand break
- double strand breaks occur with DNA replication
- S Phase-specific
***(Grayed out on slide)- Uses: colorectal cancer, and Dose Limiting: severe diarrhea
leucovorin
“Folic Acid Rescue;” formyl H4-folate.
-reverses the effects of methotrexate
lapatinib
Targeted Agent
- EGFR AND HER2 kinase inhibitor
- used in breast cancer
5-fluorouracil
Pyrimidine Antagonist (anti-tumor anti-metabolite)
- metabolite fDUMP inhibits thymidylate synthetase leading to thymineless death.
- S-Phase specific
- synergistic effects when administered with leucovorin
DNA intercalation
insertion of molecules between the planar bases of DNA
DOXOrubicin (Adriamycin)
- anti-tumor antibiotic (Anthracycline) AND topoisomerase II inhibitor
- DNA intercalation (mutagenic, carcinogenic)
- DNA topoisomerase II binding (double-strand break), DNA scission
- widely used with broad spectrum of activity
- DOSE LIMITING: irreversible cardiac toxicity at high doses
- most commonly used anti-tumor antibiotic
- used in combination therapies (“A”BVD in Hodgkin Lymphoma)
cetuximab (Erbitux)
Targeted agent
- CHIMERIC EGFR ANTIBODY that prevents receptor activation
- colon, head and neck cancer
S phase-specific
synthetic phase DNA replication
anastrozole
- antagonist of hormone action
- AROMATASE inhibitor that inhibits conversion of androgens to estrogen
- effectively blocks estrogen production in POSTMENOPAUSAL women
- not used in premenopausal women because of compensatory gonadotropin and ovarian estrogen production
- MORE effective than tamoxifen in treatment of ER+ breast cancers in postmenopausal women
- no enhanced risk of thrombosis or uterine cancer
DNA topoisomerase
disconnects one or both DNA strands and allows them to unwind, also reconnects the strands drugs can interfere with reconnection
adjuvant
chemotherapy used in addition to surgery
bioactivation
process in which enzymes activate drugs
