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Block 5 Pharmacology > Cancer Chemotherapy- DNA Alkylating Drugs > Flashcards

Cancer Chemotherapy- DNA Alkylating Drugs Flashcards

1
Q

What are the 4 main classes of Alkylating Drugs and examples of them

A
  • Nitrogen Mustards: (cyclophosphamide)
  • Nitrosureas: (carmustine)
  • Platinum Compounds: (cisplatin, carboplatin, oxaliplatin)
  • Others: (darcarbazine, procarbazine, busulfan)
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2
Q

What is the general Mechanism of Action for all DNA alkylating agents

A
  • MOA 1: covalent DNA binding (across strands) causing DNA denaturation/strand breakage
  • MOA 2: DNA adducts alter the structure of DNA and activate DNA repair machinery, leads to cell death
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3
Q

What is the specific Mechanism of action of Cyclophosphamide

A
  • Nitrogen mustard
  • activated by liver P450 (CYP2B) to numerous active, inactive, and cytotoxic molecules
  • alkylates DNA at the N7 position of neighboring guanine residues
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4
Q

Describe the mechanism by which Cyclophosphamide can induce secondary cancer

A
  • Cyclophosphamide crosslinks adjacent guanine residues this can be either interstrand (a guanine on each strand is bound) or Intrastrand (two guanines on the same strand are bound)
  • INTERstrand (more common): correlates to tumor cell toxicity
  • INTRAstrand: introduces mutations which may lead to secondary cancer formation
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5
Q

What Combination therapies and cancers would Cyclophosphamide be commonly used with and what Non Cancer uses does it have

A
  • CLL and Non-Hodgkin’s Lymphoma
    • CHOP- R:
      (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, rituximab)

-Breast Cancer
- CMF: (cyclophosphamide, MTX, 5-FU)
-Lung Cancer
- CAV: (cyclophosphamide, adriamycin, vincristine)
- CAE: (cylcophosphamide, adriamycin, etoposide)
NON Cancer
- Immuno supressant
- Autoimmune disease
- Transplant recipients

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6
Q

What are 7 adverse effects associated with Cyclophosphamide and which one is dose limiting and which is most dangerous

A
  • myelosuppression (dose limiting)
  • Pulmonary Toxicity (can be fatal)
  • GI toxicity
  • Secondary Malignancies
  • Severe alopecia
  • High risk emetogenic agent
  • HEMORRHAGIC CYSTITIS
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7
Q

What is the Pathophysiology associated with Cyclophosphamide induced hemorrhagic cystitis and what is used to prevent/treat it

A
  • Aldophosphamide active breakdown product of cyclophosphamide
  • In the bladder can be broken down enzymatically by aldehyde oxidase into inactive carboxyphosphamide
  • or it can be degrade nonenzymatically into cytotoxic acrolein
  • Give MESNA and increase fluid intake to prevent
  • mesna serves as an antioxidant to inactivate acrolein
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8
Q

What is a mechanism of resistance seen against cyclophosphamide

A
  • Decreased Drug activation: lower levels of CYP2B to decrease conversion of cyclophos to acitve metabolites
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9
Q

What is the mechanism of action of Carmustine

A
  • Nitrosourea
  • Activated intermediate formed spontaneously
  • it crosslinks the DNA (interstrand) at guanine-Cytosine residues
  • this causes DNA damage and also activates repair enzymes (more damage) and apoptosis
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10
Q

What is replacing carmustine in chemo regimens and why?`

A
  • Bendamustine
  • Fewer adverse effects
  • Generally less toxic
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11
Q

How is Carmustine:

  • Administered
  • Absorbed/Distributed (CNS?)
  • Metabolized
  • Eliminated
A
  • Parenteral or wafer insertion
    • wafers are 4000 a piece and need 8, paired with sugery or radiation
  • Well distributed, Lipophillic
  • Penetrates CNS
  • Metabolized to various metabolites
  • Renal excretion
    • some also expired as CO2
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12
Q

What are the clinical uses of Carmustine

A
  • CNS tumors

- Lymphomas

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13
Q

List 6 adverse effects noted with Carmustine

A
  • Delayed Myelosuppression
  • Delayed pulmonary toxicity
    • 1 month to 10 yrs after treatment
    • treat with corticosteroids to slow progression
  • Various CNS effects (seizures)
  • Secondary cancer (intrastrand bonds?)
  • High risk emetogenic agent
  • Tumor lysis Syndrome
    • Give prophylactic allopurinol
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14
Q

Describe the mechanism of resistance against Carmustine

A
  • Increased DNA Damage Repair: increased AGT (alkylguanine DNA alkyltransferase)
  • Crosslinking is a two step process with a bond first at Guanine and 10-12hrs later at cytosine, if AGT is increased it is better able to remove the Carmustine (BCNU) before it is able to crosslink Cytosine
  • INC AGT, INC Repair, INC Resistance
  • DEC AGT, DEC Repair, INC Efficacy
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15
Q

Describe the mechanism of action of Cisplatin

A
  • Platinum Compound
  • Forms DNA crosslinks; Primarily with adjacent guanines, but also adenine and cytosine
  • BONDS ARE INTRAstrand
  • Bends the dna and binds irreversibly inhibiting DNA synthesis and PREVENTING DNA Repair
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16
Q

Common Combinations and cancer treatments that would involve Platinum compounds

A
  • Testicular Cancer
    • 90% cure with bleomycin,etoposide, platin
  • Colon Cancer
    • FolFOx: (folinic acid, 5-FU, Oxaliplatin)
  • Ovarian Cancer
    • platin, taxanes
  • Melenoma
17
Q

List 4 adverse effects of Cisplatin

A
  • Renal toxicity (more than carboplatin and oxaliplatin)
  • Peripheral neuropathy
  • Ototoxicity
  • High Risk Emetogenic Agent
18
Q

What treatment can be used to prevent/treat the renal toxicity of Cisplatin

A

Mannitol, Sodium thiosulfate, and increased hydration

19
Q

Describe 3 mechanisms of resistance to Cisplatin

A
  • Decreased drug accumulation: dec influx, CTR1 copper transporter which brings it in degredaded and delocalized
  • Decreased Drug accumulation: inc efflux, adenosine triphosphate transporter ATP7B upregulated
  • Inc Drug inactivation/inc efflux: Glutatione (antiox made by cell and inc in concentration by cisplatin) inactivates cisplatin, then it is removed from cell by MRP2
20
Q

Compare Carboplatin to Cisplatin

A
  • Anticancer spectrum is identical to Cisplatin

- Less Renal, Oto, and Neuro-toxicity than Cisplatin

21
Q

Compare Oxaliplatin to Cisplatin

A
  • Anticancer spectrum: same as Cisplatin, but it has GREATER activity against COLON cancer (folfOX)
  • Activity against Cisplatin RESISTANT cancer
  • Less renal and ototoxicity than Cisplatin
  • Prominent Neurotoxicity
22
Q

Describe the mechanism of action of Darcarbazine and Procarbazine

A
  • Alkylates DNA
  • Metabolically activated by liver enzymes and cross links to cause DNA damage
  • Also inhibits RNA and protein synth by unkown mechanism
23
Q

Common Combinations and cancer treatments that would involve Darcarbazine

A
  • Hodgkins Disease
    • ABVD: (adriamycin, bleomycin, vinblastine,darcarbazine)
  • Melanoma
24
Q

Common Combinations and cancer treatments that would involve Procarbazine

A
  • Brain Disease

- Hodgkins Disease

25
Q

List 4 adverse effects of Darcarbazine

A
  • High risk emetogenic agent
  • Alopecia
  • Myelosuppression
  • Leukemogenic, teratogenic, mutagenic (darcarbazine LESS severe)
26
Q

List 4 adverse effects of Procarbazine

A
  • Disulfirim like effects
  • Alopecia
  • Myelosuppression
  • Leukemogenic, teratogenic, mutagenic (Procarbazine MORE severe)
27
Q

Define the mechanism of action of Busulfan

A
  • Alkylates DNA causing DNA cross linking and DNA damage
28
Q

Common use of Busulfan

A
  • CML
29
Q

List 3 adverse effects of Busulfan and which is dose limiting

A
  • Myelosuppression (dose limiting)
  • Pulmonary fibrosis (busulfan lung)
    • 4% of patients
    • onset 3-10 years after treatment begins
    • no successful treatment, avg survival 5 mo.
  • Alopecia (permanent)
30
Q

What is interesting about the Alopecia of Busulfan

A

it is permanent

31
Q

Define Pharmacogenetics and Its application/utility in chemotherapy

A
  • study of genetic variation s that cause differences in drug response among idividuals or populations
  • potential application Screen indiv pts to identify these differences before perscribing a drug
    In chemo
  • reduce adverse effects
  • increase drug efficacy
  • identify drug resistance
32
Q

With regards to Pharmacogenetic testing which enzyme would be tested for 6-MP/6-TG and what information would be gained?

A
  • Enzyme tested: TPMT

Information Gained:

  • LOW: Adverse Effects
  • HIGH: Drug Resistance
33
Q

With regards to Pharmacogenetic testing which enzyme would be tested for 5-FU and what information would be gained?

A
  • Enzyme tested: DPD

Information Gained:

  • LOW: Adverse Effects
  • HIGH: Drug Resistance
34
Q

With regards to Pharmacogenetic testing which enzyme would be tested for Irinotecan and what information would be gained?

A
  • Enzyme tested: UGT1A1

Information Gained:
- Low: Adverse Effects

Block 5 Pharmacology (8 decks)

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