Cancer Pharmacology Flashcards
What Tx counteracts the myelosuppressive side-effects of cancer drugs?
Prophylactic administration of growth factors protect against myelosupression
Primary toxicity of cisplatin
nephrotoxicity
How to prevent methotrexate-induced nephrotoxicity
Alkalinization of urine and leucovorin rescue
How to prevent cycloposphamide-induced hemorrhagic cystitis
Concomitant use of MESNA
What cancer drugs have a low or negligible myelosupressive mechanism?
Vincristine
Bleomycin
Cisplatin
Asparaginase
Trastuzumab
What cancer drugs can cause acoustic nerve damage?
Cisplatin/Carboplatin
How do chemotherapeutic drugs cause nasuea and vomiting?
Major receptors involved:
5-HT3 receptor
NK1 receptor
Dopamine receptor
Serotonin receptor antagonist used to Tx nausea
5-HT3 antagonist:
Ondanestron and granisetron
Neurokinin-1 receptor antagonist to Tx nausea
NK-1 antagonist:
Aprepitant and fosaprepitant
Dopamine antagonist to Tx nausea
promethazine, prochlroperazine
Which pathway is activates the emetic response within 24 hours after initiation of chemotherapy
The peripheral pathway- acute chemotherapy-induced emesis
Mechlorethamine
Component of MOPP regimen for Hodgkin’s disease
Alkylating agent that is activated into its intermediate in body fluids
Given IV and can have pronounced vesicant activity and cuase extravasation, tissue necrosis, and sloughing
Nitrogen mustard
Chlorambucil
Indications:
Chronic lymphocytic leukemia
Hodgkin lymphoma
Non-Hodgkin lymphoma
Given PO - alkylating compound with 70-100% bioavailability
US Boxed Warning: Bone marrow suppression
Cyclophosphamide
Clinical uses:
Leukemias/lymphomas and cancers of soft tissues and neuroblastoma
Also an immunosuppressant drug
Converted to active metabolite phosphoramide mustard by liver P450 - metabolites alkylate DNA
Given IV - no vesicant effects
Dose-limiting myelosuppression, hemorrhagic cystitis due to production of acrolein (risk can be decreased w/ use of 2-mercaptoethane-sulfonate [MESNA])
Cardiac dysfunction, pulmonary fibrosis, and excessive ADH secretion may occur
Cisplatin
Kills cells in all stages of the cell cycle inhibits DNA biosynthesis, and binds DNA through the formation of interstrand cross-links
Inside cell - drug is converted to positively charged intermediate that binds DNA and forms both interstrand and intrastrand cross-links
Used in solid tumors (cancer of testis, ovary, bladder, lun, H&E, neuroblastoma, osteogenic sarcoma)
Cisplatin ADME
Given IV and cleared in unchanged form by kidneys
Toxicity:
Nephrotoxic (reduced by forceful hydration)
Neurotoxic (peripheral neuritis, acoustic nerve damage)
Myelosuppresssion, nausea and vomiting
Procarbazine
Prodrug converted to active intermediate that can cause DNA strand breaks due to formation of free radicals (inhibits DNA/RNA and protein synthesis - prolongs interphase, and produces chromosome breaks)
Used as component of the MOPP regimen
MOPP regimen
Mechlorethamine, vincristine, procarbazine, and prednisone used to Tx Hodgkins disease
Used in combination w/ BEACOPP regimen
Nitrosoureas
Carmustine and lomustine
Undergo spontaneous degradation in body fluid w/ formation of metabolites that alkylate DNA (do not cause cross-resistance w/ other alkylating agents)
Carmustine is highly lipohilic and can easily enter brain
Neurotoxicity and hepatoxic
Used in brain tumors
Can also cause pulmonary toxicity
Mechanism of drug resistance to cytotoxic Abx’s
Increased production of glycoprotein P-170 which leads to an increased efflux of the drug from tumor cells
Enhanced rates of DNA repair
Anthracyclines
Doxorubicin and Daunorubicin
Fx:
1. intercalate between DNA bps
2. Inhibit topoisomerase II
3. Generate free radicals which can oxidize DNA bases
Tox:
Severe cardiomyopathy - acute form w/i 2-3 days after beginning regimen (dexrazoxane - chelates iron - can reduce cardiac damage)
Doxorubicin
Clinical use
aka Adriamycin
Component of the ABVD regimen for Hodgkin’s disease; also used in many solid tumors
Anthracycline
ABVD = doxorubicin, bleomycin, vinblastine, and dacarbazine (originally developed for Pt’s w/ disease resistant to MOPP)
ABVD Regimen
ABVD = doxorubicin, bleomycin, vinblastine, and dacarbazine (originally developed for Pt’s w/ disease resistant to MOPP)
Regimen for Hodgkin’s disease and also used in many solid tumors
Dactinomycin
Antitumor Abx isolated from Streptomyces - binds tightly to dsDNA through intercalation between adjacent guanine-cytosine bps and inhibits all forms of DNA-dependent RNA synthesis
Clinical use:
Mainly to Tx pediatric tumors such as Wilm’s tumor (affects kidneys)
Daunorubicin
Used in acute myelogenous leukemia
Anthracycline
Bleomycin
CCS drug that acts in the G2 phase of the cell cycle
Associated w/ pulmonary fibrosis in 2-3% of Pt’s
Clinical use:
ABVD regimen for Hodgkin’s disease - used in lymphomas, lung and testicular cancers
Acquired resistance to antimetabolite therapy
Methotrexate - decreased target receptor affinity
Mercaptopurine/thioguanine/cytarabine/fluorouracil - reduced activation of prodrugs
Mercaptopurine/fluorouracil/mehotrexate - decreased sensitivity of a target enzyme
Methotrexate
Competively inhibits dihdrofolate reductase resulting in decreased synthesis of tetrahydrofolate
Clinical use:
Acute leukemias, lymphomas, choriocarcinoma, breast and lung cancer
Also used in graft rejection control, RA, and psoriasis
THFA is used in purine/pyrimidine synthesis
What enzyme do mercaptopurine and thioguanine inhibit when they are transformed into false purine nucleotides?
Phophsoribosylpyrophosphate synthetase and phosphoribosylpyrophosphate aminotransferase
Critical for synthesis of phosphoribosylamine - essential in purine synthesis
Fludarabine
Nucleotide analog which is phosphorylated intracelluarly and incorporated into DNA and RNA - metabolite interferes w/ DNA synthesis through inhibition of DNA polymerase ribonucleotide reductase
Clinical use:
Mainly for remission maintenance in acute lymphoblastic leukemia (ALL) and is the DOC for chronic lymphocytic leukemia (CLL)
Induces apoptosis
May cause peripheral neuropathy (neurotoxic)
Long term use may cause hepatotoxicity
Pentostatin
Inhibits adenosine deaminase - leads to intracellular accumulation of adenosine - blocks DNA synthesis
Allopurinol increases the toxicity of what drug used to treat hematologic cancers?
Mercaptopurine (6-MP) - converted to an inactive metabolite (6-thiouric acid) by oxidation catalyzed by xantine oxidase
Fluorouracil
Activated to a false nucleotide which inhibits thymidylate synthease - reduces availability of thymidylic acid - impairing DNA synthesis
Clinical use:
Slow growing, solid tumors (H&E, bladder, stomach, and colon cancers)
Capecitabine is a prodrug converted to 5-fluorouracil
Cytarabine (cytosine arabinoside)
Activated to false nucleotide that is incorporated at the terminal position of a growing DNA chain
Used in acute myelogenous leukemia
Can cause neurotoxicity after intrathecal administration
What antimitotic drugs bind to tubulin and inhibit tubulin polymerization (prevents microtubule assembly)
Vincristine and vinblastine
Vincristine clinical uses
Component of MOPP regiment
Also leukemias, lymphomas, and Wilms’ tumor
Vinblastine clinical uses
Componenet of ABVD regimen
Also used to Tx neuroblastoma and testicular cancer
What antimitotic drugs bind to tubulin and inhibit tubulin depolymerization?
Paclitaxel and docetaxel (taxanes) prevent microtubule disassembly
They are used to Tx breast and ovarian cancers
Etoposide
Podophyllin analogue - inhibits topoisomerase II
Mainly used to Tx testicular and small cell lung cancers, but is also used to Tx Hodgkin’s and non-Hodgkin’s lymphomas
Mainly act in the S and G2 phases of cell cycle
Topotecan
Camptothecin analogue - inhibits topoisomerase I
Used to Tx ovarian and lung cancer
Mainly act in the S and G2 phases of cell cycle
Asparaginase
Ezyme isolated from bacteria that acts in the G1 phase of the cell cycle by depleting serum asparagine - results in inhibition of protein synthesis in some neoplastic cells (lymphoblastic leukemic cells) that are not able to synthesize R
Mainly used in luekemias and lymphomas
Hydroxyurea
Analog of urea - inhibits DNA synthesis in S phase by inhibiting ribonucleotide reductase - depletes deoxynucleosides
Used to Tx melanoma and chronic myelogenous leukemia
IFN-α in cancer Tx
Approved for Tx of hairy cell leukemia, chronic myelogenous leukemia, malignant melanoma, and Kaposi sarcoma
increased host expression of major histocompatibility complex antigens, enhanced phagocytic activity of macrophages, and augmentation of the proliferation and survival of cytotoxic T cells.
Erlotinib
Reversible inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase
Competitively inhibits ATP binding at the site of the kinase - regulates G1 restriction
Rituximab
mAb to the CD20 surface protein on normal and malignant B lymphocytes
Used in non-Hodgkin’s lymphomas
May cause reactivation of Hep B or rarely JC virus (w/ progressive multifocal leukencrephalopathy)
Trastuzumab
mAb to human epidermal growth factor receptor 2 (HER-2) - may be overexpressed in some primary breast carcinoma
Used in HER-2 + metastatic breast and gastric cancers
Toxic: cardiac dysfunction
Bevacizumab
Anti-angiogenic drug that inhibits VEGF from binding to it receptor - especially on endothelial cells
Humanized IgG1 mAB
Approved for Pt’s w/ metastatic colorectal cancer
Used off label by intravitreal injection to slow progression of neovascular macular degeneration
Gemtuzumab ozogamicin
Humanized mAb against CD33 covalently linked to a derivative of caliheamicin (potent antitumor Abx)
CD33 present on most hematopoietic cells - on more than 80% of acute mylogenous leukemias
Following binding to CD33 - undergoes endocytosis; cleavage of calicheamicin from Ab takes place w/i the lysosome - enters nucleus and binds in the minor groove of DNA and causes dsDNA break and cell death
Aletuzumab
Humanized IgG-kappa mAb that binds to CD52 Ag
CD52 is found on subset of normal neutrophils and on all B/T lymphocytes
Approved for Tx of B-cell chronic lymphocytic leukemia
Also used in Tx of Pt’s w/ relapsing forms of multiple sclerosis
Anastrazole
Aromatase inhibitor
Aromatase catalyzes conversion of andostenedione to estrone
Fulvestrant
Competitive estrogen receptor antagonist (effective in some Pt’s that have become resistant to tamoxifen)
Drugs used in prostatic carcinoma
Leuprolide and goserelin (GnRH agonist) - inhibit release of LH and FSH when administered in constant doses
Flutamide - competitive androgen receptor antagonist
Why are glucocorticoids used in conjunction w/ chemotherapy regimens?
- Their lymphocytotoxic action (Tx of lymphocytic leukemia/lymphoma and multiple myeloma)
- Anti-inflammatory and immunosuppressant actions - pallative therapy
- Decreases chemotherapy induced NV
Anthracycline antibiotics - cell cycle nonspecific
A patient recently diagnosed with chronic lymphocytic leukemia began a treatment with chlorambucil. The mechanism of action of the drug is likely due to?
the formation of covalent bonds with nucleophile groups on DNA bases.
Vincristine
Cell cycle nonspecific cancer drugs
C. Dactinomycin
E. Vincristine
F. Etoposide
What cytotoxic Abx is cell cycle specific?
Bleomycin
G2 phase
Side-effects associated w/ most cancer therapeutics
N&V
Alopecia
Myelosuppression
C. Increased synthesis of glycoprotein P-170
A. The formation of covalent bonds w/ nucleophile groups on DNA bases
Answer choic B = Cytarabine (cytosine arabinoside)
When is leucovorin rescue used during chemotherapy?
In conjugation w/ methotrexate
D. Inhibits both purine and pyrimidine synthesis
A. Inhibition of thymidylate synthetase
B. Bleomycin
A. Depletion of endothelial growth factors for angiogensis
Bevacizumab blocks VEGF activity
Bonus: what Abx is associated with ototoxicity
A. Cisplatin
Bonus: aminoglycosides
D. Dactinomycin binds to dsDNA inhibiting DNA transcription
C. Inhibiting uric acid formation after cell lysis
A. To improve chemotherapy-induced NV
i.e. aprepitant and fosaprepitant
E. Xanthine oxidase
Can lead to toxic accumulation
B. Rituximab
D. Cisplatin and paclitaxel
B. It is highly lipid soluble and therefore can easily enter the brain
Carumstine = nitrosourea
Can be associated w/ pulmonary toxicity
D. Cyclophosphamide
C. MESNA (2-mercaptoethane sulfonate)
