Upgrade to remove ads
Only $2.99/month

Antineoplastics

Terms in this set (50)

1. Describe the specific criteria that are important for cells to pass the following cell cycle phase checkpoints (G1/S, G2/M, metaphase/anaphase).
G1/S: cell nutrition, size, and environment are favorable; all DNA is intact
G2/M: DNA is completely replicated
Metaphase/anaphase: all DNA is intact; all chromosomes are attached to mitotic spindle
2. Identify and describe 3 mechanisms of oncogene formation.
Point mutation within the protein coding region of a gene resulting in hyperactive or degradation-resistant gene product
Gene amplification leading to extra chromosomal copies of the mutated gene.
Chromosomal translocations leading to proto-oncogene fusion and a secondary gene, resulting in a fusion protein with oncogenic activity
3. Describe first‐order killing of cancer cells.
It has been observed that chemotherapy often causes the elimination of a fixed percentage of cells. This is called logarithmic or first‐order kill. (Ex.: If the first dose of chemotherapy kills 99 % of the cells in a patient with 1010 tumor cells, there will still 108 cancer cells remaining. The second dose will not kill the remaining 1 % of the cells; instead it will only kill 99 % of the remaining 108 cells. Thus, there will still be 106 tumor cells remaining)
6-Thioguanine (6-TG) 6-Mercaptopurine (6-MP):
- Incorporated into DNA, which inhibits synthesis and function
- Reduce precursors for RNA and DNA by inhibiting purine synthesis
Fludarabine:
- Incorporated into DNA, which inhibits DNA synthesis and function
- Inhibits DNA polymerase which prevents DNA synthesis
5‐fluorouracil (5‐FU):
- Incorporated into DNA and RNA, which inhibits synthesis and function
- Inhibits thymidylate synthetase, which reduces DNA precursors
Capecitabine
prodrug of 5‐FU that had improved oral bioavailability allowing it to be given orally
Cytarabine (cytosine arabinoside, ara‐C):
- Incorporated into DNA and RNA, which inhibits synthesis and function
- Inhibits DNA synthesis by inhibiting DNA polymerase
Gemcitabine:
- Incorporated into DNA, which inhibits synthesis and function
- Inhibits ribonucleotide reductase, which reduces precursors for DNA
Methotrexate:
- Inhibits dihydrofolate reductase, which reduces precursors for RNA and DNA synthesis
Hydroxyurea:
- Inhibits ribonucleotide reductase, which reduces DNA precursors
Mechlorethamine, cyclophosphamide, Carmustine (BCNU):
- Causes DNA crosslinking and strand breakage (common binding site is seven‐nitrogen group of guanine, damages cells in all phases of cell cycle)
Doxorubicin:
- Intercalate with DNA
- Cause DNA strand breaks by inhibiting topoisomerase II
Bleomycin
- Small glycopeptide antibiotic that chelates iron and copper and binds to DNA and
causes single and double strand breaks.
- Cell cycle specific drug (causes cells to arrest in G2 phase)
Cisplatin, carboplatin:
- binding to DNA and causing inter‐strand and intra-strand crosslinking
- Like the alkylating agents, the platinum compounds are cytotoxic cell cycle nonspecific agents (damages cells in all phases of cell cycle)
Irinotecan, topotecan:
- induce cytotoxicity by inhibiting topoisomerase I (prevents repair of cuts leading to DNA damage)
Etoposide:
- is a class II topoisomerase inhibitor
Vinblastine, vincristine
- Inhibit microtubule formation which prevents mitotic spindle from forming
- Causes cells to arrest in metaphase which leads to cell death
Paclitaxel (taxol):
- prevents the depolymerization of microtubules which kills tumor cells by arresting them in mitosis
Prednisone, dexamethasone:
- Inhibit lymphocyte proliferation (used to treat leukemias and lymphomas)
Tamoxifen:
- competitively binds to estrogen receptor
Anastrozole:
- inhibits aromatase activity, which can lower estrogen levels
Flutamide:
- competitively inhibit testosterone from binding to the testosterone receptor
Imatinib (Gleevec):
- binds BCR-ABL and prevents kinase from binding its substrate/phosphate donor (ATP)
Vemurafenib:
- inhibits RAF kinase activity (BRAF)
Bevacizumab:
- binds to VEGF, which prevents VEGF from binding to VEGFR (prevents angiogenesis)
Trastuzumab (Herceptin):
- Binds to extracellular portion of the receptor HER-2 which prevents activation and causes antibody-dependent cellular toxicity
Thalidomide
- potent inhibitor of interleukin‐6 (IL‐6) and tumor necrosis factor α (TNFα) expression, release, and signaling.
- inhibits the release of VEGF, thereby reducing angiogenesis
- enhances activity of natural killer (NK) cells (tumor cell eliminators) and T cells
Bortezomib:
- inhibits the proteasome which elevates levels of the tumor suppressor and apoptotic initiator protein p53
- Can also reduce levels of a protein that normally inhibits apoptosis called NF-kappaB
Interleukin‐2 (IL‐2):
- increase in the killing activity of natural killer (NK) cells and increases T-cell proliferation
- Mechanism of tumor cell killing is thought to be related to these immunomodulatory effects
Tretinoin (all trans retinoic acid, ATRA):
- Induces differentiation of acute promyelocytic leukemia (APL) which prevents continued proliferation of the cancer cells
1. Identify the cancer that cytarabine (ara‐C) is used to treat.
Most important antimetabolite to treat acute myelogenous leukemia (AML)
5. Describe the general mechanisms of resistance for chemotherapeutic agents.
Efflux pumps (MDR transporter), decrease drug uptake, increase drug metabolism, alter drug targets, impair apoptotic pathway, alter cell cycle checkpoints
6. Describe the mechanisms of resistance for methotrexate
- Impaired transport
- Altered forms of DHFR with decreased affinity for methotrexate
- Elevated DHFR expression (gene amplification)
- Numerous other mechanisms
6. Describe the mechanisms of resistance for cytarabine
- Cytidine deaminase upregulation in tumor cells increases ara-C inactivation
- Tumor cell overexpression of antiapoptotic proteins can prevent ara-C from killing tumor cells
- Reduced ability of tumor cells to transport ara-C across cell membrane causes resistance
6. Describe the mechanisms of resistance for Imatinib
- Point mutations in ABL cause a reduced affinity for imatinib.
- These mutations also appear to lock the enzyme into its open state allowing continuous access to substrates that it phosphorylates.
- Fortunately, the analogs of imatinib (nilotinib and dasatinib) can still inhibitABL kinase with many of these mutations
Identify the drugs that lead to adverse effects in the kidney
cisplatin, methotrexate
Identify the drugs that lead to adverse effects in the nervous system
vincristine, ara C, cisplatin, bortezomib, thalidomide, paclitaxel
Identify the drugs that lead to adverse effects in the heart
doxorubicin, trastuzumab
Identify the drugs that lead to adverse effects in the lungs.
methotrexate, bleomycin, alkylating agents (Mechlorethamine, cyclophosphamide, Carmustine (BCNU)
Identify the dose‐limiting toxicity of bleomycin
Dose-limiting adverse side effect is pulmonary toxicity
Identify the unique adverse effect of (doxorubicin). Describe the mechanism by which this adverse effect occurs.
Binds to iron and generates free radicals, which leads to DNA and protein damage. Free radical formation causes adverse effects, but not thought to be the major mechanism of tumor cell killing. Unique adverse effect is irreversible cardiomyopathy caused by free radical formation.
. Identify which drug leads to hemorrhagic cystitis.
Cyclophosphamide
. Identify the cell cycle stage that vincristine, vinblastine, and paclitaxel arrest cells in.
mitotic arrest in metaphase, thought that cells are killed by the metaphase‐anaphase cell cycle
checkpoint
Identify which cancers are commonly treated with imatinib
Chronic myelogenous leukemia (CML)
Identify which cancers are commonly treated with bortezomib
relapsed or refractory multiple myeloma
Identify which cancers are commonly treated with trastuzumab
HER2 overexpressing metastatic breast cancer
Identify which cancers are commonly treated with tamoxifen, .
estrogen-dependent breast cancers
Identify which cancers are commonly treated with flutamide.
prostate cancer
Identify which cancers are commonly treated with tretinoin.
acute promyelocytic leukemia (APL)
YOU MIGHT ALSO LIKE...