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Pharmacology > Anticancer Drugs > Flashcards

Anticancer Drugs Flashcards

1
Q

General MOA of antimetabolites

A

Target pathways related to nucleotide and nucleic acid synthesis

Cell-cycle specific –> S-phase

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2
Q

Methotrexate MOA

A

Antimetabolite -

Folate analog that competitively inhibits dihydrofolate reductase –> decreased synthesis of dTMP and purine nucleotides –> decreased DNA synthesis –> cell death

Undergoes conversion to a series of polyglutamates. Process is catalysed by folypolyglutamate synthase (FPGS). They increase the inhibitory potency of MTX for additional sites, including, thymidylate synthase and enzymes of de novo purine biosynthetic pathway

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3
Q

Methotrexate PK

A

After high doses, MTX undergoes hydroxylation at the 7 position –> hydroxylated derivative is less hydrosoluble and may lead to crystalluria.

Renal excretion occurs through a combination of glomerular filtration and tubular secretion so the concurrent use of drugs that reduce renal blood flow (e.g. NSAIDs), that are nephrotoxic (e.g. cisplatin) or that are weak organic acids (e.g. aspirin or piperacillin) can delay drug excretion and lead to severe myelosuppression. Particular caution must be exercised in patients with renal insufficiency.

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4
Q

Methotrexate AE

A

Myelosuppression - reversible with leucovorin ‘rescue’

Hepatic fibrosis and cirrhosis

Pneumonitis - characterised by patchy inflammatory infiltrates that regress upon discontinuation of drug

Renal Damage - uncommon. Complication of high dose MTX if clearance is inadequate.

Neurologic Toxicities - with intrathecal administration as it does not normally cross BBB

Teratogenic - due to folate deficiency (neural tube defects) therefore contraindicated in pregnancy

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5
Q

Leucovorin

A

N5-formyl-THF

Antidote to drugs that decrease levels of folic acid (e.g.: MTX) to rescue the bone marrow

Provides normal tissues with the reduced folate, so it circumvents the inhibitor of dihydrofolate reductase

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6
Q

6-mercaptopurine MOA

A

Antimetabolite

Thio analog of hypoxanthine. Is a prodrug which is converted to Thio-IMP by the salvage pathway enzyme HGPRT:

1) Inhibits the first step of the de novo purine ring biosynthesis
2) Blocks formation of AMP and GMP from IMP
3) Formation of dysfunctional RNA and DNA by incorporation of guanylate analogs

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7
Q

6-mercaptopurine and 6-thioguanine resistance

A

Patients with Lesch-Nyhan Syndrome will be unresponsive to these drugs as they are prodrugs that need to be converted to their active metabolite by HGPRT.

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8
Q

6-mercaptopurine PK

A

Metabolised in liver to thiouric acid by xanthine oxidase and excreted by kidneys.

Because allopurinol, a xanthine oxidase inhibitor, is frequently administered to cancer patients receiving chemotherapy to reduce hyperuricemia, it is important to decrease the dose of 6-MP to avoid accumulation of the drug

Also metabolised by enzyme thiopurine methyltransferase (TPMT) –> patients who have weak activity of TPMT are at increased risk for severe toxicities such as myelosuppression

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9
Q

6-mercaptopurine AE

A

Nausea, vomiting, diarrhoea

Myelosuppression

Hepatotoxicity

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10
Q

6-thioguanine MOA

A

Converted to nucleotide TGMP by enzyme HGPRT which then:

1) Inhibits purine synthesis and phosphorylation of GMP to GTP
2) Can be incorporated into RNA and DNA

Allopurinol foes not potentiate 6-TG action because very little is metabolised to thiouric acid (unlike 6-MP)

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11
Q

6-thioguanine Indication

A

Acute nonlymphocytic leukemias

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12
Q

6-thioguanine AE

A

Nausea, vomiting, diarrhoea

Bone marrow suppression

Hepatotoxicity

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13
Q

6-thioguanine PK

A

Also metabolised by enzyme thiopurine methyltransferase (TPMT) –> patients who have weak activity of TPMT are at increased risk for severe toxicities such as myelosuppression

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14
Q

5-Flurouracil

A

Antimetabolite: pyrimidine analog

Converted to 5-FdUMP –> inhibits thymidylate synthase (conversion of dUMP to dTMP) –> DNA synthesis is inhibited –> Known as ‘thymineless death’

Also converted to 5-FUTP –> incorporates into RNA –> interferes with RNA processing and function

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15
Q

5-Flurouracil PK

A

Mainly metabolised by dihydropyrimidine dehydrogenase (DPD)

DPD deficiency seen in up to 5% of cancer patients –> may experience severe toxicity such as myelosuppression, neurotoxicity and life-threatening diarrhea

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16
Q

5-Fluorouracil/Leucovorin Use and MOA

A

Combination used as chemotherapy for colorectal cancer

5FU inhibits thmidylate synthase by forming a ternary complex (enzyme, substrate (5-FdUMP) + cofactor (N5, N10-methylene-THF/leucovorin)

Increasing levels of N5, N10-methylene-THF potentiates activity of 5FU.

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17
Q

5-Fluorouracil AE

A

Myelosupression

Hand-food syndrome: an erythematous desquamation of the palms and soles is seen after extended infusions as 5FU accumulates in the merocrine glands

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18
Q

Capecitabine MOA

A

Antimetabolite. Pyrimidine analog

Orally available prodrug of 5FU

Inhibits thymidylate synthase (conversion of dUMP to dTMP) –> DNA synthesis is inhibited –> Known as ‘thymineless death’

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19
Q

Capecitabine AE

A

Same as 5FU:

Myelosupression (less than with 5FU)

Hand-foot syndrome: an erythematous desquamation of the palms and soles is seen after extended infusions as 5FU accumulates in the merocrine glands

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20
Q

Cytarabine MOA

A

Antimetabolite. Pyrimidine analog of deoxycytidine.

Sequentially phosphorylated to the triphosphate –> incorporated into DNA –> incorporated residue inhibits DNA polymerase

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21
Q

Cytarabine PK

A

Not effective orally because of its deamination to the noncytotoxic ara-U by cytidine deaminase in the intestinal mucosa. –> Given IV.

Does not enter CNS. May be injected IT.

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22
Q

Cytarabine AE

A

Severe myelosuppression

Hepatic dysfunction

High doses or IT –> seizures or altered mental states

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23
Q

Antitumor antibiotics general MOA

A

Bind to DNA through intercalation between bases and block synthesis or new RNA or DNA, cause strand breakage and Interfere with cell replication

Anthracyclines (doxorubicin and daunorubicin) and Bleomycin

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24
Q

Anthracyclines MOA

A

Doxorubicin (one of the most widely used anticancer drugs) and daunorubicin: have closely related chemical structures

Are cell cycle nonspecific

1) Inhibition of topoisomerase II
2) Intercalation in DNA –> blockade of DNA and RNA synthesis and strand breakage
3) Binding to cell membranes to alter fluidity and ion transport
4) Generation of free radicals through iron-dependent, enzyme-mediated process

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25
Q

Anthracyclines AE

A

Myelosuppression - main dose-limiting toxicity

Cardiotoxicity (chronic form)

  • dose-dependent, dilated cardiomyopathy associated with heart failure
  • due to free radicals
  • Iron-chelating agent dexrazoxane can reduce cardiotoxicity

All anthracyclines can produce “radiation recall reaction” with erythema and desquamation of the skin observed at sites of prior radiation therapy.
Other adverse effects are stomatitis, gastrointestinal disturbances, alopecia.

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26
Q

Dexrazoxan

A

Minimizes adverse events due to anthracycline toxicity (daxorubicin)

Iron-chelating agent that reduces cardiotoxicity

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27
Q

Bleomycin MOA

A

Antitumor antibiotic - mixture of glycopeptides

Cell-cycle specific - arrests cells in G2 phase

DNA-bleomycin-Fe2+ complex undergoes oxidation to bleomycin-Fe3+ –> liberated electrons react with O2 to form free radicals (superoxide, hydroxyl radicals) –> DNA strand breakage

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28
Q

Bleomycin AE

A

Pulmonary toxicity - pneumonitis and pulmonary fibrosis (bleomycin is inactivated by bleomycin hydrolase which is not found in the lungs and skin)

Very little myelosuppression

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29
Q

Alkylating agents general MOA

A

Exert cytotoxic effects via transfer of their alkyl groups to various cellular components

Alkylation of DNA leads to cell death. Can occur on a single strand or on both strands through corse-linking. Most alkylating agents are bifunctional

Cell cycle non-specific but cells are most susceptible to alkylation in late G1 and S phases of the cell cycle, and arrest in G2

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30
Q

Alkylating agents general toxicities

A

Occur mainly in rapidly growing tissues like bone marrow, GI tract and gonads

Nausea and vomiting are common: The emetic effects are of CNS origin and can be reduced by pre-treatment with 5-HT3 receptor antagonists like ondansetron or granisetron.

Are mutagenic and carcinogenic

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31
Q

Mechlorethamine MOA

A

Nitrogen mustard - alkylating agent –> causes DNA strand breakage

Very unstable - solutions must be made up just prior to administeration –> only given IV

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32
Q

Mechlorethamine AE

A

Powerful vesicant = causes painful blisters

Severe nausea and vomiting

Severe myelosuppression

Alopecia

Immunosuppression

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33
Q

Cyclophosphamide MOA

A

Prodrug: activated to 4OH-cycylophosphamide by CYP2B

Most widely used alkykating agent (a nitrogen mustard) –> alkylation of DNA –> strand breakage –> cell death

34
Q

Cyclophosphamide AE

A

Hemorrhagic cystitis due to acrolein a toxic metabolite of cyclophosphamide –> prevented with adequate fluid intake (IV hydration) and mesna (reacts with acrolein in bladder)

Myelosuppression

Sterility

Nausea, vomiting, alopecia

35
Q

Melphelan MOA

A

Nitrogen mustard - bifunctional alkylating agent

36
Q

Melphelan AE

A

Myelosuppression

37
Q

Carmustine and Lomustine MOA

A

Nitrosoureas - alkylating agent

Require biotransformation, which occurs by non-enzymatic decomposition to alkylating and carbamoylating derivatives

Very lipophilic - cross the BBB –> useful in treatment of brain tumours

38
Q

Busulfan MOA

A

Alkylating agent

39
Q

Busulfan AE

A

Myelosuppression is main toxicity

May cause pulmonary fibrosis

40
Q

Dacarbazine MOA

A

Alkylating agent

Acts as methylating agent after activation in the liver

Given IV

41
Q

Dacarbazine AE

A

Nausea and vomiting

Mild to moderate myelosuppression

42
Q

Procarbazine MOA

A

Converted by liver P450 enzymes to alkylating metabolites

Methylate DNA –> DNA, RNA and protein synthesis are inhibited

43
Q

Procarbazine AE

A

Bone marrow depression

Weak MOA inhibitor -> hypertensive reactions may result if given with sympathomimetic agents or tyramine-containing foods

Disulfiram-like reactions –> Antabuse –> given to chronic alcoholics as it produces hangover life symptoms as soon as alcohol is taken. It inhibits alcohol dehydrogenase

Mutagenic and teratogenic

44
Q

Platinum coordination complexes general MOA

A

Cisplatin
Carboplatin

Do not alkylate DNA.
Covalently find to DNA and share many pharmacological properties with alkylating agents –> Inhibit DNA synthesis and bind DNA through formation of cross-links

Given IV

45
Q

Cisplatin AE

A

Myelosuppression: mild-to-moderate

Ototoxicity

Peripheral neuropathy

Nephrotoxicity - reduced by hydration and diuresis and with amifostine

46
Q

Amifostine MOA

A

Cytoprotective agent used to reduce the renal toxicity associated with cisplatin

47
Q

Carboplatin AE

A

Relatively well tolerated, with less nausea, neurotoxicity, ototoxicity and
nephrotoxicity than cisplatin.

Dose-limiting toxicity is myelosuppression

48
Q

Vinca alkaloids MOA

A

Vincristine
Vinblastine

Microtubule inhibitors –> bind to b-tubulin and inhibit its ability to polymerise with a-tubulin –> cannot form microtubules –> cannot form mitotic spindle –> mitotic arrest in metaphase –> cell division stops –> cells die by apoptosis

Cell cycle specific - M-phase

Microtubules also have other functions in the cells such as axonal transport, phagocytosis and movement therefore inhibiting microtubules will lead to adverse affects

49
Q

Vincristine AE

A

Peripheral neuropathy

Mild bone marrow depression

Alopecia

50
Q

Vinblastine AE

A

Myelosuppression is dose-limiting

Peripheral neuropathy

Alopecia

51
Q

Taxanes MOA

A

Paclitaxel
Docetaxel

Micrtobule inhibitors –> taxanes bind to b-tubulin subunit of microtubules –> promote microtubule polymerization –> prevent their depolymerisation –> arrests cells in mitosis and leads to apoptosis

52
Q

Paclitaxel AE

A

Hypersensitivity –> reduced by premedication with dexamethasone, diphenhydramine and an H2 blocker

Myelosuppression

Peripheral neuropathy

Alopecia

53
Q

Docetaxel AE

A

Myelosuppression - dose-limiting

Peripheral neuropathy - not as frequently as paclitaxel

Fluid retention - pretreatment with dexamethasone is required to prevent this

Alopecia

Mucositis

54
Q

Etoposide MOA

A

Epipodophyllotoxin

Inhibits topoisomerase II –> breaks DNA on both strands –> DNA damage through strand breakage

Blocks cells in late S-G2 phase

55
Q

Topotecan and Irinotecan MOA

A

Camptothecins

Inhibit topoisomerase I –> which normally breaks DNA on one strand to relieve supercoils –> inhibition results in DNA damage

S phase specific

56
Q

Irinotecan AE

A

Myelosuppression

Diarrhea

  • Early diarrhea occurs within 24 hours after administration, is believed to be due to cholinergic activity, and can be treated with atropine.
  • Late diarrhea occurs 2–10 days after treatment, and can be life-threatening, leading to significant electrolyte imbalance and dehydration.
  • Late diarrhea should be treated with loperamide.
57
Q

Prednisone MOA

A

Glucocorticoid

Are lymphocytic –> suppress mitosis in lymphocytes

Used to treat acute leukemias and malignant lymphomas

Especially effective in the management of autoimmune hemolytic anemia and thrombocytopenia associated with chronic lymphocytic leukemia. This is due to the fact that they increase the number of platelets and red blood cells.

58
Q

Tomoxifen MOA

A

SERMs –> bind to estrogen receptors and act as agonists or antagonists depending on the tissue

Antagonist on breast tissue –> used for receptor positive breast cancer

Agonist in non breast tissue

  • a partial agonist in the endometrium so by giving this drug, estrogen will lead to hyperplasia of the endometrium which can potentially lead to endometrial cancer
  • agonist on bone –> can prevent bone resorption
59
Q

Tomoxifen AE

A

Hot flashes

Nausea

Fluid retention

Tamoxifen increases incidence of endometrial cancer

60
Q

Roloxifene MOA

A

SERMs –> bind to estrogen receptors and act as agonists or antagonists depending on the tissue

Antagonist in uterus and breast

Agonist on bone –> promotes oestrogen effects in bone to inhibit resorption

Used for prevention of postmenopausal osteoporosis and prophylaxis of breast cancer in high risk postmenopausal women

61
Q

Roloxifene AE

A

Hot flashes

Fluid retention

62
Q

Fulvestrant MOA

A

SERDs –> no estrogen receptor (ER) agonist activity

Binds to ER –> inhibits its dimerisation and increases its degradation –> ER-mediated transcription is abolished

63
Q

Aromatase Inhibitors Indication

A

Aromatase converts androstenedione to estrone

In postmenopausal women, this conversion is the primary source of circulating estrogen

Aromatase inhibitors are standard of care for adjuvant treatment of postmenopausal women with hormone receptor-postive breast cancer

64
Q

Anastrazole and Letrozole MOA

A

Non-steriodal

Reversible competitive inhibitors of aromatase

Aromatase inhibitors are standard of care for adjuvant treatment of postmenopausal women with hormone receptor-postive breast cancer

65
Q

Exemestane MOA

A

Steroidal

Irreversible inhibitor of aromatase

Aromatase inhibitors are standard of care for adjuvant treatment of postmenopausal women with hormone receptor-postive breast cancer

66
Q

Androgen Inhibitors Indication

A

Two types - GnRH agonists and androgen receptor blockers

Therapy of prostate cancer - use of GnRH agonists along or in combination with androgen receptors blocker

67
Q

Goserelin and Leuprolide MOA

A

GnRH agonists

GnRH release from hypothalamus is usually pulsatile

When given continuously or as a depot, GnRH agonists cause an initial surge in LH and FSH levels followed by inhibiton of gonodotropin release –> testosterone levels fall to 10% of their initial values after a month

Initial surge can be counteracted with administration of flutamide for 2-4 weeks

68
Q

Goserelin and Leuprolide AE

A

Impotence

Hot flashes

Testicular atrophy

69
Q

Flutamide MOA

A

Synthetic, nonsteroidal, androgen receptor blocker

Metabolised to an active metabolite that acts as a competitive agonist at the androgen receptor –> prevents its translocation to nucleus

70
Q

Imatinib

A

Inhibitor of Bcr-Abl tyrosine kinase

9:22 translocation - used to treat chronic myelogenous leukemia

71
Q

Transtuzumab

A

Monoclonal antibody against ErbB2 tyrosine kinase

Causes cardiotoxicity - but it is reversible

72
Q

Transtuzumab

A

Monoclonal antibody against ErbB2 tyrosine kinase

Causes cardiotoxicity - but it is reversible

73
Q

Flutamide AE

A

Gynecomastia

Hot flushes

Liver dysfunction

74
Q

Asparaginase MOA

A

Most normal tissues synthesise L-aparagine in amount sufficient for protein synthesis

Neoplastic tissue require exogenous course of asparagine

Asparaginase hydrolyses serum asparagine to aspartate and ammonia–> deprives tumor cells of asparagine needed for protein synthesis –> cell death

75
Q

Asparaginase AE

A

Hypersensitivity

Decrease in clotting factors: There is an imbalance between coagulation and anticoagulation –> coagulation wins so patients have more thrombotic events than bleeding events

Liver abnormalities

Pancreatitis –> it can activate pancreatic enzymes

Seizures/coma due to ammonia toxicity

76
Q

Hydroxyurea MOA

A

Inhibits ribonucleotide reductase –> deletion of deoxynucleoside triphosphate pools –> inhibits DNA synthesis

Kills cells in S phase

Given orally

77
Q

Hydroxyurea AE

A

Myelosuppression is major toxicity

At high doses megaloblastosis unresponsive to vitamin B12 may appear

GI symptoms, including nausea, vomiting and diarrhea are common with high doses

78
Q

Interferon a Indication

A

Hairy cell leukemias, chronic myelogenous leukemias, malignant melanoma and Kaposi’s sarcoma

79
Q

Interferon a MOA

A

IFNa can stimulate NK cells to attack malignant cells

Tumor cells can evade the immune system by not producing HLA. IFNa can also increase HLA expression in tumor cells so that the immune cells can attack the cancer cells

80
Q

Interferon a AE

A

Depression

Fever with chills

Leukopenia, thrombocytopenia.

Fatigue, malaise, anorexia, weight loss, alopecia

Transient elevation of liver enzymes.

Pharmacology (20 decks)

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