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

Lecture 26 / 27: Anti - Cancer Agents Flashcards

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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
Mechlorethamine hydrochloride: MOA / t1/2 / indications for use / route
* 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
26
Cyclophosphamide: Pharmacologic properties | structure / metabolic activation / half-life / route
* Cyclic phosphamide derivative of mechlorethamine * Requires metabolic activation by cytochrome P-450 in liver * Half-life: 4-7 hours * Intravenous, oral
27
Cyclophosphamide: Indications for use in cancers (7)
**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
28
Cyclophosphamide: Indications as Immunosuppressive agent
* Wegener's granulomatosis * **Rheumatoid Arthritis** * **Organ transplantation**
29
Carmustine: Pharmacologic properties | type of alkylator / phase / solubility / half life / route
* Bifunctional alkylator * Phase - nonspecific * Highly lipid soluble * half life: 90 min * Oral / intravenous
30
Carmustine: Indications for use
* Brain tumors * Hodgkin's and non - Hodgkin's lymphomas * Multiple myelomas
31
Cisplatin: Pharmacologic properties | type / phase / effects / half life / toxicity / route
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
Cisplatin: Effect on DNA
* bifunctional alkylating agent (2 sites for binding) * Causes inter - intrastrand DNA crosslinking * Disrupts DNA double helix / interferes w/ synthesis
33
Cisplatin: Indications for use (not bolded)
* Testicular, ovarian, bladder, gastric, esophageal, pancreatic, lung, head and neck cancers
34
What is the most prevalent form of cross-linking caused by Cisplatin?
* 1,2 - intrastrand crosslink * Platinum is covalently bound to the N7 position of adjacent purine bases
35
Primary MOA of antimetabolites?
Impede intermediary metabolism of proliferating neoplastic cells Cell cycle specific agents
36
3 ways antimetabolites may inhibit metabolism in cancer cells?
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
Methotrexate: Pharmacological properties | enzyme / effect / protection of normal cells
* 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
Methotrexate: Pharmacological properties | CNS penetration / plasma proteins / phase
* **Poor CNS penetration** - requires intrathecal use or high dose IV * **50% bound to plasma protein** * **cell cycle specific** - kills cells in S phase
39
Methotrexate Toxicity: Acute / Delayed effects
* **Acute effects: Nausea, vomiting, diarrhea** * Delayed effects: GI and oral ulceration, **bone marrow suppression**, alopecia, hepatotoxicity, pulmonary infiltrates, fever
40
Methotrexate: Indications for use
* Acute lymphocytic **leukemia** * Non-Hodgkin's lymphomas, leukemia, breast, pancreatic and bladder carcinoma * **Psoriasis, rheumatoid arthritis**
41
Mercaptopurine: Pharmacological properties | analog of? / enzyme / inhibits / effects / metabolized by / phase?
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
Mercaptopurine: Toxicity | acute / delayed
Acute: infrequent nausea, vomiting, diarrhea Delayed: gradual bone-marrow depression
43
Fluorouracil: Pharmacological Properties | active form / binds / blocks / phase
* 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
Fluorouracil: Indications for use | not highlighted
Carcinoma of: * Breast * Colon * Pancreatic * Ovarian * Head * Gastric * Esophageal * Head / Neck
45
Fluorouracil: Toxicity
Delayed toxicity These drugs dont cause acute toxicity. nausea, oral and gatrointestinal ulceration, bone marrow depression
46
Cytarabine: Pharmacological Properties | converted into / competes with / phase
* Converted to **cytarabine triphosphate** * Inhibits **DNA polymerase** by competing with biological substrate (**deoxycitidine triphosphate**) * Cell cycle specific (**S-phase**)
47
Cytarabine: Toxicity | not highlighted
Delayed toxicity * Nausea * Vomiting * Bone Marrow Depression * Megaloblastosis * Leukopenia * Thrombocytopenia
48
Cytarabine: Indications for use | not highlighted
* Remission induction in acute non-lymphocytic leukemia * Acute lymphocytic leukemia * Chronic myelocytic leukemia * Meningeal Leukemia
49
What is overall MOA of many anti-cancer antibiotics? What are they derived from?
Bind to DNA through intercalation between specific bases and block DNA / RNA syn. Derived from soil fungus streptomyces Cell cycle non-specific
50
Daunorubicin hydrochloride & Doxorubicin hydrochloride: Pharmacological effects | MOA / effects / phase / antitumor activity / difference in structure
* 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
Daunorubicin hydrochloride & Doxorubicin hydrochloride: Toxicity | acute / delayed
Acute: nausea, vomiting, red urine, tissue necrosis, arrhythmias Delayed: bone-marrow depression, alopecia, GI upset and **cardiomyopathy (important)**
52
Daunorubicin: Indications
Acute non lymphocytic leukemia of adults Greater activity than doxorubicin in acute lymphocytic leukemia (children and adults)
53
Doxorubicin: Indications
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
Vinblastine sulfate and Vincristine sulfate: Pharmacological effects | structure / bind to / effect / phase
* 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
Vincristine: Toxicity | Acute / delayed
Acute: local reactivity if extravasated Delayed: **neurological,** constipation, alopecia, mild bone depression
56
Vinblastine: Toxicity | Acute / Delayed
Acute: mild nausea, vomiting, phlebitis Delayed: **neurological** and bone marrow depression
57
Vincristine and Vinblastine: indications | not highlighted
Vincristine: Breast carcinoma, acute leukemia, Hodgkin's and non - Hodgkins Vinblastine: Hodgkin's disease, Kaposi's sarcoma, testicular, bladder, lung carcinoma
58
Etoposide: Pharmacological Properties | Derivative of / forms what / results / phase specific
* 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
Etoposide: Toxicity | acute / delayed
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
Etoposide: Indications for use | not highlighted
1. Testicular cancer (w/ bleimycin and cisplatin) 2. Small cell carcinoma of lung (w/ cisplatin)
61
Paclitaxel: Pharmacological Properties | extracted from / MOA / effect / phase specific
* 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
Paclitaxel: Toxicity | Acute / Delayed
Acute: Nausea, vomiting (52 %) Delayed: Bone marrow suppression (neutropenia, leukopenia, thrombocytopenia, anemia) Hypersensitivity; peripheral neuropathy (60%) Alopecia - pretty much everybody
63
Paclitaxel: Indications
1. Metastatic Ovarian Cancer 2. Metastatic Breast Cancer 3. Non-small cell lung carcinoma
64
Prednisone and Dexamethasone: Cancer indications
Palliative management of leukemia and lymphoma in adults Acute leukemia of childhood Breast Cancer
65
Prednisone and dexamethasone: Anti-inflammatory and Immunosuppressive effects
* 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
Prednisone and Dexamethasone: Effects on enzymes
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
Where are steroids metabolized?
Liver and excreted in the kidney's
68
Steroids: Toxicity | short / long
Shorter (less than one week): Insomnia, behavioral changes, acute peptic ulcers and pancreatitis Longer: iatrogenic Cushing's syndrome
69
Steroids: Other adverse effects
* GI: Peptic Ulcers * Increased bacterial and mycotic infections * Adrenal suppression * Obesity, dyslipidemia and glucose intolerance
70
Tamoxifen: Pharmacologic properties | type / inhibits / phase / route / t1/2 / metabolism
* 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
Tamoxifen: Toxicity | short / long / most serious

MWU Pharmacology II (8 decks)

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