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

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

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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
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?
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**
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-phas**e 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**

_MS2 HemeOnc (33 decks)

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