Cancer Chemotherapy- DNA Alkylating Drugs Flashcards
(34 cards)
What are the 4 main classes of Alkylating Drugs and examples of them
- Nitrogen Mustards: (cyclophosphamide)
- Nitrosureas: (carmustine)
- Platinum Compounds: (cisplatin, carboplatin, oxaliplatin)
- Others: (darcarbazine, procarbazine, busulfan)
What is the general Mechanism of Action for all DNA alkylating agents
- 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
What is the specific Mechanism of action of Cyclophosphamide
- Nitrogen mustard
- activated by liver P450 (CYP2B) to numerous active, inactive, and cytotoxic molecules
- alkylates DNA at the N7 position of neighboring guanine residues
Describe the mechanism by which Cyclophosphamide can induce secondary cancer
- 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
What Combination therapies and cancers would Cyclophosphamide be commonly used with and what Non Cancer uses does it have
- CLL and Non-Hodgkin’s Lymphoma
- CHOP- R:
(cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, rituximab)
- CHOP- R:
-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
What are 7 adverse effects associated with Cyclophosphamide and which one is dose limiting and which is most dangerous
- myelosuppression (dose limiting)
- Pulmonary Toxicity (can be fatal)
- GI toxicity
- Secondary Malignancies
- Severe alopecia
- High risk emetogenic agent
- HEMORRHAGIC CYSTITIS
What is the Pathophysiology associated with Cyclophosphamide induced hemorrhagic cystitis and what is used to prevent/treat it
- 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
What is a mechanism of resistance seen against cyclophosphamide
- Decreased Drug activation: lower levels of CYP2B to decrease conversion of cyclophos to acitve metabolites
What is the mechanism of action of Carmustine
- 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
What is replacing carmustine in chemo regimens and why?`
- Bendamustine
- Fewer adverse effects
- Generally less toxic
How is Carmustine:
- Administered
- Absorbed/Distributed (CNS?)
- Metabolized
- Eliminated
- 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
What are the clinical uses of Carmustine
- CNS tumors
- Lymphomas
List 6 adverse effects noted with Carmustine
- 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
Describe the mechanism of resistance against Carmustine
- 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
Describe the mechanism of action of Cisplatin
- 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
Common Combinations and cancer treatments that would involve Platinum compounds
- Testicular Cancer
- 90% cure with bleomycin,etoposide, platin
- Colon Cancer
- FolFOx: (folinic acid, 5-FU, Oxaliplatin)
- Ovarian Cancer
- platin, taxanes
- Melenoma
List 4 adverse effects of Cisplatin
- Renal toxicity (more than carboplatin and oxaliplatin)
- Peripheral neuropathy
- Ototoxicity
- High Risk Emetogenic Agent
What treatment can be used to prevent/treat the renal toxicity of Cisplatin
Mannitol, Sodium thiosulfate, and increased hydration
Describe 3 mechanisms of resistance to Cisplatin
- 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
Compare Carboplatin to Cisplatin
- Anticancer spectrum is identical to Cisplatin
- Less Renal, Oto, and Neuro-toxicity than Cisplatin
Compare Oxaliplatin to Cisplatin
- 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
Describe the mechanism of action of Darcarbazine and Procarbazine
- Alkylates DNA
- Metabolically activated by liver enzymes and cross links to cause DNA damage
- Also inhibits RNA and protein synth by unkown mechanism
Common Combinations and cancer treatments that would involve Darcarbazine
- Hodgkins Disease
- ABVD: (adriamycin, bleomycin, vinblastine,darcarbazine)
- Melanoma
Common Combinations and cancer treatments that would involve Procarbazine
- Brain Disease
- Hodgkins Disease
