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Pharmacology > Cancer II > Flashcards

Cancer II Flashcards

1
Q

Antibiotic anticancer drugs:

  1. Form ________ complexes with DNA: how? Examples?
  2. Form _____ linkages with DNA. Example?
  3. Cause DNA backbone _____. Examples?
A

Antibiotic anticancer drugs:

  1. Form non-covalent complexes via intercalation (daunorubicin/doxorubicin) or groove binding (distamycin A)
  2. Covalent linkages = mitomycin C
  3. Cause DNA backbone cleavages = bleomycin
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2
Q

Dactinomycin:

  1. Molocule consist of?
  2. MOA: ___ into ____ rich regions of DNA. Net effect is a depression of ____ ______, specifically ___ in the nucleolus due to the high ____ content of these genes. Can also?
  3. Dactinomycin may be metabolized to produce? What do these do?
A

Dactinomycin:

  1. Consists of a 3-ring chromophore and 2 cyclic peptides
  2. MOA: intercalation into G-C rich regions of DNA. Net effect is a depression of RNA transcription, specifically rRNA in the nucleolous due to the high G-C content of these genes. Can also inhibit DNA synthesis
  3. Metabolized to produce ROS which may cause DNA SS-breaks
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3
Q

Dactinomycin:

  1. Primary toxicities are ___ and ___. Dose limiting ___ suppression may occur within _____ days with a decrease in ___ count indicative of ___ ___ suppression. ___ may also occur.
  2. Clinical uses?
A

Dactinomycin:

  1. Primary toxicities are nausea and vomitting. Dose limiting hematopoietic suppression may occur within 1-7 days with a decrease in platelet count indicative of bone marrow suppression. Alopecia may also occur
  2. Clinical uses = Wilm’s tumor, rhabdomyosarcoma, and choriocarcinoma
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4
Q

Plicamycin:

  1. MOA?
  2. Primary result is depression of?
  3. Interesting side effect of?
A

Plicamycin:

  1. MOA: similar to dactinomycin - intercalates into DNA and competes for binding sites in G-C rich DNA
  2. Depression of DNA, RNA, and protein synthesis
  3. Plicamycin lowers calcium levels in patients with hypercalcemia***
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5
Q

Plicamycin:

  1. Best for what kind of patients?
  2. Toxicities?
A

Plicamycin:

  1. Best for hypercalcemic patients
  2. Toxicity = BM suppression, GI upset, and liver toxicity
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6
Q

Anthracyclines:

  1. Name 4 drugs?
  2. The agent contains a ___-ring anthracycline chromophore with an attached ____ that can interact with the ___ phosphate backbone of DNA by ______ binding.
A

Anthracyclines:

  1. Danuorubicin, doxorubicin, idarubicin, and epirubacin
  2. The agent contains a 4-ring anthracycline chromophore with an attached sugar that can interact with the sugar phosphate backbone of DNA by non-covalent binding
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7
Q

Daunorubicin:

MOA - 3 potential:

  1. Molecular ___ into DNA resulting in? It is also a complex stabilizing inhibitor of?
A

Daunorubicin:

MOA:

  1. Molecular intercalation into DNA resulting in decreased DNA, RNA, and protein synthesis. DNA strang breaks are observed and it is a complex stabilizing inhibitor of topoisomerase II
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8
Q

Daunorubicin:

MOA - 3 potential:

  1. Metabolism of the moecule to a form capable of generating? This produces?
  2. Activation of ___ signaling pathway through ____ pathway.
A

Daunorubicin:

MOA - 3 potential:

  1. Metabolism of the molecule to a form capable of making free radicals producing strand breaks
  2. Activation of apoptosis signaling pathway through _extrinsic _pathway
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9
Q

Daunorubicin:

  1. Administration? Metabolized to ___ in the liver. Excretion? Color?
  2. Treatment of?
  3. Main toxicities?
A

Daunorubicin:

  1. IV administration. Metabolized to daunorubicinol in the liver. Excretion via the kidney - may be red
  2. Treats AML in combo with Ara-C
  3. Toxicity = BM suppression, GI disturbances, and dermatological toxicities
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10
Q

Daunorubicin:

  1. What is the limiting toxicity?
  2. Who should daunorubicin not be used in?
  3. Why should it ONLY be administered in a rapid IV infusion?
A

Daunorubicin:

  1. Limiting toxicity = cardiac toxicity (arrythmias, tachycardia, and delayed CHF)
  2. Not for patients with cardiac disease
  3. IM or subcutaneous = extensive tissue necrosis; intrathecally = extensive CNS/PNS damage and may cause death. IV = only safe route
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11
Q

Doxorubicin:

  1. MOA?
  2. Difference compared to daunorubicin?
A

Doxorubicin:

  1. MOA = same as daunorubicin (1. decreased DNA/RNA/protein synthesis; 2. ROS; 3. activation of apoptosis)
  2. Extensively metabolized by the liver and it should be avoided in patients with impaired hepatic function
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12
Q

Doxorubicin:

  1. Treatment of?
  2. Main toxicities? Marked ____ toxicity.
A

Doxorubicin:

  1. Treat = leukemia and lymphomas and solid tumors of ovary, breast, lung and several sarcomas. As a single agent its good against metastatic breast tumors, bronchogenic carcinoma, bladder cancer, and metastatic thyroid cancer
  2. Toxicity = myelosuppression, alopecia, and GI disturbances. Marked cardiac toxicity
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13
Q

Doxorubicin:

  1. Mechanism of cardiac toxicity?
  2. Heart muscle cells are deficient at? So the metabolism of doxorubicin may be particularly toxic.
A

Doxorubicin:

  1. Destruction of mitochondria in the heart muscle or membrane damage with destruction of enzymes of mitochondrial membrane.
  2. Heart muscle cells are deficient at scavenging of free radicals and is more suceptible to damage
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14
Q

Epirubicin:

The same spectrum of activity as _____. The agent has ____ _____ toxicity relative to ___.

A

Epirubicin.

Same spectrum of activity as doxorubicin. Has LOWER cardiac toxicity relative to doxorubicin

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15
Q

Idarubicin:

  1. Used in combination with _____ for?
  2. Improved clinical activity may be due to reduced ___ ____ toward idarubicin.
  3. Toxicity is similar to ___ with the exception of high frequency of _____ toxicity after ____ administration
A

Idarubicin:

  1. Used in combo with Ara-C for Acute Myelogenous leukemia
  2. Reduced multidrug resistance
  3. Toxicity is similar to daunorubicin with the exception of high frequency GI toxicity after oral administration
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16
Q

Other Anthracycline derivatives:

  1. All of these are DNA ___ and produce DNA ____ ___. They are also inhibitors of DNA ___________ __.
  2. Name two other drugs?
A

Other Anthracycline derivatives:

  1. All of these are DNA intercalators and produce DNA strand breaks. They are also inhibitors of DNA topoisomerase II.
  2. Dihydroxyanthracenedione and Mitoxantrone
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17
Q

Mitoxantrone:

  1. Has limited ability to produce ___ ___ and causes less cardiac toxicity than ___.
  2. Route of administration? Treats?
  3. Other than cancer what does it treat?
  4. Toxicities? Compared to doxorubicin?
A

Mitoxantrone:

  1. Has limited ability to produce Free radicals with less cardiac toxicity than doxorubicin
  2. IV: leukemias and breast cancer
  3. MS** (slows progression and increases time between relapse)
  4. Toxicity = acute myelosupressio and mucositis; LESS N/V and alopecia than doxorubicin
18
Q

Bleomycin:

MOA: DNA _____ and DNA chain _____. The molecule binds _____ which can be oxidized to ___. The lost electron forms ___ ___ with oxygen and subsequently produces ____ ___ which can attack and break DNA

A

Bleomycin

MOA: DNA binding and DNA chain scission. The molecule binds Fe++ which can be oxidized to Fe+++. The lost electron forms free radicals with oxygen and subsequently produces hydroxyl radicals that attack and break DNA

19
Q

Bleomycin:

  1. Administration? T1/2?
  2. Often used in _____ chemotherapy
  3. Has minimal toxicity to? Thus is useful in regimens containing ________ agents.
A

Bleomycin:

  1. Administered IV; T1/2 = very short (<30 min)
  2. Often used in combination chemo
  3. Minimal toxicity to BONE MARROW and is useful in regimens containing myelosuppressive agents
20
Q

Bleomycin:

  1. Major toxicity?
  2. Where is bleomycin hydrolase?
A

Bleomycin:

  1. Major toxicity: reduced or impaired pulmonary function that may lead to pulmonary fibrosis
  2. Bleomycin hydrolase is in most tissues except lung and skin
21
Q

Mitomycin:

The molecule is _____ in hypoxic tumor tissues producing a ___ ___ generating, _____ agent. The final product of metabolism of mitomycin produces a molecule capable of producing DNA _______ and ______ crosslinks.

A

Mitomycin:

The molecule is reduced in hypoxic tumor tissues producing a free radical generating, alkylating agent. The final product of metabolism of mitomycin produces a molecule capable of producing DNA interstrand and intrastrand crosslinks

22
Q

Antimitotic drugs:

  1. Name of the class?
  2. Name of 4 drugs?
A

Antimitotic drugs:

  1. Vinca alkaloids
  2. Vincristine, vinblastine, vinorelbine, and vindesine
23
Q

Vinca Alkaloids:

  1. Vinorelbine is made from _____ with a substitution which results in less _____.
  2. Vindesine is a metabolic byproduct of ____ metabolism
A

Vinca Alkaloids

  1. Vinorelbine is made from vinblastine with a substitution which results in less neurotoxicity
  2. Vindesine is a metabolic byproduct of vinblastine metabolism
24
Q

Vinca Alkaloids:

  1. MOA: bind to ______ and block ability to polymerize with ___ and cause ______.
  2. They are cell cycle ____ and block cells in ____.
  3. Result of the moa?
A

Vinca Alkaloids:

  1. MOA: bind to beta-tubulin and block ability to polymerize with alpha-tubulin and cause depolymerization
  2. They are cell cycle specific and block cells in mitosis
  3. Result = dissolution of microtubules because they cant grow (so they are being taken apart at the other side)
25
Q

Vinca alkaloids:

  1. What happens with chromosomes?
  2. Disruption of microtubule structures also results in activation of? This causes?
  3. 2 mechanisms of resistance?
A

Vinca alkaloids:

  1. Chromosomes cant separate properly –> cell death
  2. Also results in activation of p53 –> apoptosis
  3. Mechanisms of resistance: drug transporter (P glycoprotein and MRP1) - transmembrane efflux pumps AND decreased binding of vinca alkaloids to tubulin
26
Q

Vinca alkaloids:

  1. Vincristine is used to treat what in children? adults?
  2. Vinblastine treats what?
  3. Toxicity of vincristine?
  4. Toxicity of vinblastine, vindesine, and vinorelbine?
  5. Toxicity of ALL?
A

Vinca alkaloids:

  1. Vincristine = pediatric tumors and solid tumors; adult lymphoma and breast carcinoma
  2. Vinblastine = testicular carcinoma and lymphoma
  3. Vincristine = peripheral neurotoxicity
  4. The rest = neutropenia
  5. ALL cause GI side effects
27
Q

Taxanes:

  1. MOA: bind to ___ and promote ____. It antagonizes the ___ of actin and results in bundles of microtubules with _____ structures
  2. Drug examples
A

Taxanes:

  1. MOA: bind to beta tubulin and promote polymerization. It antagonizes the diassembly of actin and results in aberrant structures
  2. Paclitaxel and Docetaxel
28
Q

Taxanes:

  1. Activates ___ pathway (__trinsic ____ pathway) and blocks cells in ___ or ___ phase of the cell cycles.
  2. Resistance to paclitaxel is associated with increased expression of _______. Other resistant cells have ____ mutations. Absolute basis is unknown.
A

Taxanes:

  1. Activates p53 (extrinsic apoptosis pathway) and blocks cells in G2 or M phase of the cell cycles.
  2. Resistance to paclitaxes is associated with increased expression of P-glycoprotein. Other resistant cell have tubulin mutations.
29
Q

Taxanes:

  1. Toxicity? Less frequent toxicities?
  2. Clinical uses?
A

Taxanes:

  1. Toxicity = Neutropenia, mucositis, and neurotoxicity; Less frequent = cardiac arrhythmias and joint pain
  2. Clinical = ovarian, breast, non-small cell lung, melanoma, and renal cancer as well as leukemia
30
Q

So basically what two drugs cause the opposite things? Explain?

A

Taxanes inhibit formation of tubulin from microtubules ( lead to clumped irregular microtubules) and vinca alkaloids inhibit formation of microtubules from tubulin (via depolymerization)

31
Q

Epipodophyllotoxins:

  1. Semisynthetic ___ derivative of _____. From the ____ plant
  2. Drugs?
A

Epipodophyllotoxins:

  1. Semisynthetic glycoside derivatives of podophyllotoxin from the mayapple (mandrake) plant.
  2. VP-16 (etoposide) and VM26 (teniposide)
32
Q

Topoisomerases:

  1. Govern the topilogical ______ of DNA by transiantly ____/____ the phosphodieterase of ___ or both strands of the double helix
  2. TOPO1 is responsible for?
  3. TOPO2 is responsible for?
A

Topoisomerases:

  1. Govern the topological interconversions of DNA by transiently breaking/rejoining the phosphodiesterase of one or both strands of the double helix
  2. Topo 1 = recombination, DNA repair, and RNA transcription***
  3. Topo 2 = DNA replication, chromosome segregation, and maintenance of chromosome structure
33
Q

Epipodophyllotoxins:

  1. Cells in the __ and ___ phases are most sensitive to VP16 and VM26.
  2. They cause DNA strand breaks and are ____ __ inhibitors. They trap and stabilize ______ __-DNA ____.
  3. They inhibit _____ transport and incorporation into ____ ___ _____.
A

Epipodophyllotoxins:

  1. Cells in the S and G2 phases are most sensitive
  2. They are topoisomerase II inhibitors. Trap and stabilize topoisomerase II-DNA intermediates.
  3. They inhibit nucleotide transport and incorporation into nucleic acids
34
Q

Epipodophyllotoxins:

  1. Activate apoptosis via _____ pathway.
  2. Mechanisms of resistance? (2)
  3. Toxicity?
A

Epipodophyllotoxins:

  1. Intrinsic pathway
  2. Decreased expression of enzyme, or mutations to decrease activity of the enzyme
  3. Toxicity = myelosupression
35
Q

Camptothecin analogs:

  1. Drugs?
  2. Inhibit?
A

Camptothecin analogs:

  1. Camptothecin, irinotecan, and topotecan
  2. Topoisomerase I inhibitors
36
Q

Topoisomerase I:

MOA: enzyme binds to DNA, ______ the double helix and ___ one strand and prevents the ___ ___ of the helix by remaining ___ to each broken end. The enzyme passes the other strand _____ the ___ and ligates the ___ ends. The enzyme falls away and the strands ____, leaving DNA with one less _____ ____.

A

Topoisomerase I

MOA: enzyme binds to DNA, unwinding the double helix and cutting one strand and prevents the free rotation of the helix by remaining bound to each broken end. The enzyme passes the other strand _ through_ the breaks and ligats the cut ends. The enzyme falls away and the strands renature, leaving DNA with one less negative supercoil

37
Q

Camptothecin:

  1. The FDA has approved two ___ soluble analogs: _____ and ____.
  2. These agents trap and stablize? They also interfere with the moving DNA _____ ___. Result?
A

Camptothecin analogs:

  1. Two water soluble analogs: irinotecan and topotecan
  2. Trap and stabilize Topoisomeraze intermediates and also interfere with moving DNA replication forks resulting in a block of DNA reclosure and persistance of multiple cleavable complexes
38
Q

Camptothecin analogs:

Irinotecan:

  1. Use?
  2. Toxicity?

Topotecan:

  1. Toxicity?
A

Camptothecin analogs:

Irinotecan:

  1. Use: colorectal cancer (second to 5-fluorouracil) and 2nd line for ovarian and small cell lung cancer
  2. Tox: delayed diarrhea and then myelosuppression

Topotecan

  1. Tox - neutropenia
39
Q

L-asparaginase:

  1. It catalyzes the hydrolysis of L-asparagine to?
  2. What tissues lack the ability to synthesize L-asparagine?
  3. The treatment with L asparaginase deprives cells of ___ required for ____ synthesis leading to cell ____.
A

L-asparaginase:

  1. Catalyzes L-asparagine to L-aspartic acid and ammonia
  2. Lymph tissue
  3. Deprives cells of L-asparagine (ASN) required for protein synthesis leading to cell death
40
Q

L-asparaginase:

  1. Commonly used with other agents for?
  2. Administration?
  3. Major toxicity? Other toxicity?
  4. Minimal toxicity on?
A

L-asparaginase:

  1. Used for ALL (acute lymphocytic leukemia) and lymphoma
  2. Parenteral administration
  3. Major tox: allergic reaction; other may result from inhibition of protein synthesis in normal tissues such as hyperglycemia and clotting abnormalities
  4. Minimal BM and GI mucosa toxicity

Pharmacology (24 decks)

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