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Pharm 2 > Anti-cancer drugs > Flashcards

Anti-cancer drugs Flashcards

1
Q

Log Kill hypothesis?

A

Action of chemo follows 1st order kinetics - a given dose of chemo kills a constant FRACTION of available tumor cells. Repeated doses of chemo agents are needed to be administered.
[administer chemo to prevent tumor cell number to reach 10^9 - 10^12]

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2
Q

Common adverse effects of chemo tx?

A
  • Nausea and vomiting (treated with 5HT3 blockers [ex. ondansetron] and NK1 inhibitors).
  • Stomatitis
  • Alopecia
  • Myelosuppression (Filgrastim [G-CSF stimulator] is used to treat neutropenia).
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3
Q

Categorize chemotherapeutic agents into strong, moderate and mild myelosuppression?

A

Strong - Cytarabine, alkylating agents, doxorubicin, Daunorubicin, Vinblastin

Moderate - Carboplatin, methotrexate, 5-FU

Mild - Bleomycin, Vincristine, asparaginase [use in pt who is already at risk of developing myelosuppression]

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4
Q

Specific AE of Doxorubicin, Cyclophosphamide, Ifosphamide, bleomycin?

A

Doxorubicin - cardiotoxicity
Cyclophosphamide and Ifosphamide - hemorrhagic cystitis
Bleomycin - pulmonary fibrosis

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5
Q

Use of what agents most commonly leads to treatment-induced neoplasms?

A

alkylating agents

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6
Q

What drugs can be used to rescue bone marrow, reduce hemorrhagic cystitis, reduce anthracycline-induced cardiotoxicity, reverse neutropenia and reduce renal toxicity caused by cisplatin?

A
  • Leucovorin rescues bone marrow from methotrexate.
  • Mesna reduces hemorrhagic cystitis caused by cyclophosphamide and ifosfamide.
  • Dexrazoxane reduces anthracycline-induced cardiotoxicity.
  • Filgrastim reverses neutropenia caused by many anticancer agents.
  • Amifostine is a cytoprotective agent that reduces renal toxicity caused by cisplatin.
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7
Q

Primary vs acquired resistance?

A

Primary - no response to drug on 1st exposure

Acquired - single drug resistance (increased expression of one or more genes) or multidrug resistance (resistance emerges to several different drugs after exposure to a single agent)

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8
Q

cell cycle specific vs cell cycle nonspecific drugs?

A

cell cycle specific - drug that exert action ONLY on cells going through cell cycle [hematologic malignancies - high growth fraction only]

cell cycle non-specific - can kill tumor cells whether they are cycling through cell cycle or resting in the Go compartment [hematological and solid tumors - low or high growth-fraction]

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9
Q

Methotrexate?

A

folate analog active against cells in S phase of cell cycle (DNA replication)

MTX to MTX polyglutamate intracellularly – MTX polyglutamate then binds and inhibits dihydrofolate reductase (DHFR) enzyme. Inhibiting this enzyme inhibits synthesis of THF involved in de novo synthesis of Deoxythymidylate nucleotides (inhibition DNA synthesis) and Purine nucleotides (inhibition DNA and RNA synthesis). No available pyrimidine or purine nucleotides are present to form the DNA.

AE:
• Common: Stomatitis, mucositis, myelosuppression (drug also affects normal cells therefore administer with Leucovorin), alopecia, nausea, vomiting.
• Hepatic fibrosis and cirrhosis.
• Pneumonitis.
• Neurologic Toxicities (with IT administration).
• Renal Damage: Uncommon. Complication of high-dose methotrexate.(MTX precipitates in the tubular lumen causing damage)

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10
Q

Leucovorin?

A

Leucovorin is a folinic acid derivative that is used in combination with methotrexate to revive some folate in the normal tissues. Leucovorin circumvents the inhibition of DHFR. [Antidote to drugs that decrease levels of folic acid]

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11
Q

6-Mercaptopurine

A

Purine analog of Hypoxanthine

  1. 6-MP to TIMP via HGPRT (salvage pathway)
  2. Thio-IMP inhibits first step of de novo purine ring biosynthesis [PRPP to IMP]
  3. Thio-IMP also blocks formation of AMP and GMP from IMP [IMP to AMP and GMP]
  4. TIMP can also be converted to TGTP incorporating in to RNA leading to dysfunctional RNA, OR TdGTP incorporating in to DNA leading to dysfunction

Clinical Application - ALL (CHILDHOOD acute leukemia)

AE - nausea, vomiting, diarrhea (b/c chemo drugs are toxic to rapidly dividing cells in the mucosa/GI tract), hepatotoxicity, bone marrow suppression

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12
Q

6-mercaptopurine metabolism?

A

6-MP to 6-methylmercaptopurine via thiopurine methyltransferase
*can be altered due to genetic deficiency (1:300 people have mutant alleles) of the enzymes, therefore you don’t want accumulation of 6-MP therefore decrease 6-MP dose

6-MP to oxidized metabolite via xanthine oxidase

  • if pt is on allopurinol, it will inhibit the xanthine oxidase enzyme therefore a reduced 6-MP dose is required b/c you do not want 6-MP to accumulate to toxic levels
  • *give allopurinol with 6-MP due to increased breakdown of cells/RNA/DNA that mostly end up producing uric acid
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13
Q

6-Thioguanine

A

Purine analog similar to 6-MP

  1. 6-TG to TGMP via HGPRT
  2. TGMP to TGTP and TdGTP
  3. TGMP inhibits amidotransferase (converst PRPP to IMP) and GMP to GDP conversion
  4. TGTP can be incorporated to RNA making it unstable
  5. TdGTP can be incorporated in to DNA making it unstable

Clinical Application - Non-lymphocytic leukemias

AE - nausea, vomiting, diarrhea, hepatotoxicity, bone marrow suppression

  • unlike 6-MP Allopurinol does not affect metabolite production therefore reduction is not required (deamination no oxidation)
  • genetic deficiency of thiopurine methyltransferase causing an increase in 6-TG concentration and therefore you require a decreased dose of 6-TG [very similar to 6-MP]
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14
Q

5-fluorouracil?

A

Pyrimidine analog

  1. 5-FU to 5-FdUMP via Dihydropyrimidine dehydrogenase (DPD)
  2. 5-FdUMP inhibits thymidylate synthase – thereby inhibiting DNA synthesis [dUMP can’t be converted to dTMP]
  3. 5-FU is also converted to 5-FUTP and incorporated into RNA interfering with RNA processing and function

*Leucovorin administration would produce N5-N10-methylene-THF which would potentiate the inhibition of the thymidylate synthase - enhance cytotoxicity in the tumor cells (different from its actions with methotrexate when it actually skips the inhibition and saves the cells)

Tx - colorectal cancer

AE - nausea, vomiting, alopecia, bone marrow, depression, HAND-FOOT SYNDROME (erythematous desquamation of palms and soles seen after extended infusion - location of the apocrine sweat glands)

*pts with partial or complete deficiency of DPD may lead to severe toxicity (myelosuppression, neurotoxicity, life-threatening diarrhea)

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15
Q

Capecitabine?

A

Pyrimidine analog

Oral prodrug that is converted to 5-FU via 3 enzymatic steps [1st step occurs in liver, last step occurs in tumor when it is catalyzed by thymidine phosphorylase - this enzyme is in much higher concentration in tumor cells than normal cells]

*used in management of metaststic colorectal and breast cancer due to increased concentration of the enzyme

AE - diarrhea, hand-food syndrome, myelosupression, etc (less toxic compared to 5-FU)

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16
Q

Cytarabine?

A

Deoxycytidine analog

Cytarabine to cytarabine triphoshate which..

  1. competitively inhibits DNA polymerase-a (blocks DNA synthesis)
  2. competitive inhibits DNA polymerase-B (blocks DNA repair)
  3. incorporated into RNA and DNA leading to interference with chain elongation and defective ligation of fragments of newly synthesized DNA

Tx - hematologic malignancies - NOT active against solid tumors

AE - Ocular toxicity, cerebellar toxicity and peripheral toxicity, then myelosupression, mucositis, nausea, vomiting

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17
Q

Gemicitabine?

A

Deoxycytidine analog

Phosphorylated to nucleoside di and triphosphate which leads to inhibition of DNA synthesis. Inhibition causes ribonucleotide reductase inhibition via diphosphate and chain termination via gemcitabine triphosphate incorporation.

AE - flu-like syndrome, nausea, vomiting, myelosuppression (neutropenia), renal microangiopathy syndromes, HUS and TTP (rare)

Broad-spectrum activity against solid tumors as well as hematologic malignancies (ex. non-hodgkin’s lymphoma)

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18
Q

Vinca alkaloids?

A

Microtubule inhibitors

Metabolized in the liver via P450, excreted in the feces

MOA - alkaloids bind B-tubulin disrupting assembly of microtubules therefore mitotic spindles (why they are active with cells in cell cycle). Inhibiting microtubules also prevents movement phagocytosis and axonal transport.

AE - neurotoxiciy (esp peripheral toxicity)

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19
Q

Vinblastine?

A

Vinca alkaloid (microtubule inhibitor)

Use for: Hodgkin’s and non-hodgkin’s lymphomas, breast cancer and germ cell cancer

AE - bone marrow suppression, alopecia, peripheral neuropathy, nausea and vomiting, potent vesicant (local tissue destruction therefore administer with extra are) [MYELOSUPPRESSION!!!]

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20
Q

Vincristine?

A

Vinca alkaloid (microtubule inhibitor)

Use for hematologic malignancies as well as PEDIATRIC TUMORS (rhabdomyosarcoma, neuroblastoma, Wilm’s tumor)

AE - neurotoxicity WITH peripheral neuropathy, paralytic ileus, optic atrophy, MILD myelosuppression, alopecia, SIADH (known mechanism) [NEUROPATHY!!!]

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21
Q

Taxans?

A

Microtubule inhibitors - Paclitaxel and Docetaxel

Metabolized in liver via P45- system and excreted via hepatobiliary route

MOA - binds B-tubulin at site different from vinca alkaloids promoting microtubule polymerization and INHIBIT DEPOLYMERIZATION leading to cell damage, cell arrest and cell death

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22
Q

Paclitaxel?

A

Taxans (Microtubule inhibitors)

Used against SOLID TUMORS

AE - HSN rxn, myelosuppression, peripheral neuropathy, alopecia

HSN rxn is reduced by premedication with dexamethazone, diphenhydramine and H2 BLOCKER (Ranitidine).

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23
Q

Abraxane

A

Albumin bound form of PACLITAXEL that DOES NOT cause HSN rxn that does not require premedication. It also causes less myelosuppression than traditional paclitaxel.

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24
Q

Docetaxel

A

Taxans (Microtubule inhibitors)

Used as 2nd line therapy for advanced breast cancer and NSCLC as well as solid tumors.

AE - myelosuppression, FLUID RETENTION, NEUROTOXICITY (not as frequent as Paclitaxel), mucositis, alopecia, HSN

Pre-treat with Dexamethasone to prevent fluid retention.

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25
Q

Epipodophyllotoxins?

A

Etoposide and Teniposide

Inhibit topoisomerase II resulting in DNA damage through strand breakage by blocking cells in late S-G2 phase.

Etoposide - used for testicular cancer and SCLC

Teniposide - used for refractory childhood ALL

AE - nausea, vomiting, alopecia, myelosuppression

*associated with increased risk of secondary tumors

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26
Q

Camptothecins?

A

Topotecan and Irinotecan

Inhibits activity of topoisomerase I causing DNA damage @ 2-G2

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27
Q

Topotectan

A

2nd line therapy for advanced ovarian cancer post treatment with platinum-based chemo

2nd line for SCLC

Renal excretion

AE - nausea, vomiting, myelosuppression

28
Q

Irinotecan

A

Prodrug converted in the liver to active metabolite

Eliminated in bile and feces

Used for metastatic colorectal cancer

AE - myelosuppression and severe diarrhea

29
Q

Bleomycin?

A

Antitumor antibiotic that is cell cycle specific

Specific to G2 phase

MOA - binds DNA and iron resulting in single and double strand breaks following free radical formation that destroys cels [Fe2+ to Fe3+]

Renal excretion

Used for: hodgkin’s and non-hodgkin’s lymphoma and solid tumors

AE - pulmonary fibrosis, skin hyperpigmentation, mucositis, MINIMAL bone marrow suppression

belomycin hydrolase - low levels of enzyme in lungs and skin which is why those organs are the most severely effected

30
Q

Anthracyclines

A

Antitumor antibiotic that is cell cycle nonspecific

Binding to cell membranes alters fluidity and ion transport, inhibits topo II, binds DNA through intercalation blocking DNA and RNA synthesis causing strand breakage AND generates free radicals through iron-dependent enzyme-mediated reductive process

AE - myelosupprsesion***, CARDIOTOXICITY (dilated cardiomyopathy due to free radicals but administering with iron-chelating agent dexrazoxane reduces cardiotoxicity risk), Erythema (“radiation recall reaction”)

31
Q

Radiation recall reaction?

A

desquamation of the skin observed at sites of prior radiation therapy

32
Q

Doxorubicin?

A

Anthracycline

solid, childhood and blood malignancies

33
Q

Daunorubicin?

A

Anthracycline

tx of AML, LIMITED efficacy against solid tumor

34
Q

Alkylating agents?

A

cell cycle non-secfic drugs

Transfer alkylyl groups to various cell constituents (esp DNA) leading to cell death.
Major sites of alkylation [bifunctional with 2 reactive groups leading to crosslinking] within DNA is N7 position of GUANINE.

AE - nausea and vomiting (pretreat with 5-HT3 receptor antagonist), potent vesicants at site of administration, CARCINOGENIC increasing risk of secondary malignancies (esp AML)

5 classe:

  1. nitrogen mustards
  2. Nitrosoureas
  3. alkyl sulfonates
  4. methylhydrazines
  5. triazines
35
Q

Nitrogen mustards

A

CYCLOPHOSPHAMIDE
IFOSFAMIDE
MECHLORETHAMINE
MELPHALAN

36
Q

Cyclophosphamide?

A

Nitrogen mustard

Oral or IV administration

AE - nausea, vomiting, bone marrow suppression, alopecia, sterility, HEMORRHAGIC CYSTITIS

hemorrhagic cystitis is due to production of acrolein in kidney from aldophosphamide metabolite. Once in the bladder, acrolein interacts and causes hemorrhagic cystitis. To prevent the cystitis, give Mesna to interact with acrolein.

37
Q

Ifosfamide?

A

Nitrogen mustard

IV administration - prodrug activated by p450 3A4

**More toxic than cyclophosamide due to active metabolite production, esp Chloracetaldehyde which is nephrotoxic and neurotoxic

AE - nausea, vomiting, bone marrow suppression, alopecia, sterility, HEMORRHAGIC CYSTITIS (prevent with Mesna administration)

38
Q

Mechlorethamine?

A

Nitrogen mustard

Unstable, made up as a solution that is made just prior to administration

Replaced by cyclophosamide, melphalen and other more stable agents

POWERFUL VESICANT (IV only)

AE - bone marrow suppression, nausea, vomiting, diarrhea, ORAL ULCERATION, HEPATOTOXICITY, pulmonary fibrosis (rare)

39
Q

Nitrosureas?

A

Alkylating agents

Carmustine (IV)
Lomatine (oral)

Lipid soluble that helps them cross BBB and treat BRAIN TUMORS. Also effective against lymphomas.

AE - myelosuppression, renal failure, pulmonary fibrosis

*no cross resistance with with alkylating agetns

40
Q

BUSULFAN

A

alkylating agents (Alkyl sulfonates)

Tx - CML

AE - myelosuppresion (main toxicity), pulmonary fibrosis

41
Q

Procarbazine?

A

alkylating agents (methylhydrazines)

Tx hodgkins, non-hodkins leukemia and brain tumors

AE - CNS deppresion, leukopenia, thrombocytopneia, disulfiram-like reaction

• One metabolite is a weak monoamine oxidase (MAO)
inhibitor, and adverse events can occur when
procarbazine is given with other MAO inhibitors as well
as tyramine-containing foods.

• Carcinogenic potential is higher than that of most
other alkylating agents (increased risk of secondary
cancers in the form of acute leukemia).

42
Q

Dacarbazine (DTIC)?

A

alkylating agent (Triazine)

Malignant melanoma, hodgkin’s lymphoma, soft tissue sarcoma, neuroblastoma

potent vesicant

AE - MILD-MODERATE myelosuppression, nausea and vomitting

43
Q

Platinum analogs?

A

Cisplatin and Carboplatin

MOA - bind DNA at N7 position of guanine leading to intra-strand cross-linking causing damage to DNA. They also generate free radicals and reactive oxygen species

Cleared by kidneys

44
Q

Cisplatin

A

TESTICULAR, ovarian and bladder cancer tx

AE - mild-moderate myelosuppression, nausea, comiting, peripheral sensory neuropathy, otoxicity, NEPHROTOXICITY (electrolyte disturbances), anaphylactic-like reactions

*testicular cancer treated with cisplatin, vinblastine and bleomycin

45
Q

Carboplatin

A

Solid tumors

AE - relatively safer compared to cisplatin presenting with only nausea, neurotoxicity, ototoxicity, meyelosuppression (most worrisome)

46
Q

How to prevent cisplatin induced nephrotoxicity?

A

Pre-treatment with hydration and diuresis

OR

administer AMIFOSTINE (thiphosphate cytoprotective agent) that reduces renal toxicity associated with repeated administration

47
Q

Prednisone?

A

Glucocorticodes that induces lymphocyte apoptosis in lymphocyte driven neoplasms. Also associated with management of autoimmune hemolytic anemia and thrombocytopenia associated with CLL.

48
Q

SELECTIVE ESTROGEN -RECEPTOR MODULATORS (SERMS)

A

Binds to and activates/blocks estrogen receptors depending on target tissue.

Tamoxifen and Raloxifene

49
Q

Tamoxifen?

A

Binds Estrogen receptors in breast inhibiting action of estrogen on breast cancer cells.

It can also bind estrogen receptors in the bone and activate them enhancing anabolism (prevention of osteoporosis). It can bind ER in endometrium tissue and partially activate receptors leading to endometrial hyperplasia, which is a problem b/c this is a risk factor for endometrial cancer.

50
Q

Raloxifene?

A

Binds estrogen receptors in breast and inhibits them preventing breast cancer. Used mainly as PROPHYLAXIS.

It can also bind to ER in endometrium inhibiting them therefore NOT leading to hyperplasia.

It can bind to ER in bone activating them preventing osteoporosis.

Breast cancer prophylaxis
Does NOT cause endometrial hyperplasia
Treats osteoporosis

51
Q

Fulvestrant?

A

Pure estrogen receptor antagonist with no agonist activity. It increases ER degradation and reduces number of ER molecule sin cell. It is used in Tamoxifen-resistant breast cancer.

52
Q

Aromatase inhibitors

A

• Inhibit aromatase enzyme which is required for
estrone, the primary estrogen in
postmenopausal women, synthesis from
androstenedione.
• Used as Adjuvant chemotherapy in estrogen
receptor positive breast cancer.

ANASTROZOLE and LETROZOLE - Non-steroidal, Competitive (reversible)
inhibitors of aromatase
enzyme

EXEMESTANE- steroidal,
Irreversible inhibitor of
aromatase enzyme

53
Q

Flutamide?

A

non-steroidal, competitive antagonist of Androgen receptor - blocks prostate from effect of androgens

Tx PROSTATIC CARCINOMA

May cause mild gynecomastia (b/c estrogens support breast tissue growth whereas androgens inhibit breast tissue growth so when you inhibit androgens you increase breast tissue) and reversible hepatic toxicity

54
Q

gonadotropin-releasing hormone analogs

A

Goserelin and Leuprolide

Pulsative admin stimulates FSH and LH release from ant pituitary stimulating release of gonadal hormones - continuous GnRH analogs produces a biphasic response (initial flare then delayed)

Initial phase (flare) - stimulates FSH and LH leading to increased testosterone [used Flutamide to counteract this effect]

Delayed phase - GnRH receptors on ant pituitary are going to be down regulated due to continuous exposure resulting in low LH, low FSH, low Testosterone

Tx - prostate cancer

55
Q

Signal transduction inhibitors?

A

protein kinases are required for the signaling, so blocking them decrease growth

  1. tyrosine kinase
  2. serine/threonine kinase
  3. kinase with activity towards all 3 residues
56
Q

EGFR tyrosine kinase inhibitors?

A

Gefitinib - NSCLC

Erlotinib - NSCLC, pancreatic carcinoma

Cetuximab - colorectal cancer (with KRAS overexpression), head and neck cancer

*overexpression of EGFR only

57
Q

Lapatinib

A

Inhibit EGFR and ErbB2

Tx NSCLC and pancreatic carcinoma

58
Q

Trastuzimab?

A

Humanized monoclonal antibody against ErbB2 (HER2) in breast cancer with HER2 overexpresssion.

Main AE is CARDIOTOXICITY but mechanism is unknown.

59
Q

Imatinib?

A

Inhibits Bcr-Abl tyrosine kinase in CML.

inhibits c-kit (tyrosine kinase receptor) in Kit-positive GIST.

Also used in idiopathic hypereosinophilic syndrome (non-cancer).

60
Q

Sorafenib?

A

Inhibits RAF serine/threonine kinase, VEGF-R2, VEGF-R3, PDGFR-B

Tx renal cell carcinoma

61
Q

Bortezomib?

A

Proteasome inhibitor (destroying proteins) that induces growth inhibition and apoptosis of tumor cells.

Tx - multiple myeloma, mantle cell lymphoma

62
Q

Subitinib?

A

Inhibits angiogenesis, VEGFR-1, VEGFR-2, PDGFR by acting as a protease inhibitors?

Tx - renal cell carcnoma, GIST

63
Q

Asparaginase?

A

breaks down asparagine to aspartate and ammonia via asparaginase. Aspartate can be converted back to asparagine through asparagine synthase increasing protein synthesis. Tumor cells do not have asparagine synthase decreasing amt of aspargaine available inhibiting protein synthesis.
???? dont’ you not want protein synthesis and cell growth?

tx ALL b/c they lack asparagine synthetase

64
Q

Hydroxyurea?

A

Kills cells in the S phase as they inhibit ribonucleotide reductase converting ribonucletoside diphosphate to deoxyribonucleoside diphosphate depleting deoxyribonucleoside triphosphate pool thereby inhibiting DNA synthesis.

Tx - malignant melanoma, CML, ovarian cancer, adult sickle cell disease and primary squamous cell carcinomas of head and neck

AE - myelosuppression, nausea, vomiting, diarrhea, skin rash, hyperpigmentation, macrocytosis

65
Q

Interferon a?

A

Stimulates NK cells to kill transformed cells by increasing expression of HLA molecules on tumor cells.

Tx - kaposi carcinoma, hairy cell leukemia, renal cell carcinoma, antiviral activity against HPV, HBV and HCV

AE - flu like symptoms

Pharm 2 (18 decks)

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