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oncology drugs Flashcards

1
Q

MOA of alkylating agents

A

Alkylation = covalent attachment of alkyl groups to other molecules

Major target of alkylation is N7 of guanine

Single base alkylation or cross-linking of DNA can occur

Leads to mismatched base pairs, prevention of DNA separation

No cell cycle specificity

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2
Q

alkylating agent toxicities

A

Myelosuppression (Febrile neutropenia)

Mucositis

Nausea/vomiting

Allopecia

Secondary malignancies

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3
Q

Mechlorethaminea

A

*historical drug–alkylating agent derivative of mustard gas

Toxicities include myelosuppression, alopecia, and nausea/vomiting (N/V)

Mechlorethamine cured many patients, but caused DNA damage, sterility in most patients, and increased the risk of secondary malignancies

Potent vesicant

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4
Q

cyclophosphamide

A

alkylating agent derivative of mustard gas

Prodrug. Activated by liver to active and toxic metabolites

IV and PO

Hemorrhagic cystitis: production of acrolein causes irritation to bladder wall. (Adequate hydration, Mesna with high doses)

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5
Q

ifosfamide

A

alkylating agent derivative of mustard gas. Analog of cyclophosphamide. Also requires hepatic activation to same active metabolites

Less potent, requires 4 x dose for efficacy

Increased production of acrolein accumulates in bladder and causes hemorrhagic cystitis

Administer with Mesna (IV/PO), hydration important.

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6
Q

Melphalan

A

alkylating agent derivative of mustard gas

Oral and IV

High dose (200 mg/m2) used for autologous HSCT

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7
Q

Bendamustine

A

Combination alkylating agent and purine analog

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8
Q

nitrosureas

A

alkylating agents

Lipophilic, good CNS penetration

Delayed myelosuppression, 4 week nadir

Severe N/V, pulmonary toxicity, hepatotoxicity

Carmustine implant: Gliadel Wafer

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9
Q

Dacarbazine

A

alkylating agent w/ good CNS penetration

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10
Q

Temozolamide

A

oral, converted to dacarbazine–>alkylating agent w/ good CNS penetration

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11
Q

platinum analogues

A

-alkylating agents (carboplatin, cisplatin, oxaliplatin)

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12
Q

cisplatin

A

alkylating agent, platinum analog

nephrotoxiticy, ototoxicity, N/V (Hydration, antiemetics)

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13
Q

Carboplatin

A

alkylating agent, platinum analog

Carboplatin: myelosupression, less N/V, neuropathy, nephrotoxocity than cisplatin

dosing based on renal function

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14
Q

Oxaliplatin

A

alkylating agent, platinum analog

acute: cold induced neuropathy, cumulative peripheral neuropathy

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15
Q

topoisomerase II inhibitors

A

Anthracyclines: daunorubicin, doxorubicin, epirubicin, idarubicin

mitoxantrone

etoposide

  • High affinity binding to DNA
  • Intercalates between base pairs, inhibits the activity of enzymes involved in DNA replication (topoisomerase II)
  • Anthracyclines form free radical compounds that damage biological macromolecules
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16
Q

topoisomerase I inhibitors

A

Camptothecins: irinotecan, topotecan

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17
Q

topoisomerase inhibitors MOA

A

Topoisomerases (I and II) are nuclear enzymes that unravel DNA for repair and replication

Specifically they participate in DNA replication and repair by:

  • cleaving and resealing the phosphodiester bonds that comprise the backbone of DNA (Topo II)
  • unwinding DNA (Topo I)

Inhibiting topoisomerases can induce DNA damage such as unrepairable strand breaks leading to cell apoptosis

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18
Q

anthracyclines: drugs?

toxicities?

A

doxorubicin, daunorubicin, idarubicin, epirubicin

CHF after a cumulative dose is reached, high/delayed emetogenicity, vesicants

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19
Q

topotecan

A

topoisomerase I inhibitor (undwinding DNA)

dose limited marrow suppression

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20
Q

irinotecan

A

topoisomerase I inhibitor

Diarrhea is a dose limiting side effect

  • Early form–Cholinergic syndrome treated with IV atropine
  • Late form–Direct GI toxicity. Loperamide 4 mg x 1, 2 mg q2hr. May cause serious dehydration
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21
Q

Bleomycin

MOA and toxicities

A

Bleomycin produces single and double strand breaks in DNA through the production of highly reactive free radicals

Toxicity: pulmonary fibrosis (avoid cumulative dose >400 units, current radiation/oxygen). Hyperpigmentation, rash, fever, allergic rxn.

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22
Q

antimicrotubule drugs

A

Vinca Alkaloids: vinblastine, vincristine, vinorelbine

Taxanes: docetaxel, paclitaxel

Epothilones: ixabepilone

Disrupt cell division in M phase

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23
Q

vinblastine, vincristine, vinorelbine

drugs

MOA

toxicities

A

vinca alkaloids

inhibit the formation of tubulin, which prevents polymerization into microtubules

inhibit cell division dring M phase cell cycle

Vincristine:
neurotoxicity, constipation
Max dose 2 mg/week

Vinblastine/vinorelbine:
Myelosuppression
Less neurotoxicity

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24
Q

docetaxel, paclitaxel, carbazitaxel

MOA

A

Taxanes bind to beta tubulin and stabilize the alpha and Beta tubulin heterodimers, preventing the breakdown of microtubules

disrupts cell division in M phase

Toxicities:

Require premedication with steroids due to solubilizing agents

Paclitaxel
Neuropathy
Albumin-bound paclitaxel (Abraxane), no solubilizer

Docetaxel
Fluid retention syndrome: dex 8 mg PO BID x 3 days

Cabazitaxel
Crosses BBB, not affected by P-glycoprotein

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25
ixabepilone
epithalones bind to beta tubulin and stabilize the alpha and Beta tubulin heterodimers, preventing the breakdown of microtubules disrupts cell division in M phase Distinct tubulin binding site, not effected by Pgp
26
general MOA of antimetabolites categories/drugs
Structurally these agents mimic their naturally occurring nucleotide cousins S-phase specific They work by one or a combination of the following: - inhibiting enzymes involved in nucleotide synthesis - inhibiting enzymes involved in DNA replication - replacing naturally occurring nucleotides in DNA that is actively being replicated. This serves to disrupt the -natural structure of DNA, causing apoptosis. Folate Antagonists: methotrexate, pemetrexed, pralatrexate Purine Analogues: cladribine, fludarabine, mercaptopurine, nelarabine, pentostatin, thioguanine Pyrimidine Analogues: capecitabine, cytarabine, fluorouracil, floxuridine, gemcitabine
27
Methotrexate
folate antagonist - Inhibits dihydrofolate reductase (decreases reduced folates, inhibits thymidylate synthase) - IV, IM, IT, PO - Cleared renally, accumulates in third-space fluids - High-dose therapy: hydrate with bicarb containing fluids until urine pH \> 7, leucovorin rescue, and monitor MTX blood levels, \< .05 µM (5 x 10-8 M) - Mucositis, pneumonitis, renal failure, inc LFT’s
28
Thioguanine (6-TG) and mercaptopurine (6-MP)
purine analog Oral agents Liver toxicity, mucositis Mercaptopurine metabolized by xanthine oxidase
29
Fludarabine, cladrabine, pentostatin
pyrimidine analogs Immunosuppression (lymphopenia)
30
nelabarine
purine analog neurotoxicity is dose limiting
31
cytarabine (Ara-C)
cytidine analog flu-like syndrome, rash High dose: HiDAC * marrow suppression * cerebellar toxicity * conjunctivitis (steroid eye drops)
32
Flourouracil (5-FU)
converted to F-FdUMP, inhibits thymidilate synthase (dUMP--\>dTMP) toxicity is dose and frequency dependent * intermittent bolus: myelosuppression * continuous: hand-foot syndrome administration of leucovorin potentiates effects
33
capecitabine
oral agent converted to flourouracil selectively activated by tumor cells Toxiciites: hand-foot syndrome, GI
34
5-azacitidine, decitabine
inhibits DNA methyltransferase hypomethylates DNA activates previously "silenced" tumor suppressor genes * inhibits angiogenesis, metastasis * allows apoptosis *
35
general MOA of monoclonal antibodies
Disrupt signal transduction * neutralizing the ligand (bevacizumab) * inhibiting extracellular receptors (cetuximab, panitumab) Direct Cytotoxicity (rituximab, alemtuzumab) * complement dependent * antibody dependent * induction apoptosis Delivery of cytotoxic agents * radioactive moieties (tositumab, ibritumomab) * anti-neoplastic (brentuximab, vedotin)
36
rituximab/ofatumumab
cytotoxic anti-CD20 antibody CD20 on B lymphocytes Present on \>90% of all B cell NHL and leukemias mediates ADCC and CDCC ADE: * infusion reactions (titrate infusions) * tumor lysis syndrome Ofatumumab binds to a different epitope on CD20
37
Alemtuzumab
cytotoxic anti-CD52 antibody CD52 on normal and malignant T cells, NK cells, monocytes, and macrophages Used in refractory CLL, T-cell leukemia ADE: * Infusion reactions, anaphylaxis * profound prolonged immunosuppression, HSV and PCP prophylaxis
38
Ibritumomab and Tositumomab
anti-CD20 antibody conjugated to radioactive compounds Use in Relapsed and/or refractory CD20-positive, follicular NHL Avoid in patients with \> 25% involvement of the bone marrow by lymphoma and/or impaired bone marrow reserve. ADE: myelosuppresion, leukopenia (prolonged)
39
brentuximab vedotin
Anti-CD30 antibody attached to monomethyl auristatin E (MMAE) MMAE is a mitotic spindle poison Used in Hodgkin, anaplastic large cell lymphoma ADE: Infusion reactions, myelosuppression, peripheral neuropathy
40
denileukin diftitox
anti-CD25 antibody (IL2-receptor) attached to diptheria toxin used in persistent or recurrent cutaneous T-cell lymphoma ADE: infusion reactions, vascular leak, flu-like syndromes, hepatotoxicity
41
Trastuzumab/pertuzumab
anti-HER2/neu receptor antibody (signal blocking antibody) HER2 overexpressed on 25% breast cancers binding results in apoptosis and ADCC ADE: infusion reactions, anaphylaxis Trastazumab: cardiotoxicity, esp when used w/ cyclyophosphamide or anthracycline
42
cetuximab/panitumab
Anti-EGFR antibody (signal blocking antibody) EGFR overexpressed in many solid tumors antibody binding results in inhibition of proliferation, growth, metastasis, and angiogenesis enhances response to chemo and radiation ADE: infusion reactions, anaphylaxis * skin toxicity may be severe * electroylyte imbalances
43
bevacizumab
anti-VEGF antibody (signal blocking) inhibits formation of new blood vessels in primary and metastatic tumors ADE: infusion reactions, anaphylaxis * GI perforations tracheoesophageal fistulasand * circulatory: bleeding, arterial thrombosis, hypertension, impaired wound healing, proteinuria
44
Ipilimumab
binds cytotoxicy T-lymphocyte-associated-antigen 4 (CTLA-4) blockage of CTLA-4 augments T cell activation and proliferation can result in severe and fatal immune-mediated adverse reactions due to T cell activation ADE: colitis, hepatitis, toxic epidermal necrolysis
45
tyrosine kinase inhibitors general
These enzymes are involved in cellular signaling pathways and regulate key cell functions such as proliferation, differentiation, anti-apoptotic signaling Inhibitors occupy ATP binding site and prevent phosphorlyation of substrates All are CYP3A4 substrates
46
erlotinib gefitinib
RTK inhibitor inhibited EGFR (TK) NSCLC ADE: diarrhea, skin rash (correlates with efficacy)
47
imatinib
intracellular TKI inhibits BCR-ABL TK (philadelphia chr t(9;22)) used in CML ADE: myelosuppression
48
Dasatinib
Intracellular TKI Inhibits BCR-ABL TK created by Ph chromosome translocation (9;22), PDGF, cKIT Used in CML Dasatinib also inhibits SRC kinase toxicity is myelosuppression
49
Nilotinib
Intracellular TKI Inhibits BCR-ABL TK created by Ph chromosome translocation (9;22), PDGF, cKIT Used in CML Nilotinib more potent than imatinib Toxicity: myelosuppression
50
sunitinib
inhibits PDGFR and VEGFR used in renal cell cancer Toxicities: GI, skin discoloration, fatigue, hypertension, bleeding, CHF
51
sorafinib
inhibits PDGFR and VEGFR used in RCC and hepatocellular cancer Toxicites: GI, rash, hypertension, bleeding, hand-foot syndrome
52
lapatinib
Inhibits EGFR ad Her-2 Used in Her2+ breast cancer Toxicities: diarrhea, decreased LVEF, QT prolongation (cardio)
53
vemurafenib
BRAF inhibitor melanoma w/ BRAF V600E mutation
54
crizotinib
ALK inhibitor ALK postiive NSCLC
55
ruxolitinib
JAK inhibitor used in myelofibrosis
56
Vismodegib
hedgehog inhibitor used in basal cell skin cancer embryotoxic and teratogenic
57
rapamycin
mTOR inhibitor Binds to FK Binding Protein FKBP-drug complex inhibits mTOR kinase activity Decreased production of Hypoxia Inducible Factor, VEGF, PDGF, TGF
58
Temsirolimus
mTOR inhibitor Binds to FK Binding Protein FKBP-drug complex inhibits mTOR kinase activity Decreased production of Hypoxia Inducible Factor, VEGF, PDGF, TGF Toxicities: * hyperglycemia * inc. TG/cholesterol * rash, asthenia, mucositis *
59
all-trans-retinoic acid (ATRA)
ATRA provides high levels of retinoic acid Induces differentiation and maturation of acute promyelocytic cells to normal myelocyte cells used in APL w/ PML-RAR fusion (suppresses DNA txn at normal retinoic acid levels--\>accumulation promyelocytes/differentiation block) Differentiation syndrome. * Fever, leukocytosis, dyspnea, weight gain, diffuse pulmonary infiltrates, and pleural and/or pericardial effusions. * Observed with WBC \> 10,000/mm3. Usually observed during the first month of therapy but may follow the initial drug dose.
60
Arsenic Trioxide
Induces differentiation of APL cells by degrading the chimeric PML/RAR-α protein, resulting in release of the maturation block. ADE: Differentiation syndrome, QT prolongation
61
thalidomide
induce apoptosis, enhance T-cell and NK cell cytotoxicity, inhibit angiogenesis Used for multiple myeloma ADE: sedation, constipation, rash, neuropathy * restricted distribution system, teratogen
62
lenalidomide
induce apoptosis, enhance T-cell and NK cell cytotoxicity, inhibit angiogenesis Used for multiple myeloma ADE: marrow suppression, thromboembolism, restricted distribution system, teratogen
63
pomalidomide
induce apoptosis, enhance T-cell and NK cell cytotoxicity, inhibit angiogenesis Used for multiple myeloma ADE: restricted distribution system, teratogen
64
Bortezomin
inhibits proteasome--\>prevents degradation of pro-apoptotic proteins highly active in MM toxicities: neuropathy and thrombocytopenia
65
immediate effects of chemotherapy
within hours to days after chem/RT nausea, vomiting flushing, immediate hypersensitivity hemorrhagic cystitis (cyclophosphosphamide) fever, chills
66
early effects of chemo therapy
days to weeks after Chemo/RT corresponds to rapidly proliferating cell compartments hematopoeitic: dec. WBC, platelets stomatitis cerebellar ataxia (5-FU) alopecia pancreatitis (L-asparaginase)
67
delayed effects of chemotherapy
observed wks to months after therapy anemia (lifespan RBC 120d) pulmonary fibrosis (bleomycin, busulfan) cardiotoxicity (anthracyclines: doxorubicin) SIADH (cyclophosphamide, vincristine) hepatocellular damage cholestatic jaundice (6-MP) azoospermia
68
late effects of chemotherapy
occur months or years after therapy sterility and hypogonadism endocrinopathies second malignancies encephelopathy
69
Grading of toxicity
NCI: CTEP, RTOG; other Grades 1-4, with 4 the worse 1: no interference w/ activity 2: interferes w/ activity: outpt treatment 3,4: may require hospitalization, sig. change in functional status 5: fatal CTC: common toxicity criteria (standard use protocol)
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Toxicity: hypersensitivity
I: bronchospasm, wheezing, agitation, rash, angioedema; starts in minutes (esp. monoclonal antibodies) II: delayed, includes hemolytic anemia III: interstitial penumonitis, vasculitis (eg. methotrexate) Drugs: * L-asparaginase * paclitaxel, docetaxel (premedicate w/ steroids, anti-HI, H2) * procarbazine * teniposide uncommon drugs: * anthracyclines, bleomycin * carboplatin, cisplatin * cyclophosphadmide, chlorambucil, busulfate * cytarabine, gemcitibine * interferosn * vicas, etc
71
Toxicity: nausea and vomiting
Mechanism: * chemoreceptor trigger zone: CNS * cerebral cortex: anticipatory * vestibular stimuli * vagal afferents * chemical and physical stimuli to GI tract * metabolic (hypercalcemia hepatic, renal failure, DKA etc)\*\*causes other than chemo itself Anti-emetics: * 5-HT3 receptor antagonists * antihistamines * corticosteroids * cannabinoids * benzodiazepines * phenothiazines (compazine) * substituted benzamides (reglan) * substance P (NK1) antagonist (for delayed nausea and vomiting)
72
toxicity: mucositis
early complication both radiation and chemo erythema,early ulceration--\>confluent ulceration and pseudomembranes assoc. w/ pain bacterial and fungal superinfection common
73
toxicities: neuro peripheral or central
peripheral neurotoxicity: motor or sensory neuropathy * taxanes * vincas (motor neuropathy) * platinum based compounds central neurotoxicity: * ifosphamide * high dose methotrexate * fluorouracil * procarbazine * ara-C (cerebellar) * fludarabine
74
toxicities: nephrotoxicity
cisplatin, gallium, high dose methotrexate azactidine, streptozocin occasional: fludarabine, mitomycin, interferons, lomustine uncommon: carboplatin, low dose methotrexate \*nephrotoxicity and ototoxicity go together
75
toxicities: cystitis
early or late suprapubic pain, dysuria, urgency, hematuria cyclophosphamide, ifosphamide mesna (sodium 2 mercaptoethanol sulfonate)--\>prevent hemorrhagic cystitis
76
toxicities: pulmonary
drug or radiation radiation: varies w/ total dose, number of fractions, volume irradiated bleomycin (dose dependent, early idiosyncratic rxns, toxicity enhanced by inc. FiO2 and concurrent RT) Other drugs: * busulfan, cyclophosphamide, chloambucol * nitrosureas * bleomycin, mitomycin * methotrexate, ara-C, mercaptopurine * procarbazine, etoposide, retinoic acid MOA: * free radical formation, activation of inflammation * upregulate collagen formation by fibroblasts * cytokines (IL1, TGFbeta etc) Pathology: * vascular damage * desquamation of type 1 pneumocytes * delamellation and proliferation of type II pneumocytes * mononuclear cell infiltration Sx: * dyspnea * cough, fatigue, fever * chest pain, rarely * hemoptysis, uncommon Acute: * taxols (bronchospasm, anaphylaxis or pulmonary edema) * ATRA (respiratory distress, mediated by marginating leukemia cells in pulmonary circulation, w/ cytokine release and neutrophil migration, prevented by steroids) Radiology: * reticulonodular pattern * pleural effusions * nodules
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toxicity: cardiotoxicity
anthracyclin (doxorubicin/adriamycin) * dose and schedule dependent * preexisting cardiac disease inc. risk * older age inc. risk * concurrent radiation to heart, cyclophosphamide inc. risk Acute toxicity: uncommon--myopericarditis, arrhythmias, effusion subacute: classic--up to 30months, inc. tachycardia, fatigue, pulmonary edema and CHF late: 5+ years after anthracycline late decompensation in those who recovered (systolic function abnormality, arrythmias and death) mechanism: * mitochondrial injury * depletion ATP and phosphocreatine * depression contractility * free radical formation, lipid peroxidation monitoring/prevention: baseline evaluation prior to anthracyclines (EKG, ejection fraction, biopsy) Other agents: * cyclophosphamide and ifosphamide (only high doses) * paclitaxel: arrythmias, sinus bradycardia (infrequent) * vincristine and vinblastine: rare autonomic dysfx * mitomycin: enhances cardiotoxicity * 5-FU: infrequent-pain, atrial arrythmia, ventricular dysfx, rare cardiac failure, coronary artery spasm. _silent ischemic changes w/ continuous infusion_ * traztuzumab: herceptin
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toxicities: bevacizumab erlotinib, cetuximab
angiogenesist inhibitors: bevacizumab: * hypertension, proteinuria, inc. bleeding, clottting, bowel perforation EGFR inhibitors: erlotinib, cetuximab: * folliculitis, diarrhea, interstitial pulmonary fibrosis
79
toxicity: acute endocrine effects
early hypothyroidism: pazopanib autoimmune: ipilumumab, T cell activation (diarrhea, thyroid) hyperglycemia: steroids, pazopanib
80
late endocrine effects
hypothyroidism after radiation therapy to neck and chest areas hypopituitarism as late effect of radiation therapy reproductive failure after either chemo or RT * accelerated menopause in women (longer time for osteoporosis, pyschosocial, hormonal manipulation) * sterility and azoospermia in men * aklyating agents most likely to cause this * antimitotic agents have reversible effects on reproduction
81
toxicity: second malignancy
continued exposure to carcinogen underlying germ line abnormality or susceptibility related to primary tumor radiation induced leukemia: atomic bomb, nuclear accident breast cancer following low dose radiation, esp. in childhood or adolescence radiation and lung cancer: minimal alkylating agents: risk of leukemia and myelodysplasia topoisomerase II inhibitors: leukemia risk
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