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_MS2 HemeOnc > 8/26- Common Cancer Drugs 1: Classes & Mechanisms > Flashcards

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

1
Q

What are the 5 major classes of traditional antineoplastic drugs?

A
  1. Alkylating Agents
  2. Antimetabolites
  3. Anticancer antibiotics
  4. Platinum Coordination Complexes
  5. Plant Derived Products
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2
Q

What are alkylating agents (basics)?

A

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

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3
Q

What is the mechanism of action for alkylating agents?

A
  • Inhibit DNA synthesis and cell division by covalent attachment at 2 points on DNA
  • Crosslink DNA and achieve a 50-100x enhancement in cytotoxicity
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4
Q

What are categories of alkylating agents?

A

- Nitrogen mustards

  • Nitrosoureas
  • Alkyl sulfonates
  • Ethylenimines and methylmelamines
  • Triazenes
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5
Q

What are some nitrogen mustard agents?

A
  • Mechlorethamine (nitrogen mustard)
  • Cyclophosphamide
  • Ifosfamide
  • Melphalan
  • Chlorambucil

“cyclophosphamide is the most useful and versatile of the nitrogen mustards”

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6
Q

What is the mechanism of cyclophosphamide?

A
  • 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
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7
Q

What are the kinetics of Cyclophosphamide?

  • Absorption
  • Half life
  • Elimination
A
  • Well absorbed orally
  • Plasma t1/2 of 6.5 hr
  • Eliminated by kidney
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8
Q

What is Cyclophosphamide used for?

A

Lymphoma in regimens:

  • CVP
  • COP
  • MOPP

Breast cancer in the CMF regimen

Ovarian cancer

Oat cell lung cancer

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9
Q

What are the combo chemo regimens:

  • CVP/COP
  • MOPP/C-MOPP
  • CMF
A

- CVP/COP

  • cyclophosphamide, vincristine (Oncovin), prednisone

- MOPP/C-MOPP

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

- CMF

  • cyclophosphamide, methotrexate, 5-fluorouracil
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10
Q

What are the adverse effects of Cyclophosphamide?

A
  • 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

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11
Q

What are antimetabolites (broadly)?

A

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
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12
Q

What is the mechanism of folate antagonists?

A

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
Q

What are some folate antagonists?

A

May be large or small folate analogs

  • Methotrexate (MTX)- an analog of folic acid
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14
Q

What is the mechanism of Methotrexate (MTX)?

A

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

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15
Q

Kinetics of Methotrexate (MTX)?

  • Absorption
  • Distribution
  • Elimination
A
  • Well absorbed orally
  • Triphasic decay from plasma following IV injection
  • Excreted by the kidney
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16
Q

Use of methotrexate (MTX)?

A

Part of a curative regimen for:

  • Acute lymphoblastic leukemia (ALL)
  • Trophoblastic choriocarcinoma
  • Burkitt’s lymphoma
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17
Q

What are the adverse effects of methotrexate (MTX)?

A
  • Dose-limiting myelosuppression (Leucovorin rescue)
  • Hepatotoxicity
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18
Q

Contraindications for methotrexate (MTX)?

A

Patients with renal impairment

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19
Q

Drug interactions with methotrexate (MTX)?

A
  • Salicylates
  • Probenecid
  • Sulfonamides
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20
Q

What is myelosuppression?

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

A

Chemo-induced bone marrow suppression

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21
Q

Summary: Alkylating agents

  • Subclass
  • Drug
  • Mechanism
  • Use
  • Adverse Effect
A

Alkylating agents

  • Subclass: N-mustard
  • Drug: cyclophosphamide
  • Mechanism: bivalent alk of DNA
  • Use: lymphoma
  • Adverse Effect: myelosuppressive
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22
Q

Summary: Anti-folate

  • Subclass
  • Drug
  • Mechanism
  • Use
  • Adverse Effect
A

Anti-folate

  • Subclass: large folate
  • Drug: MTX
  • Mechanism: inhibits DHF and thymidine synthesis
  • Use: ALL
  • Adverse Effect: myelosuppressive
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23
Q

What is the mechanism for Purine Analogues?

A
  • 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
Q

What are some categories of purine analogs? Agents?

A

- Thiolated purine analogs

  • Inhibitors of glutamine dependent synthesis
  • Inhibitors of xanthine oxidase

Agents:

  • Thioguanine (6-thioguaniine)
  • Mercaptopurine (6-MP) Analogs of guanine
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25
Q

What is the mechanism for thioguanine?

A

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

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26
Q

What are the kinetics of thioguanine?

  • Absolute
  • Distribution volume
  • Elmination
A
  • Oral absorption is slow, incomplete, and erratic
  • Excreted by the kidney
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27
Q

What is the mechanism of Pseudo-feedback Inhibition?

A
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28
Q

What are some uses for thioguanine?

A
  • AGL
  • ALL
  • CGL
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29
Q

Adverse effects of thioguanine?

A
  • Myelosuppression
  • Concommitant use of allopurinal with thioguanine is okay
  • Use of allopurinal with 6-MP increases its toxicity
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30
Q

What is the mechanism of Pyrimidine Analogues?

A
  • 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
Q

What are some categories of pyrimidine analogues? Agents?

A

- Halogenated pyrimidines

  • Modified sugar
  • Azapyrimidines

Agents:

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

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32
Q

What is the mechanism of 5-fluorouracil?

A

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

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33
Q

What are the kinetics of 5-fluorouracil?

  • Absorption
  • Distribution
  • Half life
  • Elimination
A
  • Oral route erratic
  • Plasma t1/2 is 10-20 min
  • Readily enters CSF
  • Metabolized in the liver
34
Q

Uses of 5-fluorouracil?

A
  • Carcinoma of the breast
  • Stomach, colon, and rectum
  • Pancreas, liver, and ovary
35
Q

Adverse effects of 5-fluorouracil?

A

ASEs are dependent upon schedule and mode

  • Delayed in appearance
  • Myelosuppression is major
36
Q

What is the mechanism of Hydroxurea?

A

Inhibits the enzyme ribonucleoside diphosphate reductase

37
Q

Use of Hydroxyurea?

A

Myeloproliferative syndromes and CGL

38
Q

Adverse effects of Hydroxyurea?

A
  • Leukopenia
  • Anemia
  • Occasional thrombocytopenia
39
Q

Summary: Anti-purines

  • Subclass
  • Drug
  • Mechanism
  • Use
  • Adverse Effect
A

Anti-purines

  • Subclass: Thiolated purine
  • Drug; Thioguanine
  • Mechanism: inhibits purine synthesis
  • Use: Leukemia
  • Adverse effect: Myelosuppressive
40
Q

Summary: Anti-pyrimidines

  • Subclass
  • Drug
  • Mechanism
  • Use
  • Adverse Effect
A

Anti-pyrimidines

  • Subclass: halogenated pyrimidines
  • Drug: 5-FU
  • Mechanism: inhibits thymidine synthetase
  • Use: Colon cancer
  • Adverse effect: Myelosuppressive
41
Q

What is the mechanism of anticancer antibiotics?

A

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
Q

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

A

- Direct interaction with DNA

  • Interaction with DNA polymerase(s)
  • Interaction with RNA polymerase(s)

Subclasses:

  • Anthracyclines: doxorubicin, daunorubicin, idarubicin
  • Bleomycins
43
Q

What are the mechanisms for Doxorubicin?

A
  • Interacalating agents insert between DNA base pairs
  • Bind tightly to DNA

- S-phase specific

44
Q

What are the kinetics of Doxorubicin?

  • Absorption
  • Distribution
  • Elimination
A
  • Not oral, IM, or SQ
  • Metabolized in liver
45
Q

Uses of Doxorubicin?

A
  • Carcinoma of the breast, ovary, endometrium, bladder, thryoid
  • Oat cell carcinoma of the lung

(used to treat solid tumors)

46
Q

Adverse effects of Doxorubicin?

A
  • Cardiac toxic (cumulative dose-dependent)
  • Myelosuppressive (major)
47
Q

What is the mechanism for Bleomycin?

A

Strand scission

  • binds to DNA and cuts the phosphate backbone (both SS & DS)
48
Q

Kinetics of bleomycin?

  • Absorption
  • Distribution
  • Elimination
A
  • IV, IM, IA, and SQ routes
  • Excreted in the kidney
49
Q

Uses of bleomycin?

A

Potentially curative when used in combination protocols to treat:

  • Testicular carcinoma

- Hodgkin’s and non-Hodgkin’s lymphoma

50
Q

What are the adverse effects of Bleomycin?

A
  • Incidence of lung toxicity (10%); fatal in 1%
  • Also skin toxic
51
Q

Summary Antibiotic

  • Subclass
  • Drug
  • Mechanism
  • Use
  • Adverse Effect
A

Summary: Antibiotic

  • Subclass: Anthracyclin
  • Drug: Doxorubicin
  • Mechanism: Intercalate
  • use: Solid Tumors
  • Adverse Effect: Cardiac and myelosuppressive
52
Q

Summary: Antibiotic

  • Subclass: Bleomycin
  • Drug
  • Mechanism
  • use
  • Adverse Effect
A

Summary: Antibiotic

  • Subclass: Bleomycin
  • Drug: Bleomycin
  • Mechanism: Cuts DNA
  • use: Testicular
  • Adverse Effect: Lung
53
Q

What is the mechanism for platinum coordination complexes?

A

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

54
Q

What is a platinum coordination complex agent?

A

Cisplatin (cis-platinum)

55
Q

Kinetics for cisplatin?

  • Absorption
  • Distribution
  • Elimination
A
  • Biphasic plasma decay
  • Excretion is renal
56
Q

Uses of cisplatin?

A

Curative for testicular cancer when used in combinations

57
Q

Adverse effects of cisplatin?

A
  • Renal toxicity
  • Hearing loss
  • Nausea- prevent with ondansetron (5-HT3)
58
Q

What phase of replication do plant-derived products affect?

A

All plant derived are M-phase specific tubulin binders

59
Q

What is the mechanism for plan-derived products?

A

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

60
Q

Categories of plant-derived products? Agents?

A

- Vinca alkaloids

- Taxanes

  • Camptothecan analogs
  • Epipodophyllotoxins

Agents:

- Vincristine

  • Vinblastine
61
Q

What is the mechanism for vincristine?

A

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

62
Q

Kinetics for vincristine?

  • Absorption
  • Distribution
  • Elimination
A
  • Unusual triphasic half life
  • Excreted in the bile
63
Q

Uses for vincristine?

A

Curative for:

  • ALL
  • Hodgkin’s and NHL when used in regimens
64
Q

Adverse effects of vincristine?

A

Dose-limiting neurological toxicity

65
Q

What is a Taxane Agent?

A

Paclitaxel (Taxol)

66
Q

What is the mechanism of Paclitaxel?

A

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

67
Q

Kinetics of Paclitaxel?

  • Absorption
  • Distribution
  • Elimination
A
  • 3 or 24 hour infusion
  • P450 mediated hepatic metabolism
  • Excreted in the bile
68
Q

Uses of Paclitaxel (taxol)?

A

Cisplatin-refractory metastatic ovarian and breast cancers

69
Q

ASEs of Paclitaxel?

A
  • Myelosuppressive
  • Myalgias
  • Stocking-glove sensory neuropathy
70
Q

What is a Camptotehcin Analog?

A

Topotecan

71
Q

What is the mechanism of Topotecan (Camptothecin analog)?

A

Binds to topoisomerase I; causes single strand DNA breaks

72
Q

Uses for Topotecan?

A

Ovarian and small cell lung cancer

73
Q

ASEs of Topotecan?

A

Neutropenia

74
Q

What is Epipodophyllotoxin?

A

Etoposide

75
Q

What is the mechanism of Etoposide?

A

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

76
Q

Uses of Etoposide?

A

Testicular cancer

77
Q

ASEs of Etoposide?

A

Causes leukemia with a chromsomal translocation

78
Q

Summary: Platinum compound

  • Subclass
  • Drug
  • Mechanism
  • Use
  • Adverse Effect
A

Platinum compound

  • Subclass:–
  • Drug: Cisplatin
  • Mechanism: Coordination complex
  • Use: Testicular
  • Adverse Effect: Renal
79
Q

Summary: Plant derived

  • Subclass
  • Drug
  • Mechanism
  • Use
  • Adverse Effect
A

Plant derived

  • Subclass: Vinca alkaloid
  • Drug: Vincristine
  • Mechanism: Block assembly
  • use: ALL and Lymphoma
  • Adverse Effect: Neurotoxic
80
Q

Summary: Plant derived

  • Subclass
  • Drug
  • Mechanism
  • Use
  • Adverse Effect
A

Summary: Plant derived

  • Subclass: Taxane
  • Drug: Paclitaxel
  • Mechanism: Block disassembly
  • Use: Ovary and breast
  • Adverse Effect: Myelosuppressive

_MS2 HemeOnc (33 decks)

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