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Pharmacology > Anticancer Drugs > Flashcards

Anticancer Drugs Flashcards

1
Q

What makes a normal cell into an abnormal cell? (6 things)

A

1) Sustaining proliferative signal
2) Evading growth suppressors
3) Activating invasion and metastasis
4) Eliciting replicative immortality
5) Inducing angiogenesis
6) Resisting Cell Death
These are all targeted with anticancer drugs

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2
Q

What are the 4 things an anticancer drug can act on?

A

1) Action on DNA
2) Action on Mitotic Signal
3) “Targeted” drugs
4) Hormonal Agents

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3
Q

What two things do DNA drugs do?

A

1) Damage DNA

2) Inhibit synthesis or function

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4
Q

What kind of drugs damage DNA?

A

1) Cyclophosphamide by alkylation

2) Doxorubicin by free radical generation

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5
Q

What kind of drugs inhibit synthesis or function?

A

1) Antimetabolites like methotrexate

2) Topoisomerase inhibitors like etoposide

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6
Q

What kind of drugs act on mitotic spindle?

A

Microtubule inhibitors like vincristine

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7
Q

What are some targeted drugs?

A

MABs directed at surface cell receptors
NIBs directed at receptor tyr kin (inside cell below cell surface)
mTOR inhibitors (prevent 2nd phase of Tcell activation)

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8
Q

An ideal agent would be what?

A

100% selective, eradicating tumor and sparing the host; no drugs currently meet this criteria

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9
Q

Newer agents aim to? (5 things)

A

1) Force terminal maturation with no proliferative potential
2) Alter invasive/metastatic potential of tumors
3) Prevent angiogenesis and thereby tumor growth
4) Produce tumor radio-sensitization or radioprotection of bystander tissues
5) Peterub tumor - host metabolic and immunologic relationship

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10
Q

These 5 things combined make sure patient does not what?

A

Die due to treatment instead of disease

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11
Q

What is local therapy done with? and when is it effective?

A

Radiation or surgery; when metastasis has NOT occurred

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12
Q

What are the two types of chemotherapy?

A

Systemic adjuvant or neoadjuvant

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13
Q

What is chemotherapy used for? When?

A

For “de-bulking” and for locally advanced early-stage disease; given prior to surgery or after surgery to end or lessen cancer

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14
Q

What is systemic chemotherapy used for?

A

Disseminated disease (often only to improve quality of life)

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15
Q

What are hormonal agonists/antagonists used for?

A

Treatment of hormonally responsive breast and prostate tumors

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16
Q

What is an example of biological therapy?

A

HER-2/neu targeted agents

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17
Q

Can drugs induce both clinical improvement and significant toxicity?

A

Yes

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18
Q

Can there be a quality of life improvement without a longevity increase?

A

Yes

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19
Q

What are some toxicities?

A

Secondary malignancies, myelosuppression, N/V, alopecia, organ toxicity

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20
Q

What is Tumor Lysis Syndrome (TLS)?

A

It is a multifactorial process of volume depletion, tubular obstruction, and cytotoxic chemotherapy. When lysis of tumor cells release purine nucleic acids, K+ and P. Causes renal elimination to be saturated (high K and P, low Ca, and gout), uric acid is deposited along with calcium phosphate.

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21
Q

When is TLS seen?

A

With ALL, burkitts lymphoma, non-Hodgkin’s lymphoma, or solid tumors

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22
Q

What is management of TLS?

A

Done with hydration (drugs ppt on kidney tubules), acid/base correction, sodium bicarb to alkanlinize the urine; allopurinol to prevent uric acid (gout); rasburicase (recombinant urate oxidase) to degrade uric acid to water soluble allantoin for elimination

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23
Q

What is the normal pathway of Nucleotide Precursors to Uric Acid?

A

Nucleotide precursors –> Hypoxanthine –> Xanthine –> Uric Acid

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24
Q

What inhibits Xanthine Oxidase?

A

Allopurinol

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25
Q

What converse Uric acid to Allantoin for elimination?

A

Rasburicase

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26
Q

When to cell cycle non specific drugs work?

A

In both cell cycle and resting time

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27
Q

T or F. Cell cycle specific drugs are most effective in phases they are specified for?

A

Yeah, dummy. Targets appear in each phase

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28
Q

What drugs are specific for M phase?

A

Taxels and Vinca Alkyloids

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29
Q

What drugs are specific for S phase?

A

Antimetabolites and Podophyllotoxins

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30
Q

What drugs are specific for G2?

A

Podophyllotoxins and Bleomycin

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31
Q

What is chemotherapy damage sensed by?

A

p53 protein resultant from depolarizaton of mitochondrial membrane = release of cytochrome c = apoptosis

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32
Q

What do alkylating agents do?

A

Leave chemical moiety bound to DNA and destroys DNA topology

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33
Q

Give the 8 classes of alkylating agents and a prototype of each.

A

1) Nitrogen mustards - cyclophosphamide (Ifosfamide, mechlorethamine, melphalan)
2) Alkyl Sulfonates - Busulfan
3) Nitcosoureas - BCNU, CCNU
4) Aziridines - Thiotepa
5) Antibiotics - Mitomyocin C
6) Platinum Drugs - cisplatin (carboplatin, oxaliplatin)
7) Triazenes - Dacarbazine
8) Hydrazines - procarbazine

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34
Q

True or False. Even if drugs have similar structures they can still affect different cancers.

A

True

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35
Q

The active part of Bis(chlorotheyl)amine Alkylating agents is what?

A

Chloroacetylaldehyde

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36
Q

What are the Bic(chloroethyl)amine drugs?

A

Cyclophosphamide, isosfamide, merchlorethamine, melphalan, chlorambucil

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37
Q

What do Bic(chloroethyl)amine drugs do?

A

Transfer alkyl group to DNA

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38
Q

What are the targets of Bic(chloroethyl)amine drugs?

A

N7 Guanine&raquo_space; N1, N3 adenine, N3 cytosine, O6 guanine

39
Q

Do Bic(chloroethyl)amine drugs cause a ss or ds DNA modification?

A

Either

40
Q

What does the strand breakage through guanine excision of Bic(chloroethyl)amine drugs lead to?

A

Miscoding

41
Q

What phase cells are most suseptible to Bic(chloroethyl)amine drugs?

A

Replicating (late G1-S) are MOST; leads to G2 block

42
Q

How does resistance occur to Bic(chloroethyl)amine drugs?

A

Decrease uptake, decrease activation, increase inactivation (conjugation) of reactive moiety (increase rate and capacity) or increase repair of DNA miscodes (then supply drug to overwhelm repair mech)

43
Q

Bic(chloroethyl)amine has dose related toxicities and is especially toxic to what kind of cell populations?

A

Rapidly dividing, like bone marrow, GI (stomatitis, mucositis, diarrhea), Reproductive (oligospermia, amenorrhea), Alopecia

44
Q

How does Bis(chloroethyl)amine cause CNS problems?

A

Ifosfamide (from chloroacetaldehyde) = altered mental status, coma, generalized seizures, cerebellar ataxia

45
Q

All alkylating agents cause what kinds of problems?

A

Lung problems, specifically cyclophosphamide, chloambucil, melphalan; fibrosis, dyspnea, cyanosis, pulm insufficiency

46
Q

Do Alkylating agents cause carcinogenicity?

A

Yes; leukemias and solid tumors

47
Q

Do Alkylating agents cause Teratogenicity?

A

Yes; 1/6 chance of malformed offspring

48
Q

Renal failure is common in what 2 Alkylating agents?

A

Cyclophosphamide and ifosfamide; also they are responsible for urotoxicity/bladder tumors - they release acrolein

49
Q

What is MENSA?

A

An antidote to acrolein; toxic- binds it up

50
Q

What does MENSA do?

A

It is a prophylactic chemoprotectant from hemmorhagic cystitis

51
Q

Is cyclophosphamide an immunosuppressant?

A

YES; it prepares the body for stem cell transplantation; total body irradiation, busulfan, cyclophosphamide; also used for RA

52
Q

What are the toxicities of the alkyl sulfonate: busulfan.

A

Myelosuppression at conventional doses, pulmonary fibrosis, amenorrhea and fetal malformation; rarely develop asthenia and hypotension (Resembles addisons)

53
Q

What are the 2 nitrosoureas?

A

Carmustine - BCNU; Lomustine - CCNU

54
Q

Are BCNU and CCNU alkylators?

A

Yes

55
Q

What do carmustine decomposition products do?

A

Carbamolyate proteins - inhibit DNA repair

56
Q

Do one or both protein adducts contribute to carmustine toxicity?

A

Both

57
Q

Is cross resistance common between these 2?

A

No, because of second mechanism of action

58
Q

Does BCNU and CCNU enter the CNS in measurable amounts?

A

Yes; highly lipophilic and nonionized at psyiologic pH

59
Q

The two drugs that are known for causing hepatic toxicity?

A

Busulfan and BCNU

60
Q

What leads to the hepatic toxicity from Busulfan and BCNU?

A

Hepatic veno-occlusive disease - often fatal, caused by strong alkylating agents and starts 2-10 weeks after starting therapy; due to endothelial intimal edema venular wall fragmanetation

61
Q

What is Thiotepa (Thioplex)?

A

A polyfunctional aziridine alkylator formed by hydrolysis.

62
Q

Is thiotepa lipophilic?

A

Yes; administered IV, IVe, IC

63
Q

Is thiotepa neurotoxic?

A

Yes; coma and seizures at high doses

64
Q

How is mitomycin C administered and are there reaction?

A

Injected; yes, hemolytic anemia (endothelial damage)

65
Q

How does Cisplatin, carboplatin work?

A

Intrastrand DNA links, predominantly N7 of guanine (DNA replication and transcription interrupted)

66
Q

Is Cisplatin nephrotoxic?

A

Yes; force hydration and chloride diuresis

67
Q

What is a protective agent for Cisplatin nephrotoxicity?

A

Amifostine cytoprotective agent

68
Q

Is Cisplatin orotoxic?

A

Yes (tinnitus)

69
Q

Is Cisplatin a myelosuppressive agent?

A

Yes; mild to moderate with transient leukopenia and thrombocytopenia

70
Q

True or False, Cisplatin leads to progressive peripheral, motor, and sensory neuropathy.

A

True

71
Q

What are the 2 newer derivations to reduce toxicity of Cisplatin?

A

Carboplatin and Oxaliplatin

72
Q

What is Dacarbazine?

A

A metabolically activated DNA methylating agent; resistance by removal of methyl groups from the O6 guanine bases by AGT

73
Q

Procarbazine (matulane) (O6-guanine) is a highly reactive DNA methylator via CYP activation, what does it weakly inhibit?

A

It is a weak MAO inhibitor with Disulfiram-like actions - avoid alcohol

74
Q

The O6 alkylguanine-DNA alkyltransferase (AGT) is what?

A

A suicide protein acceptor that inactivates the protein to repair DNA to original structure

75
Q

What is the goal of Antimetabolites?

A

To not impact existing drugs but provide false building blocks for further synthesis

76
Q

What are the Folic Acid Analogs?

A

Methotrexate and Pemetrexed

77
Q

What are the Pyrimidine Analogs?

A

Fluorouracil (5-FU), Capecitabine, Cytarabine, Gemcitabine

78
Q

What are the purine analogs and related inhibitors?

A

6-mercaptopurine, thioguanine, pentostatin, Cladribine, Fludarabine

79
Q

What is the mechanism of action of Methotrexate?

A

It is a Dihydrofolate reductase inhibitor; it denies availability of the THF cofactor for RNA/DNA synthesis

80
Q

Are analogs actively uptaken by cells?

A

Yes, poor passage of BBB

81
Q

If polyglutamated inside the cell are they trapped?

A

Yes

82
Q

What is Pemetrexed?

A

GART inhibitor for mesothelioma

83
Q

What is Trimetrexate?

A

Designed for BBB penetration for pneumocystis carinii

84
Q

What is polyglutamation?

A

The process that traps drug in the cell

85
Q

What are toxicities of Methotrexate?

A

GI, N/V, abdominal distress, Bone marrow, anemia, lymphoproliferative disorders, weak acid; ppts in tubules, pneumonitis, anemia in RA or psoriasis

86
Q

Is 5-fluorouracil; 5-FU toxic?

A

You betcha

87
Q

What does FdUMP do?

A

DNA synth inhib by thmineless death

88
Q

What does FdUTP do?

A

Incorporated into DNA inhibition of synthesis and function

89
Q

What does FUTP do?

A

Interference with mRNA translation

90
Q

What are the toxicities of 5-FU?

A

Hand-foot syndrome - peripheral neuropathy

91
Q

Does Leucovorin increase formation of TS complex?

A

Yes

92
Q

What does increased formation of TS complex do?

A

Enhanced responsiveness to 5-FU

93
Q

What is Capecitabine?

A

Oral agent that is similar in toxicity to 5-FU, Hand-foot happens more frequently, it is converted to 5-FU

94
Q

What does chronic use of Capecitabine lead to?

A

Erasing of fingerprints.

Pharmacology (5 decks)

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