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Chemotherapy Agents > Chemotherapy Agents > Flashcards

Chemotherapy Agents Flashcards

1
Q

Cyclophosphamide

A
  • alkylating agent
  • orally effective
  • forms DNA X-links, resulting in inhibition of DNA synthesis and function
  • breast and ovarian cancers
  • non-Hodgkin lymphoma
  • acute toxicity: nausea and vomiting
  • delayed toxicity: myelosuppresion; hemorrhagic cystitis
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2
Q

Ifosfamide

A
  • alkylating agent
  • always given with Mesna*** (both need to be activated by cytochrome p450 complex)
  • forms DNA X-links, resulting in inhibition of DNA synthesis and function
  • testicular cancer
  • lymphoma
  • acute toxicity: nausea and vomiting
  • delayed toxicity: Mesna is given to prevent cystitis
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3
Q

Melphalan; Thiotepa

A
  • alkylating agent
  • forms DNA X-links, resulting in inhibition of DNA synthesis and function
  • multiple myeloma
  • breast and ovarian cancer
  • acute toxicity: nausea and vomiting
  • delayed toxicity: none
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4
Q

Busulfan

A
  • alkylating agent
  • cross-links DNA
  • CMS
  • used for bone marrow ablation for BMT***
  • used for glutathione-S-transferase deficiency
  • acute toxicity: nausea and vomiting
  • delayed toxicity: severe myelosuppression; skin pigmentation; pulmonary fibrosis
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5
Q

Carmustine

A
  • nitrosoureas: DNA cross-linking (N7 and O6 of guanine)
  • requires bioactivation
  • highly lipid soluble = CNS effective
  • brain tumors
  • acute toxicity: nausea and vomiting
  • delayed toxicity: myelosuppresion (except streptozocin)
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6
Q

Lomustin

A
  • nitrosoureas: DNA cross-linking (N7 and O6 of guanine)
  • requires bioactivation
  • highly lipid soluble = CNS effective
  • brain tumors
  • acute toxicity: nausea and vomiting
  • delayed toxicity: none
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7
Q

Procarbazine

A
  • nonclassic alkylating agents: DNA cross-linking (N7 and O6 guanine
  • inhibits DNA, RNA and protein synthesis
  • active metabolites include MAO inhibitor
  • Hodgkin lymphoma and non-Hodgkin lympoma
  • brain tumors
  • acute toxicity: nausea and vomiting
  • delayed toxicity: myelosuppresion; CNS toxicity w/ MAO inhibitors; high risk of secondary cancer
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8
Q

Dacarbazine

A
  • nonclassic alkylating agents: DNA cross-linking (N7 and O6 guanine
  • bioactivation required
  • malignant melanoma
  • NHL
  • neuroblastoma
  • acute toxicity: nausea and vomiting
  • delayed toxicity: myelosuppresion; potent vesicant
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9
Q

Bendamustine

A
  • nonclassic alkylating agents: DNA cross-linking (N7 and O6 guanine
  • bioactivation required
  • HL and NHL
  • multiple myeloma
  • breast cancer
  • acute toxicity: nausea and vomiting
  • delayed toxicity: hypersensitivity rxn
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10
Q

Cisplatin

A
  • alkylating agent
  • water soluble
  • renal excretion (dose modification required)
  • forms intrastrand and interstrand DNA cross-links; binds to nuclear and cellular proteins
  • NSCLC; SCLC; breast cancer; bladder cancer; GE Jx cancer; H & N (head and neck) cancer; ovarian cancer
  • acute toxicity: nausea and vomiting
  • delayed toxicity: #1 nephrotoxicity; peripheral sensory neuropathy; ototoxicity; nerve dysfunction is irreversible
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11
Q

Carboplatin

A
  • alkylating agent
  • forms intrastrand and interstrand DNA cross-links; binds to nuclear and cellular proteins
  • more lipophilic so less renal effects
  • NSCLC; SCLC; Breast cancer; bladder cancer; H&N cancer; ovarian cancer
  • acute toxicity: nausea and vomiting
  • delayed toxicity: #1 myeolosuppresion; peripheral sensory neuropathy
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12
Q

Oxaliplatin

A
  • alkylating agent
  • forms intrastrand and interstrand DNA cross-links; binds to nuclear and cellular proteins
  • renal excretion (dose modification required)
  • effective in cells with DNA MMR defects
  • colorectal cancer; gastroesophageal cancer; pancreatic cancer
  • acute toxicity: nausea and vomiting; laryngopharyngeal dysesthesia
  • delayed toxicity: #1 neurotoxicity; peripheral sensory neuropathy triggered by cold sensitivity
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13
Q

Methotrexate

A
  • folic acid analog
  • inhibits DHFR (dihydrofolate reductase); inhibits TS (tetrahydrofolate synthesis); inhibit de novo purine nucleotide synthesis
  • leukemias, lymphomas, choriocarcinoma, sarcomas
  • non-cancer Rx: abortion, ectopoic pregnancy, RA, psoriasis, IBD
  • Leucovorin* rescue is commonly used
  • dose adjustment with ASA, NSAIDs
  • toxicity: mucositis; neurotoxicity; taken up by normal cells preferentially; myelosuppression (reversible with leucovorin (folinic acid)); macrovesicular fatty change in liver; teratogenic
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14
Q

5-Fluorouracil (5-FU)

A
  • pyrimidine analogs bioactivatd to 5F-dUMP, which covalently complexes folic acid
  • “thymine-less death”
  • inactive in parent form
  • metabolites inhibit: thymidylate synthetase; RNA processing/translation; DNA synthesis and function; decreased protein synthesis
  • colon cancer, pancreatic cancer, basal cell carcinoma (topical)
  • short half-life
  • 80-85% of dose is catabolized by dihydropyridine dehydrogenase (DPD)
  • toxicity: DPD deficiency (severe toxicity); #1 myelosuppression (not reversible by leucovorin); N/V/D; photosensitivity
  • overdose: rescue with uridine
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15
Q

Capecitabine (oral 5-FU)

A
  • pyrimidine analog
  • metabolites converted to 5-FU in tumor cells by thymidine phosphorylate
  • oral availability
  • breast and colon cancer
  • toxicity: “hand-foot syndrome”; other toxicity similar to 5-FU; especially diarrhea
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16
Q

Cytosine arabinoside (Arabnofuranosyl cytidine; Ara-C; Cytarabine)

A
  • pyrimidine analog
  • converted to Ara-CMP and Ara-CTP, which inhibits DNA polymerase alpha and polymerase beta
  • leukemias, lymphomas
  • requires constant infusion - NO ACTIVITY IN SOLID TUMORS
  • toxicity: rash; neurotoxicity (esp. cerebellar) at high doses; leukopenia; thrombocytopenia; megaloblastic anemia
  • “CYTarabine causes panCYTopenia”
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17
Q

Gemcitabine

A
  • pyrimidine analog
  • can be incorporated into RNA and DNA to terminate strand
  • treats wide range of solid malignancy
  • toxicity: thrombocytopenia; hemolytic uremic syndrome (rare)
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18
Q

6-Meracaptopurine (6-MP) and 6-thioguanine (6-TG)

A
  • purine analog (guanine analog)
  • inhibits enzymes of purine nucleotide synthesis
  • incorporated into DNA and causes strand termination
  • **requires conversion by HGPRT for activation
  • preventing organ rejection, RA, SLE (azathioprine)
  • leukemia, IBD
  • is deactivated in rxn catalyzed by xanthine oxidase
  • Allopurinol (XO inhibitor) is often used for supportive care and can lead to excessive toxicity
  • deficiency of thiopurine methyl transferase can result in severe toxicities
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19
Q

Cladribine

A
  • purine analog (adenine analog)
  • inhibits DNA synthesis and repair
  • inhibits DNA polymerase leading to strand breaks
  • inhibits ribonucleotide reductase
  • CladribineTP incorporated into DNA and induces apoptosis
  • treatment for Hairy Cell Leukemia
  • toxicity: myelosuppression; immunosuppression (CD4 and CD8 cells); nephrotoxicity; neurotoxicity
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20
Q

Fludaribine

A
  • purine analog
  • inhibits DNA synthesis and repair
  • inhibits ribonucleutide reductase
  • FludaripineTP is incorporated into DNA and induces apoptosis
  • treatment for CLL and NHL
  • toxicity: myelosuppresion; fevers, arthralgias, myalgias; immunusuppresion
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21
Q

Vincristine

A
  • vinca alkaloids that bind beta-tubulin, inhibits its polymerization into microtubules, thereby preventing mitotic spindle formation (M-phase arrest)
  • microtubule destabilizer
  • inhibits microtubule polymerization by binding to beta-tubulin to inhibit assembly
  • intrathecal administration is LETHAL
  • solid tumors, leukemias, and lymphomas
  • delayed toxicity: neurotoxicity with peripheral neuropathy; potent vesicant; paralytic ileus
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22
Q

Vinblastine

A
  • vinca alkaloids that bind beta-tubulin, inhibits its polymerization into microtubules, thereby preventing mitotic spindle formation (M-phase arrest)
  • microtubule destabilizer
  • inhibits microtubule polymerization by binding to beta-tubulin to inhibit assembly
  • intrathecal administration is LETHAL
  • delayed toxicity: same as vincristine along with myelosuppresion (“vinBLASTine BLASTs Bone marrow (suppression)”
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23
Q

Paclitaxel (and other taxols)

A
  • microtubule stabilizing agent
  • hyperstabilize polymerized microtubules in M phase so that mitotic spindle cannot bread down (anaphase cannot occur)
  • “it is TAXing to stay polymerized”
  • enhances microtubule polymerization
  • treatment for ovarian and breast carcinomas
  • delayed toxicity: hypersensitivity (5%); neurotoxicity; alopecia; myelosuppression
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24
Q

Abraxane

A
  • microtubule stabilizing agent
  • enhances microtubule polymerization
  • paclitaxel formulated with albumin
  • treatment for breast cancer
  • NO hypersensitivity
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25
Q

Etoposide

A
  • inhibits topoisomerase 2 –> inc DNA degradation
  • “eTOPOside inhibits TOPOisomerase II”
  • DS DNA breaks cause cytotoxicity
  • G2 phase specific
  • txt for small cell lung cancer and all testicular cancer; leukemias; lymphomas
  • delayed toxicity: myelosuppression; nausea/vomiting; secondary cancers in children; alopecia
26
Q

Irinotecan, Topotecan

A
  • inhibits topoisomerase 1 and prevent DNA unwinding and replication
  • DS DNA breaks cause cytotoxicity
  • PRODRUG converted in the liver to S-38 metabolite - 1000x more potent!
  • first line drug for colorectal cancer; ovarian cancer
  • delayed toxicity: diarrhea… early-cholinergic event; late- 2-10d post treatment, can be severe; severe myelosuppression
27
Q

Topotecan

A
  • inhibits topoisomerase 1 inhibitor
  • DS DNA breaks cause cytotoxicity
  • Rx of SCLC
  • delayed toxicity: bone marrow suppression especially neutropenia
28
Q

Doxorubicin

A
  • anthracycline
  • inhibits topoisomerase II
  • DNA intercalation
  • generation of semi-quinone free-radicals
  • widely used
  • solid tumors, leukemias, lymphomas
  • IV administration; NOT ORAL
  • delayed toxicity: cardiac toxicity (dilated cardiomyopathy) caused by free radicals; myelosuppression; alopecia; toxic to tissues following extravasation
  • prevention of cardiotoxicity with iron chelator: Dexrazoxane vesicant
29
Q

Daunorubicin

A
  • anthracycline
  • inhibits topoisomerase II
  • DNA intercalation
  • generation of semi-quinone free-radicals
  • NOT for solid tumors
  • delayed toxicity: cardiac toxicity (dilated cardiomyopathy) caused by free radicals; myelosuppression; alopecia; toxic to tissues following extravasation
  • prevention of cardiotoxicity with iron chelator: Dexrazoxane vesicant
30
Q

Mitomycin

A
  • antitumor antibiotic
  • potent DNA X-liner through alkylation
  • requires reduction for activation
  • treatment for anal cancer
  • delayed toxicity: hemolytic uremic syndrome
31
Q

Bleomycin

A
  • antitumor antibiotic
  • binds to DNA and to metal so that it creates superoxide free radicals and damages DNA (SS and DS breaks)
  • G2 phase specific
  • renally excreted
  • treatment for HL and testicular cancer
  • delayed toxicity: pulmonary fibrosis; hyperpigmentation; mucositis; minimal myelosuppresion
32
Q

Cell-Cycle Specific Agents

A
  • antimetabolite: S phase
  • epipodophyllotoxin: G2-S phase
  • taxanes: M phase
  • vinca alkaloids: M phase
  • anti-microtubule inhibitor: M phase
  • bleomycin: G2-M phase
  • antitumor antibiotics: S phase
33
Q

Cell-Cycle Non-Specific Agents

A
  • alkylating agents
  • camptothecins
  • platinum analogs
34
Q

ATRA (A-Trans Retinoic Acid)

A

-targets nuclear receptor
-acute PML is caused by a block in differentiation of promyelocytes to mature neutrophils, due to a functional impairment of PML-RAR fusion oncogene
-ATRA (very high dose vit. A) targets the nucelar Retinoic Acid Receptor (RAR), and causes differentiation of promyelocytes into mature cells
-PML patients get DIC with chemotherapeutic treatment, causes pts to die from DIC due to degranulation of promyelocytes and release of contents from auer rods into circulation
ATRA Syndrome: characteriazed by leukocytosis and capillary leak syndrome (pulmonary edema + respiratory failure)

35
Q

Imatinib (Gleevec)

A
  • an inhibitor of the tyrosine kinase domain of the bcr-abl oncoprotein and prevents phosphorylation of the kinase substrate by ATP
  • well absorbed orally and metabolized in the liver (CYP3A4)
  • caution when taking other drugs metabolized by CYP3A4 including grapefruit juice
  • Rx of CML
  • agent also inhibits other receptor tyrosine kinases for platelet-derived growth factor receptor (PDGFR), stem cell factor, and c-kit
  • also effective in the treatment of GI stromal tumors expressing the c-kit tyrosine kinase
  • point mutations, including the T315I mutation, in BCR-ABL tyrosine kinase results in altered binding by Imatinib, leading to resistance of the disease to this agent
  • toxicity: fluid retention
36
Q

Dasatinib

A
  • inhibitor of several tyrosine kinases, including bcr-abl, Src, c-kit, and PDGFR-alpha
  • well absorbed orally and metabolized in the liver (CYP3A4)
  • caution when taking other drugs metabolized by CYP3A4 including grapefruit juice
  • differs from imatinib in that it binds to the active and inactive conformations of the abl kinase domain and overcomes imatinib resistance resulting from mutations in the bcr-able kinase, with the exception of resistance secondary to T315I
  • Rx for CML and Philadelphia chromosome-positive ALL with resistance or intolerance to imatinib therapy
  • toxicity: pulmonary edema and fluid retention
37
Q

Nilotonib

A
  • inhibits bcr-abl, c-kit, and PDGFR-beta tyrosine kinases
  • well absorbed orally and metabolized in the liver (CYP3A4)
  • caution when taking other drugs metabolized by CYP3A4 including grapefruit juice
  • higher bindings affinity for the Abl kinase when compared with imatinib, and it overcomes imatinib resistance resulting from bcr-able mutations, with the exception of resistance secondary to T315I
  • first line therapy in CML as well as to treat CML in patients with resistance or intolerance to prior therapy that included imatinib and was recently approved as first-line therapy of chronic phase CML
38
Q

Tratuzumab (Herceptin)

A
  • humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2 (a tyrosine kinase receptor)
  • produced by recombinant DNA technology
  • used in HER2+ breast cancers
  • 10% of gastric cancers have HER2 amplification and Tratsuzumab works in this setting as well
  • Adverse Rxn: CHF with significant decline in left ventricular cardiac fxn (“HEARTceptin damages the heart”); severe infusion rxns; pulmonary toxicity
39
Q

Cetuximab

A
  • chimeric monoclonal antibody directed against the extracellular domain of the EGFR (member of the erb-B family of growth factor receptors)
  • Rx of metastatic colon cancer
  • colon cancer cells widely express KRAS; the efficacy of cetuximab is restricted to only those pts whose tumors express wild-type KRAS; presence of KRAS mutations confers resistance to cetuximab
40
Q

Panitumumab

A
  • a fully human monoclonal antibody directed against the EGFR and works through inhibition of the EGFR signaling pathway
  • approved for patients with refractory metastatic colorectal cancer who have been treated with all other active agents, and as with cetuximab, this antibody is only effective in pts whose tumors express wile-type KRAS
  • adverse effects: acneiform skin rash and hypomagnesemia
  • b/c this is fully human antibody, infusion-related rxns are rarely observed
41
Q

Lapatinib

A
  • Her1 and Her2 competitive inhibitor

- combined with chemotherapy causes improved response in Her2+ breast cancer

42
Q

Pertuzumab

A
  • blocks heterodimerization of HER2
  • potent inhibitor of downstream signaling
  • treatment of breast cancer
43
Q

Erlotinib (and Gefitinib)

A
  • small molecule inhibitors of the tyrosine kinase domain associated with EGFR
  • both are used in the treatment of NSCLC
  • toxicity: rash (rash determines efficacy; the worse the rash the better the drug is working), diarrhea, anorexia, fatigue
  • patients who are nonsmokers and who have a bronchoalveolar histologic subtype appear to be more responsive to these agents, as they commonly have EFGR mutation, which is a target for Erlotinib
  • both agents metabolized by CYP3A4
  • elimination mainly hepatic with excretion in feces
44
Q

Bevacizumab

A
  • recombinant humanized monoclonal antibody that targets all forms of VEGF-A
  • antibody binds to and prevents VEGF-A from interacting with the target VEGF receptors
  • in combination with chemotherapy, it is used in the treatment of metastatic colorectal cancer, metastatic NSCLC, metastatic breast cancer; renal cell carcinoma
  • toxicity: HTN, increased incidence of arterial thromboembolic events; wound healing complications; GI perforations; proteinuria
  • CYP3A4
45
Q

Sorafenib

A
  • small molecule that inhibits multiple receptor tyrosine kinases, especially VEGF-R2 and VEGF-R3, PDGFR-beta, and raf kinase
  • approved for advanced renal cell cancer and for advanced hepatocellular cancer
  • toxicity: rash, diarrhea, HTN, fatigue, bleeding, hand-foot syndrome
  • CYP3A4
46
Q

Sunitinib

A
  • similar to sorafenib in that it inhibits multiple RTKs, although the specific types are somewhat different (PDGFR-alpha and beta, VEGF-R1, R2 and R3, and c-kit)
  • approved for treatment of advances renal cell cancer and for treatment of GI stromal tumors (GIST) after disease progression on or with intolerance to imatinib
  • toxicity: HTN, bleeding, fatigue
  • CYP3A4
47
Q

Vemurafenib

A
  • small molecule inhibitor of mutant BRAF with the V600E mutation
  • B-RAF oncogene with activating mutation occurs in 50% of melanoma
  • treatment of metastatic melanoma
  • causes squamous cell carcinomas due to effect on normal B-RAF, which usually dimerizes and vemurafenib causes this to be activated
  • combining BRAF inhibitor plus MEK inhibitor prevents skin toxicity and also is more effective against melanoma
48
Q

Crizotinib

A
  • inhibits ALK1, ROS1, HGFR, and other tyrosine kinases

- ALK inhibition in NSCLC causes enormous response with disease shrinkage, in ALK+ tumors

49
Q

MTOR Signaling Inhibitors

A
  • Sirolimus
  • Tacrolimus
  • Temsirolimus
  • Everolimus
50
Q

Bortezomib (Velcade)

A
  • proteosome inhibitor (inhibits things like p53 from being degraded… like duh!)
  • treatment of multiple myeloma
  • peripheral neuropathy is a significant side effect
51
Q

Rituximab (Rituxan)

A
  • chimeric monoclonal antibody that targets CD20 (seen on B-lymphocytes)
  • treatment of B-lymphomas and leukemias, either alone or in combination with chemotherapy
  • infusion reaction is common
  • also treatment for RA (with MTX) and ITP
  • increased risk of progressive multifocal leukoencephalopathy
52
Q

Gentuzumab ogozomicin (Myletarg)

A
  • anti-CD33 antibody

- withdrawn from market due to fatal toxicities (then why the fuck do we need to know this drug!!!)

53
Q

Alemtuzumab

A

-anti CD53 antibody

54
Q

L-Asparaginase

A
  • enzyme used in the treatment of childhood ALL
  • because tumor cells in ALL lack the enzyme asparagine synthetase (asparginase), they require an exogenous source of L-asparagine
  • thus, depletion of L-asparagine results in effective inhibition of protein synthesis
  • in contrast, normal cells can synthesize L-asparagine and thus are less susceptible to the cytotoxic action of asparagine
  • toxicity: DIC; pancreatitis; neurologic toxicity
55
Q

PARP inhibition

A
  • creates lesions that are lethal to BRCA cells

- BRCA is a tumor suppressor that is important to DNA repair and particularly important to NHEJ

56
Q

Tamoxifen and Raloxifene (covered in endocrine course)

A
  • selective estrogen receptor modulators (SERM)
  • used to prevent breast cancer recurrence in pre-menopausal hormone receptor positive (ER+/PR+) breast cancer patients
  • also used to prevent breast cancer in high risk breast diseases such as DCIS, etc.)
  • toxicity: increased risk of thromboembolism
57
Q

Aromatase Inhibitors (Anastrazole, Letrozole) (covered in endocrine course)

A

used to prevent breast cancer recurrence in post-menopausal hormone receptor positive (ER+/PR+) breast cancer patients
-significant side effect: osteoporosis

58
Q

Exemastane (covered in endocrine course)

A

-2nd generation competitive inhibitor of aromatase

59
Q

Flutamide (covered in endocrine course)

A

-androgen receptor modulator

60
Q

Dactinomycin (actinomycin D)

A
  • intercalates DNA
  • Wilms tumor, Ewing sarcoma, rhabdomyosarcoma
  • used in childhood tumors (“children ACT out”)
  • toxicity: myelosuppression
61
Q

Pazopanib

A

small molecule that inhibits many RTKs, especially VEGF

62
Q

Hydroxyurea

A
  • inhibits ribonucleotide reductase –> dec DNA synthesis
  • S phase specific
  • melanoma, CML, sickle cell disease (inc HbF)
  • toxicity: bone marrow suppression, GI upset

Chemotherapy Agents (1 decks)

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