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IHO Week 3 - WLB > Drugs that Disrupt DNA and/or Prevent DNA Replication - Fitz > Flashcards

Drugs that Disrupt DNA and/or Prevent DNA Replication - Fitz Flashcards

1
Q

What are the three types/groupings of antineoplastics that Disrupt DNA?

A
  • Drugs that crosslink DNA
  • Drug that intercalate
  • Drugs that cause strand breaks
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2
Q

What are three types/subgroups of crosslinking antineoplastic drugs that disrupt DNA?

A
  • Alkylating agents
    • Nitrogen Mustards
    • Nitroureas
  • Platinum-containing drugs (-platinum)
  • Antibiotic (Mitomycin)
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3
Q

What are the two drugs that are Nitrosoureas?

A
  • Carmustine (BCNU)
  • Lomustine (CCNU)
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4
Q

What are five drugs that are derived from Nitrogen Mustard (mustard gas)?

A
  • CHLORAMBUCIL
  • CYCLOPHOSPHAMIDE
  • IFOSFAMIDE
  • MECHLORETHAMINE
  • MELPHALAN
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5
Q

What are the three steps in the mechanism of action of crosslinking agents?

A
  1. Activation: converted to electrophiles
  2. Nucleophilic attack: on anything in the cell (especially N7-guanine)
  3. Attaches to DNA => DNA DAMAGE (crosslinking)
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6
Q

When does the primary toxicity of crosslinking agents occur?

A

late G1 and S phase

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7
Q

Why are crosslinking agents selectively toxic to cancer cells?

A
  • 50% of human cancers have mutation in p53
    • cells cannot repair the DNA alkylation
    • accumulation of errors → undergo apoptosis
  • normal cells stop the cell cycle and repair the damage
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8
Q

What are three common resistance mechanisms that cancer cells develop in response to crosslinking agents?

A
  • increased production of nucleophilic substances (e.g. glutathione - trapping agent)
  • increased DNA repair
    • increased activity of repair enzymes (e.g. guanine O6-alkyl transferase)
  • decreased activation (oral agents only)
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9
Q

How do you distinguish between crosslinking agents that can be given IV or can be given orally?

A
  • based on how quickly they are activated (become electrophiles)
    • Meclorethamine: immediate activation on exposure to H2O
    • add something to molecule to slow down activation
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10
Q

What are the therapeutic uses of crosslinking agents?

A
  1. Most commonly used antineoplastic agents
  2. Subtyping cancer to identify the best drug
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11
Q

What are the common side effects/toxicities of crosslinking agents?

(Hint: 8 total)

A

Generally, less for oral agents and greatest for MECHLORETHAMINE

  1. moderate to severe myelosuppression
  2. severe nausea and vomiting (Mechlorethamine & Cisplatin)
  3. strong vesicant (blistering) properties (not for oral agents)
  4. immunosuppression
  5. gonadal failure (sterility)
  6. carcinogeneisis (leukemias, esp. AML)
  7. mutagenesis
  8. teratogenesis
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12
Q

What are the four Anthracycline Antibiotics that are Intercalating Agents?

A
  • DOXORUBICIN
    • one of the most widely used antineoplastic drugs
  • DAUNORUBICIN
  • EPIRUBICIN
  • EPIRUBICIN
  • MITOXANTONE
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13
Q

What type of cancer are Anthracycline Antibiotics (intercalating agents) very useful for treating?

A

Breast cancer

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14
Q

What are the primary mechanisms of action of Anthracycline Antibiotics (intercalating agents)?

A
  • intercalation in major groove of DNA causing several cytotoxic actions:
    • inhibition of topoisomerase II
    • ​single- and double-strand breaks (mutagenic) or sister chromatid exchange (carcinogenic)
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15
Q

What are the secondary mechanisms of action of Anthracycline Antibiotics (intercalating agents)?

A
  • interact with cell membranes to alter fluidity and ion transport
  • in the presence of NADPH, they react with cytochrome P450 reductase to form superoxide anion radicals
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16
Q

Even though they are CCNS, when is the maximum toxicity of Anthracycline Antibiotics (intercalating agents)?

A

S phase

(at low concentrations will pass through S and die in G2)

17
Q

What are the three main forms of resistance that cancer cells can form in response to Intercalating agents?

A
  • *decreased accumulation via increased P-glycoprotein → multidrug resistance
    • Natural products
  • changes in target proteins
    • decreased topoisomerase II activity (i.e. decreased DNA synthesis)
  • increased inactivation
    • increased glutathione peroxidase activity (i.e. protection against oxidative damage)
18
Q

How are Intercalating agents administered? Metabolized?

A
  • given IV (vesicant)
  • eliminated by metabolic conversion and biliary excretion
    • dependent on adequate liver function
19
Q

What is the broadest spectrum/most common antineoplastic drug?

A
  • Doxorubicin = Adriamycin
    • first line treatment for breast cancer
20
Q

What is the most serious toxic side effect of Intercalating Agents?

A

ANTHRACYCLINE ANTIBIOTICS cause an UNUSUAL CARDIOMYOPATHY that is often IRREVERSIBLE and related to the TOTAL DOSE of the drug.

  • present years after treatment has stopped
  • unresponsive to standard treatment (digitalis)
21
Q

What are the 8 common toxic side effects of Intercalating Agents?

A
  1. Cardiomyopathy:
    1. Acute: increased heart rate, conduction abnormalities, arrhythmias
    2. Delayed: congestive heart failure that is unresponsive to digitalis (may occur years after treatment)
  2. Extravasation → necrosis (vesicant)
  3. Myelosuppression is major dose-limiting complication (individual course of treatment)
  4. Nausea and vomiting
  5. Alopecia
  6. Mutagenic, carcinogenic
  7. “Radiation recall reaction” - erythema and desquamation of the skin at sites of prior radiation therapy
  8. Hand-foot syndrome (palmar-plantar erythrodysesthesia)
22
Q

What color is the urine of a patient that received treatment with an Intercalating Agent 24-48 hours after administration?

A

Red/Reddish-Orange

(the exception is MITOXANTONE which turns the urine — and the whites of the eyes — blue!)

23
Q

What is special about the drug Procarbazine that Fitz listed as a drug that causes strand breaks and/or prevents DNA replication?

A
  • It is actually an ALKYLATING AGENT
    • has more effects on RNA & protein synthesis than other alkylating agents
    • has more strand breaks than other alkylating agents
24
Q

What two drugs are Plant Alkaloids that cause DNA strand breaks and/or prevent DNA replication?

A
  • Epipodophyllotoxin: ETOPOSIDE
  • Camptothecins: IRINOTECAN/TOPOTECAN
25
Q

What are two mechanisistic similarities between all antineoplastic drugs that cause DNA strand breaks and/or prevent DNA replication?

A
  • all are CCS
  • all require functional apoptotic machinery (esp. p53) to complete the cell kill
  • DNA breaks accumulate in G2
26
Q

What is the MOA of Bleomycin?

A
  • binds to DNA (not RNA) through its amino-terminal peptide
  • generates free radicals that cut the DNA
  • causes accumulation of cells in G2 that have chromosomal aberrations (chromatid breaks, gaps, fragments and translocations)

Bleomycin Blasts DNA

27
Q

Why is Etoposide a better antineoplastic drug than IRINOTECAN and TOPOTECAN?

A
  • Etoposide = Topo II inhibitor
    • more specific for rapidly dividing cells
    • harder to repair
  • Irinotecan/Topotecan = Topo I inhibitor
28
Q

Where are Irinotecan and Topotecan activated and metabolized in the body?

A

Liver

29
Q

What two forms of resistance are possible with Bleomycin?

A
  • increased inactivation
    • increased hydrolase activity (also important for toxicity - not in skin/lungs)
  • increased DNA repair
30
Q

What two forms of resistance are possible with Etoposide?

A
  • decreased accumulation via increased P-glycoprotein (multidrug resistance)
  • changes in target proteins
    • mutation or decreased expression of topoisomerase II
    • decreased apoptosis due to mutation of p53
31
Q

What two forms of resistance are possible with Irinotecan/Topotecan?

A
  • decreased activation
  • decreased accumulation via increased P-glycoprotein (multidrug resistance)
32
Q

Why is Bleomycin used in combination with other antineoplastic therapies?

A

Unique MOA

33
Q

What type of cancer is Irinotecan/Topotecan used for?

A

Metastatic Colon Cancer

34
Q

What are common toxicity side effects of Bleomycin?

A
  • hypersensitivity
  • GI
  • lungs (pulmonary fibrosis) and skin lack the hydrolase that degrades BLEOMYCIN
  • alopecia
  • edema of the hands
35
Q

What are common toxicity side effects of Etoposide?

A
  • nausea and vomiting
  • cardiovascular: hypotension, EKG changes
  • alopecia
  • leukopenia
36
Q

What are common toxicity side effects of Irinotecan/Topotecan?

A
  • myelosuppression
  • diarrhea (both forms may be severe):
    • early:
      • accompanied by other cholinergic symptoms (rhinitis, increased salivation, miosis, lacrimation)
      • treatable with ATROPINE
    • late:
      • prolonged
      • causes dehydration, electrolyte imbalances and sepsis that may be life-threatening
      • treated with LOPERAMIDE (opiate)
37
Q

When it comes to selectivity of alkylating agents, why are cancer cells fools?

A
  • most cancer cells have defective/dysfunctional p53
    • cannot repair damage by alkylating agents
  • normal cells are not hurt because they have functional p53 and repair mechanisms

IHO Week 3 - WLB (10 decks)

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