8/26- Common Cancer Drugs 1: Classes & Mechanisms Flashcards Preview

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Flashcards in 8/26- Common Cancer Drugs 1: Classes & Mechanisms Deck (80):
1

What are the 5 major classes of traditional antineoplastic drugs?

1. Alkylating Agents

2. Antimetabolites

3. Anticancer antibiotics

4. Platinum Coordination Complexes

5. Plant Derived Products

2

What are alkylating agents (basics)?

Strong electrophiles that form positively charged intermediates or transition complexes with target molecules and cause DNA damage

3

What is the mechanism of action for alkylating agents?

- Inhibit DNA synthesis and cell division by covalent attachment at 2 points on DNA

- Crosslink DNA and achieve a 50-100x enhancement in cytotoxicity

4

What are categories of alkylating agents?

- Nitrogen mustards

- Nitrosoureas

- Alkyl sulfonates

- Ethylenimines and methylmelamines

- Triazenes

5

What are some nitrogen mustard agents?

- Mechlorethamine (nitrogen mustard)

- Cyclophosphamide

- Ifosfamide

- Melphalan

- Chlorambucil

"cyclophosphamide is the most useful and versatile of the nitrogen mustards"

6

What is the mechanism of cyclophosphamide?

- Activated by the cytochrome P450 mixed function oxidase system

- 2-chloroethyl groups form a cyclic ethylenimonium ion

- This positively charged ion interacts with electrophilic groups

7

What are the kinetics of Cyclophosphamide?

- Absorption

- Half life

- Elimination

- Well absorbed orally

- Plasma t1/2 of 6.5 hr

- Eliminated by kidney

8

What is Cyclophosphamide used for?

Lymphoma in regimens:

- CVP

- COP

- MOPP

Breast cancer in the CMF regimen

Ovarian cancer

Oat cell lung cancer

9

What are the combo chemo regimens:

- CVP/COP

- MOPP/C-MOPP

- CMF

- CVP/COP

- cyclophosphamide, vincristine (Oncovin), prednisone

- MOPP/C-MOPP

- mechlorethamine or cyclophosphamide, vincritine (Oncovin), procarbazine, prednisone

- CMF

- cyclophosphamide, methotrexate, 5-fluorouracil

10

What are the adverse effects of Cyclophosphamide?

- Myelosuppression is dose-limiting

- Alopecia

- Humoral and cellular immuno-suppression

- Cystitis

Acrolein accumulates from poly-phosphamide breakdown in bladder; can be managed with mesna and adequate hydration

11

What are antimetabolites (broadly)?

Drugs that are structurally related to naturally occurring compounds and compete for the utilization of normal metabolites

- May inhibit key enzyme or get incorporated into nucleic acids

Classes:

- Folate antagonists

- Purine analogues

- Pyrimidine analogues

12

What is the mechanism of folate antagonists?

Block the biosynthesis of fully reduced tetrahydrofolic acid (PGA?) and prevent one-carbon transfer reactions needed to synthesize:

- Thymidylate

- Purines

- Methionine

- Glycine 

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13

What are some folate antagonists?

May be large or small folate analogs

- Methotrexate (MTX)- an analog of folic acid

14

What is the mechanism of Methotrexate (MTX)?

Competitively inhibits folic acid binding to the enzyme DHFR (binds DHFR stronger than folic acid does)

- Cell death occurs as a result of the thymidylate and purine blockage

- S-phase specific agent

15

Kinetics of Methotrexate (MTX)?

- Absorption

- Distribution

- Elimination

- Well absorbed orally

- Triphasic decay from plasma following IV injection

- Excreted by the kidney

16

Use of methotrexate (MTX)?

Part of a curative regimen for:

- Acute lymphoblastic leukemia (ALL)

- Trophoblastic choriocarcinoma

- Burkitt’s lymphoma

17

What are the adverse effects of methotrexate (MTX)?

- Dose-limiting myelosuppression (Leucovorin rescue)

- Hepatotoxicity

18

Contraindications for methotrexate (MTX)?

Patients with renal impairment

19

Drug interactions with methotrexate (MTX)?

- Salicylates

 - Probenecid

- Sulfonamides

20

What is myelosuppression?

In what conditions is it observed/what is the effect on cells/outcomes?

Chemo-induced bone marrow suppression 

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21

Summary: Alkylating agents

- Subclass

- Drug

- Mechanism

- Use

- Adverse Effect

Alkylating agents

- Subclass: N-mustard

- Drug: cyclophosphamide

- Mechanism: bivalent alk of DNA

- Use: lymphoma

- Adverse Effect: myelosuppressive

22

Summary: Anti-folate

- Subclass

- Drug 

- Mechanism

- Use

- Adverse Effect

Anti-folate

- Subclass: large folate

- Drug: MTX

- Mechanism: inhibits DHF and thymidine synthesis

- Use: ALL

- Adverse Effect: myelosuppressive

23

What is the mechanism for Purine Analogues?

- Prevent the biosynthesis of purine precursors needed for RNA and DNA synthesis

- Get incorporated into RNA and DNA; fraudulent nucleic acids are made

- Require activation: antitumor purine analogs undergo “lethal synthesis” to convert them into 5’-phosphate ribonucleotides

Type 1- "Lethal Synthesis" for BOTH purines and pyrimidines 

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24

What are some categories of purine analogs? Agents?

- Thiolated purine analogs

- Inhibitors of glutamine dependent synthesis

- Inhibitors of xanthine oxidase

Agents:

- Thioguanine (6-thioguaniine)

- Mercaptopurine (6-MP) Analogs of guanine

25

What is the mechanism for thioguanine?

Following “lethal synthesis” it inhibits purine biosynthesis; gets incorporated into DNA >> RNA

26

What are the kinetics of thioguanine?

- Absolute

- Distribution volume

- Elmination

- Oral absorption is slow, incomplete, and erratic

- Excreted by the kidney

27

What is the mechanism of Pseudo-feedback Inhibition?

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28

What are some uses for thioguanine?

- AGL

- ALL

- CGL

29

Adverse effects of thioguanine?

- Myelosuppression

- Concommitant use of allopurinal with thioguanine is okay

- Use of allopurinal with 6-MP increases its toxicity

30

What is the mechanism of Pyrimidine Analogues?

- Prevent the synthesis of pyrimidine precursors needed for RNA and DNA synthesis

- Get incorporated into RNA >> DNA; fraudulent nucleic acids are made

- Require activation: pyrimidine analogs undergo “lethal synthesis” to convert them to 5’-phosphate ribonucleotides

Type- 2 "Lethal Synthesis" for pyrimidines ONLY 

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31

What are some categories of pyrimidine analogues? Agents?

- Halogenated pyrimidines

- Modified sugar

- Azapyrimidines

Agents:

- 5-fluorouracil (5-FU)- an analog of thymine

32

What is the mechanism of 5-fluorouracil?

Following ‘lethal synthesis’ 5-FU inhibits DNA synthesis by inhibiting thymidylate synthase, causing TTP levels to drop; gets incorporated into RNA >> DNA

33

What are the kinetics of 5-fluorouracil?

- Absorption

- Distribution

- Half life

- Elimination

- Oral route erratic

- Plasma t1/2 is 10-20 min

- Readily enters CSF

- Metabolized in the liver

34

Uses of 5-fluorouracil?

- Carcinoma of the breast

- Stomach, colon, and rectum

- Pancreas, liver, and ovary

35

Adverse effects of 5-fluorouracil?

ASEs are dependent upon schedule and mode

- Delayed in appearance

- Myelosuppression is major

36

What is the mechanism of Hydroxurea?

Inhibits the enzyme ribonucleoside diphosphate reductase

37

Use of Hydroxyurea?

Myeloproliferative syndromes and CGL

38

Adverse effects of Hydroxyurea?

- Leukopenia

- Anemia

- Occasional thrombocytopenia

39

Summary: Anti-purines

- Subclass

- Drug 

- Mechanism

- Use

- Adverse Effect

Anti-purines

- Subclass: Thiolated purine

- Drug; Thioguanine

- Mechanism: inhibits purine synthesis

- Use: Leukemia

- Adverse effect: Myelosuppressive

40

Summary: Anti-pyrimidines

- Subclass

- Drug 

- Mechanism

- Use

- Adverse Effect

Anti-pyrimidines

- Subclass: halogenated pyrimidines

- Drug: 5-FU

- Mechanism: inhibits thymidine synthetase

- Use: Colon cancer

- Adverse effect: Myelosuppressive

41

What is the mechanism of anticancer antibiotics?

As a group these agents inhibit nucleic acid synthesis by blocking DNA replication or transcription either by direct binding to the nucleic acid template or the polymerizing enzyme

42

What are the categories of anticancer antibiotics? Subclasses/Agents?

- Direct interaction with DNA

- Interaction with DNA polymerase(s)

- Interaction with RNA polymerase(s)

Subclasses:

- Anthracyclines: doxorubicin, daunorubicin, idarubicin

- Bleomycins

43

What are the mechanisms for Doxorubicin?

- Interacalating agents insert between DNA base pairs

- Bind tightly to DNA

- S-phase specific

44

What are the kinetics of Doxorubicin?

- Absorption

- Distribution

- Elimination

- Not oral, IM, or SQ

- Metabolized in liver

45

Uses of Doxorubicin?

- Carcinoma of the breast, ovary, endometrium, bladder, thryoid

- Oat cell carcinoma of the lung

(used to treat solid tumors)

46

Adverse effects of Doxorubicin?

- Cardiac toxic (cumulative dose-dependent)

- Myelosuppressive (major)

47

What is the mechanism for Bleomycin?

Strand scission

- binds to DNA and cuts the phosphate backbone (both SS & DS)

48

Kinetics of bleomycin?

- Absorption

- Distribution

- Elimination

- IV, IM, IA, and SQ routes

- Excreted in the kidney

49

Uses of bleomycin?

Potentially curative when used in combination protocols to treat:

- Testicular carcinoma

- Hodgkin’s and non-Hodgkin’s lymphoma

50

What are the adverse effects of Bleomycin?

- Incidence of lung toxicity (10%); fatal in 1%

- Also skin toxic

51

Summary Antibiotic 

- Subclass

- Drug 

- Mechanism

- Use

- Adverse Effect

Summary: Antibiotic

- Subclass: Anthracyclin

- Drug: Doxorubicin

- Mechanism: Intercalate

- use: Solid Tumors

- Adverse Effect: Cardiac and myelosuppressive

52

Summary: Antibiotic

- Subclass: Bleomycin

- Drug

- Mechanism

- use

- Adverse Effect

Summary: Antibiotic

- Subclass: Bleomycin

- Drug: Bleomycin

- Mechanism: Cuts DNA

- use: Testicular

- Adverse Effect: Lung

53

What is the mechanism for platinum coordination complexes?

An electrophile that forms strong coordination complexes with DNA; binds at N7 and O6 of guanine

54

What is a platinum coordination complex agent?

Cisplatin (cis-platinum)

55

Kinetics for cisplatin?

- Absorption

- Distribution

- Elimination

- Biphasic plasma decay

- Excretion is renal

56

Uses of cisplatin?

Curative for testicular cancer when used in combinations

57

Adverse effects of cisplatin?

- Renal toxicity

- Hearing loss

- Nausea- prevent with ondansetron (5-HT3)

58

What phase of replication do plant-derived products affect?

All plant derived are M-phase specific tubulin binders

59

What is the mechanism for plan-derived products?

These compounds bind to tubulin, differ in structure, and differ in mechanism.

60

Categories of plant-derived products? Agents?

- Vinca alkaloids

- Taxanes

- Camptothecan analogs

- Epipodophyllotoxins

Agents:

- Vincristine 

- Vinblastine

61

What is the mechanism for vincristine?

Binds to ‘microtubule tubulin’ and blocks polymerization to microtubules; M-phase specific agent leading to apoptosis

62

Kinetics for vincristine?

- Absorption

- Distribution

- Elimination

- Unusual triphasic half life

- Excreted in the bile

63

Uses for vincristine?

Curative for:

- ALL

- Hodgkin's and NHL when used in regimens

64

Adverse effects of vincristine?

Dose-limiting neurological toxicity

65

What is a Taxane Agent?

Paclitaxel (Taxol)

66

What is the mechanism of Paclitaxel?

Binds to beta-tubulin and tubulin dimers; antagonizes microtubule disassembly

67

Kinetics of Paclitaxel?

- Absorption

- Distribution

- Elimination

- 3 or 24 hour infusion

- P450 mediated hepatic metabolism

- Excreted in the bile

68

Uses of Paclitaxel (taxol)?

Cisplatin-refractory metastatic ovarian and breast cancers

69

ASEs of Paclitaxel?

- Myelosuppressive

- Myalgias

- Stocking-glove sensory neuropathy

70

What is a Camptotehcin Analog?

Topotecan

71

What is the mechanism of Topotecan (Camptothecin analog)?

Binds to topoisomerase I; causes single strand DNA breaks

72

Uses for Topotecan?

Ovarian and small cell lung cancer

73

ASEs of Topotecan?

Neutropenia

74

What is Epipodophyllotoxin?

Etoposide

75

What is the mechanism of Etoposide?

Forms complex with topoisomerase II; causes double-strand DNA breaks

76

Uses of Etoposide?

Testicular cancer

77

ASEs of Etoposide?

Causes leukemia with a chromsomal translocation

78

Summary: Platinum compound

- Subclass

- Drug 

- Mechanism

- Use

- Adverse Effect

Platinum compound

- Subclass:--

- Drug: Cisplatin

- Mechanism: Coordination complex

- Use: Testicular

- Adverse Effect: Renal

79

Summary: Plant derived

- Subclass

- Drug 

- Mechanism

- Use

- Adverse Effect

Plant derived

- Subclass: Vinca alkaloid

- Drug: Vincristine

- Mechanism: Block assembly

- use: ALL and Lymphoma

- Adverse Effect: Neurotoxic

80

Summary: Plant derived

- Subclass

- Drug 

- Mechanism

- Use

- Adverse Effect

Summary: Plant derived

- Subclass: Taxane

- Drug: Paclitaxel

- Mechanism: Block disassembly

- Use: Ovary and breast

- Adverse Effect: Myelosuppressive