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MWU Pharmacology II > Lecture 26 / 27: Anti - Cancer Agents > Flashcards

Lecture 26 / 27: Anti - Cancer Agents Flashcards

1
Q

What are the 3 classes of Alkylating agents?

A
  1. Nitrogen Mustards
  2. Nitrosources
  3. Platinum Complexes
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2
Q

What are the 2 drugs in the nitrogen mustard class?

A
  1. Mechlorethamine
  2. Cyclophosphamide
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3
Q

1 drug in nitrosoureas class

A

Carmustine

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4
Q

1 drug in platinum complexes class

A

Cisplatin

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5
Q

What are the 3 classes of Antimetabolites?

A
  1. Folic Acid Analogs
  2. Purine Analogs
  3. Pyrimidine Analogs
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6
Q

What is the folic acid analog?

A

Methotrexate

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7
Q

What is the purine analog?

A

Mercaptopurine

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8
Q

What are the 2 pyrimidine analogs?

A
  1. Fluorouracil
  2. Cytarabine
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9
Q

What are the 2 classes of Natural products?

A
  1. Anthracycline antibiotics
  2. Vinca Alkaloids, Epipodophylotoxins and Taxanes (Plant products)
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10
Q

What are the 2 anthracycline antibiotics?

A
  1. Daunorubicin Hydrochloride
  2. Doxorubicin Hydrochloride
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11
Q

What are the 4 drugs in the Vinca alkaloids, epipodophylotoxins and Taxanes?

A
  1. Vinblastine Sulfate
  2. Vincristine Sulfate
  3. Etoposide
  4. Paclitaxel
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12
Q

What are the 2 classes of hormonal agents?

A

Adrenocorticosteroids
Estrogens and Antiestrogens

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13
Q

What are the 2 drugs in the adrenocortocosteroid class?

A
  1. Prednisone
  2. Dexamethasone
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14
Q

1 drug in the Estrogen and antiestrogen class

A

Tamoxifen

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15
Q

What is the 1 tyrosine kinase inhibitor?

A

Imatinib Mesylate

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16
Q

1 drug in the monoclonal antibody class

A

Trastuzumab

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17
Q

What is the goal of cancer chemotherapy?

A

To achieve selective toxicity against malignant tumor cells and spare normal host tissue.

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18
Q

What is the oldest successful drug in cancer treatment?

A

Mechlorethamine

Developed from mustard gas in WWI and WWII

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19
Q

Alkylating Agents MOA

A
  • Cytotoxic effects via transfer of the alkyl groups to cellular constituents
  • Alkylation of N7 guanine in DNA producing alkylated purine
  • Results in cross-linking of DNA strands
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20
Q

What can alkylation of DNA strand result in?

A
  1. Miscoding of DNA strands or excising of guanine (depurination) results in strand break
  2. Incomplete repair of alkylated segment - lead to strand break or depurination
  3. Excessive crosslinking of DNA and inability for strand separation during mitosis (kills cell)
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21
Q

What type of alkylator agents usually cause miscoding of DNA and / or incomplete repair?

A

Monofunctional alkylator agents

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22
Q

What type of alkylators result in Excessive crosslinking of DNA and inability for strand separation?

A

Polyfunctional alkylators

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23
Q

During what phase of the cell cycle are cells most susceptible to alkylation?

A

Not cell cycle specific

Most susceptible in late G1 and S phases of cell cycle

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24
Q

Alkylating agent: Toxicity / 4 kinds

A
  1. Direct vesicant (vesicle producing) damaging tissues at site of injection
  2. Systemic toxicity - dose related / rapidly dividing cells are most affected
  3. Acute toxicity - nausea, vomiting (reduced with phenothiazines or cannabinoids)
  4. **Delayed toxicity **- bone marrow depression, immunosuppression, alopecia
    - late secondary neoplasia including leukemia
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25
Q

Mechlorethamine hydrochloride: MOA / t1/2 / indications for use / route

A
  • Alkylating agent
  • Non-specific but M and G1 most sensitive
  • t1/2 - 10 min

Indications:
* Hodgkin’s disease

Route:
* Instilled into pleural space; intravenous; topical

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26
Q

Cyclophosphamide: Pharmacologic properties

structure / metabolic activation / half-life / route

A
  • Cyclic phosphamide derivative of mechlorethamine
  • Requires metabolic activation by cytochrome P-450 in liver
  • Half-life: 4-7 hours
  • Intravenous, oral
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27
Q

Cyclophosphamide: Indications for use in cancers (7)

A

Acute and chronic leukemia:
* Hodgkin’s, non-Hodgkin’s and Burkitt’s lymphoma
* Multiple myelomas
* Testicular cancer
* Breast Cancer
* Lung Cancer
* Ovarian
* Endometrial and cervical carcinoma

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28
Q

Cyclophosphamide: Indications as Immunosuppressive agent

A
  • Wegener’s granulomatosis
  • Rheumatoid Arthritis
  • Organ transplantation
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29
Q

Carmustine: Pharmacologic properties

type of alkylator / phase / solubility / half life / route

A
  • Bifunctional alkylator
  • Phase - nonspecific
  • Highly lipid soluble
  • half life: 90 min
  • Oral / intravenous
30
Q

Carmustine: Indications for use

A
  • Brain tumors
  • Hodgkin’s and non - Hodgkin’s lymphomas
  • Multiple myelomas
31
Q

Cisplatin: Pharmacologic properties

type / phase / effects / half life / toxicity / route

A

Type: Platinum coordination compound
Phase: non specific but G1 may be most sensitive
Half-life: 20-30 min
Toxicity: Nephrotoxicity and ototoxicity
Route: Intravenous

32
Q

Cisplatin: Effect on DNA

A
  • bifunctional alkylating agent (2 sites for binding)
  • Causes inter - intrastrand DNA crosslinking
  • Disrupts DNA double helix / interferes w/ synthesis
33
Q

Cisplatin: Indications for use (not bolded)

A
  • Testicular, ovarian, bladder, gastric, esophageal, pancreatic, lung, head and neck cancers
34
Q

What is the most prevalent form of cross-linking caused by Cisplatin?

A
  • 1,2 - intrastrand crosslink
  • Platinum is covalently bound to the N7 position of adjacent purine bases
35
Q

Primary MOA of antimetabolites?

A

Impede intermediary metabolism of proliferating neoplastic cells
Cell cycle specific agents

36
Q

3 ways antimetabolites may inhibit metabolism in cancer cells?

A
  1. Drug may be metabolized instead of normal substrate (making molecule non-functional)
  2. May compete w/ normal metabolite at allosteric site
  3. May effect nucleotide and nucleic acid synthesis (most important)
37
Q

Methotrexate: Pharmacological properties

enzyme / effect / protection of normal cells

A
  • Inhibitor of dihydrofolate reductase - blocks conversion of folic acid to tetrahydrofolate
  • Inability to convert deoxyuridylate to thymidylate (blocks RNA, DNA and protein syn.)
  • Leucovorin (folinic acid) bypasses metabolic block (protects normal cells)
38
Q

Methotrexate: Pharmacological properties

CNS penetration / plasma proteins / phase

A
  • Poor CNS penetration - requires intrathecal use or high dose IV
  • 50% bound to plasma protein
  • cell cycle specific - kills cells in S phase
39
Q

Methotrexate Toxicity: Acute / Delayed effects

A
  • Acute effects: Nausea, vomiting, diarrhea
  • Delayed effects: GI and oral ulceration, bone marrow suppression, alopecia, hepatotoxicity, pulmonary infiltrates, fever
40
Q

Methotrexate: Indications for use

A
  • Acute lymphocytic leukemia
  • Non-Hodgkin’s lymphomas, leukemia, breast, pancreatic and bladder carcinoma
  • Psoriasis, rheumatoid arthritis
41
Q

Mercaptopurine: Pharmacological properties

analog of? / enzyme / inhibits / effects / metabolized by / phase?

A

Purine analog
* **Sulfhydryl-substituted **analog of hypoxanthine
* Converted by HGPRT (hypoxanthine-guanine phosphoribosyl transferase) to nucleotide form (6-thioinosinic acid)
* Inhibits enzymes of purine interconversion
* Causes inhibition of purine nucleotide synthesis (DNA / RNA)
* Metabolized by xanthine oxidase to 6-thiouric acid

42
Q

Mercaptopurine: Toxicity

acute / delayed

A

Acute: infrequent nausea, vomiting, diarrhea

Delayed: gradual bone-marrow depression

43
Q

Fluorouracil: Pharmacological Properties

active form / binds / blocks / phase

A
  • Converted to active form 5 - deoxyuridine
  • Covalently binds to** thymidylate synthetase **
  • Blocks conversion of deoxyuridylate to thymidylate (rate-limiting step of DNA syn.)
    * Cell cycle specific (S Phase)
44
Q

Fluorouracil: Indications for use

not highlighted

A

Carcinoma of:
* Breast
* Colon
* Pancreatic
* Ovarian
* Head
* Gastric
* Esophageal
* Head / Neck

45
Q

Fluorouracil: Toxicity

A

Delayed toxicity
These drugs dont cause acute toxicity.

nausea, oral and gatrointestinal ulceration, bone marrow depression

46
Q

Cytarabine: Pharmacological Properties

converted into / competes with / phase

A
  • Converted to cytarabine triphosphate
  • Inhibits DNA polymerase by competing with biological substrate (deoxycitidine triphosphate)
  • Cell cycle specific (S-phase)
47
Q

Cytarabine: Toxicity

not highlighted

A

Delayed toxicity

  • Nausea
  • Vomiting
  • Bone Marrow Depression
  • Megaloblastosis
  • Leukopenia
  • Thrombocytopenia
48
Q

Cytarabine: Indications for use

not highlighted

A
  • Remission induction in acute non-lymphocytic leukemia
  • Acute lymphocytic leukemia
  • Chronic myelocytic leukemia
  • Meningeal Leukemia
49
Q

What is overall MOA of many anti-cancer antibiotics? What are they derived from?

A

Bind to DNA through intercalation between specific bases and block DNA / RNA syn.

Derived from soil fungus streptomyces

Cell cycle non-specific

50
Q

Daunorubicin hydrochloride & Doxorubicin hydrochloride: Pharmacological effects

MOA / effects / phase / antitumor activity / difference in structure

A
  • MOA: intercalate and bind to DNA between base pairs on adjacent strands
  • Results in uncoiling of DNA helix
  • Destroys DNA template
  • Non cell-cycle specific (max effect seen during S-phase)
  • Structure differes by single hydroxyl group
51
Q

Daunorubicin hydrochloride & Doxorubicin hydrochloride: Toxicity

acute / delayed

A

Acute: nausea, vomiting, red urine, tissue necrosis, arrhythmias

Delayed: bone-marrow depression, alopecia, GI upset and cardiomyopathy (important)

52
Q

Daunorubicin: Indications

A

Acute non lymphocytic leukemia of adults

Greater activity than doxorubicin in acute lymphocytic leukemia (children and adults)

53
Q

Doxorubicin: Indications

A

Lymphoma, leukemia, Hodgkin’s disease, carcinoma of breast, gastric, pancreatic, ovarian, lung, bladder neuroblastoma

Generally used in combination with other drugs with which it synergizes.

54
Q

Vinblastine sulfate and Vincristine sulfate: Pharmacological effects

structure / bind to / effect / phase

A
  • Similar structure: methyl group in vinblastine replaced w/ formyl group in vincristine
  • Bind tubulin - component of microtubules
  • Disruption of mitotic spindles / prevents chromosomal segregation
  • Cell cycle - specific for mitosis
55
Q

Vincristine: Toxicity

Acute / delayed

A

Acute: local reactivity if extravasated

Delayed: neurological, constipation, alopecia, mild bone depression

56
Q

Vinblastine: Toxicity

Acute / Delayed

A

Acute: mild nausea, vomiting, phlebitis

Delayed: neurological and bone marrow depression

57
Q

Vincristine and Vinblastine: indications

not highlighted

A

Vincristine: Breast carcinoma, acute leukemia, Hodgkin’s and non - Hodgkins

Vinblastine: Hodgkin’s disease, Kaposi’s sarcoma, testicular, bladder, lung carcinoma

58
Q

Etoposide: Pharmacological Properties

Derivative of / forms what / results / phase specific

A
  • aka VP-16. Semisynthetic derivative of podophyllotoxin
  • Forms complex with topoisomerase II and DNA
  • Results in DNA breaks, no repair and cell death
  • Cell-cycle-specific for G2 phase
59
Q

Etoposide: Toxicity

acute / delayed

A

Acute: nausea, vomiting, diarrhea (15% IV / 55% oral)

Delayed: Leukopenia (less than 4,000 WBC/mm3) 10-14 days and recover by 3 weeks
Alopecia (66%)

60
Q

Etoposide: Indications for use

not highlighted

A
  1. Testicular cancer (w/ bleimycin and cisplatin)
  2. Small cell carcinoma of lung (w/ cisplatin)
61
Q

Paclitaxel: Pharmacological Properties

extracted from / MOA / effect / phase specific

A
  • Extracted from the bark of the Western (Pacific) yew
  • Antimicrotubule agent
  • Does not inhibit, but promotes microtubule assembly
  • Enhances tubulin polymerization (stabilized microtubules)
  • Cell cycle specific for G2 and M phase
62
Q

Paclitaxel: Toxicity

Acute / Delayed

A

Acute: Nausea, vomiting (52 %)

Delayed: Bone marrow suppression (neutropenia, leukopenia, thrombocytopenia, anemia)
Hypersensitivity; peripheral neuropathy (60%)
Alopecia - pretty much everybody

63
Q

Paclitaxel: Indications

A
  1. Metastatic Ovarian Cancer
  2. Metastatic Breast Cancer
  3. Non-small cell lung carcinoma
64
Q

Prednisone and Dexamethasone: Cancer indications

A

Palliative management of leukemia and lymphoma in adults
Acute leukemia of childhood
Breast Cancer

65
Q

Prednisone and dexamethasone: Anti-inflammatory and Immunosuppressive effects

A
  • Affect concentration and distribution of peripheral leukocytes
  • Concentration of PMN increases
  • Concentration of lymphocytes (T/B cells), monocytes, eosinophils, basophils decreases
  • Reduction of anigens and mitogens
  • Reduction of cytokines
66
Q

Prednisone and Dexamethasone: Effects on enzymes

A

Inhibits phospholipase A2 enzyme:

  • Results in lower prostaglandin and leukotriene synthesis
  • Induces secretion of lipocortins that inhibit PLA2

Inhibits cyclooxygenase 2 enzyme:

  • Results in lower prostaglandin formation
67
Q

Where are steroids metabolized?

A

Liver and excreted in the kidney’s

68
Q

Steroids: Toxicity

short / long

A

Shorter (less than one week): Insomnia, behavioral changes, acute peptic ulcers and pancreatitis

Longer: iatrogenic Cushing’s syndrome

69
Q

Steroids: Other adverse effects

A
  • GI: Peptic Ulcers
  • Increased bacterial and mycotic infections
  • Adrenal suppression
  • Obesity, dyslipidemia and glucose intolerance
70
Q

Tamoxifen: Pharmacologic properties

type / inhibits / phase / route / t1/2 / metabolism

A
  • Nonsteroidal antiestrogen
  • Competitive inhibitor for estrogen receptors (nuclear transcription factors)
  • G1 phase
  • Oral
  • half life of 7-14 days
  • Extensive metabolism in liver and excreted in feces
71
Q

Tamoxifen: Toxicity

short / long / most serious

A

MWU Pharmacology II (8 decks)

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