Flashcards in Disrupt DNA & Antimitotics- Fitz Deck (35):
Describe MOA in general for cross linking agents
Activation- must be, or become strong electrophiles
Attack on cell nucleophiles (N7 position of guanine)
Cause DNA damage:
Miscoding of DNA bases
DNA strand breakage
How do crosslinking agents demonstrate selective toxicity?
DNA damage normally activates a check point in cell cycle that is dependent on p53
most cancers do not have this, so cannot repair DNA
Normal cells stop cell cycle and repair the damage
What are common resistance mechanisms to crosslinking agents?
Increased production of nucleophilic substances
Increased DNA repair
Are alkylating agents susceptible to multidrug resistance?
YES!!! If cells adapt to one alkylating agent, they will be less susceptible to other alkylating agents
What happens instantaneously when mechlorethamine is in contacted with H20?
It is activated to a strong electrophile
Causing blistering/burning (vesicant)
Also most emetic!!!
What is a unique toxicity associated with cyclophosphamide?
It is a derivative of mechlorethamine
Activated by liver CYP450 enzyme
Final activation produces phosphoramide mustard (active drug) and Acrolein
Acrolein causes the hemorrhagic cystitis
Treat with MESNA
What do you treat hemorrhagic cystitis from cyclophosphamide with?
What differentiate Ifosfamide from cyclophosphamide?
Ifosfamide is slower acting, more broad, and the MOST NEUROTOXIC of all alklyating agents
What is the MOA of melphalan? What is it used to treat? And how is administered?
Used to treat Multiple Myeloma
What is carmustine/lomustine usually used to treat?
Highly lipid soluble
Toxicities to lung and liver
What is busulfan used to treat? What are the major side effects?
Used to treat chronic myeloid leukemia
Toxicities= Hyperpigmentation, lung, and hepatotoxicity
MOA of chlorambucil?
What is temozolamide used to treat and why?
Brain tumors!!! Highly fat soluble
What type of drug is cisplatin (carboplatin, oxaloplatin)?
Platinum Analogues- Alkylating agents
Toxicity of cisplatin?
Most potent EMETIC!!!
MOA of mitomycin?
Undergoes metabolic activation to become alkylating agent
MOA of doxorubicin?
Intercalates major grooves of DNA - leads to inhibition of TOPO II- causes double/single strand breaks
Forms of resistance to doxorubicin
INCREASE P-GLYCOPROTEIN!!! (multidrug resistance)
Changes in target protein = dereased TOPO II activity
Increased inactivation through increased glutathion peroxidase = protection against oxidative damage
Therapeutic uses of doxorubicin
boradest spectrum antineoplastic agents
Hodgkins, and breast cancer
one of the most commonly used antineoplastic agents
What is the unusual and irreversible side effect related to doxorubicin?
irreversible, and related to TOTAL dose of drug
What are other side effects related to doxorubicin besides cardiomyopathy?
Radiaton Recall reaction
Red Urine - due to chemical reaction
What is the radiation recall reaction?
erythema and desquamation of the sin at sites of prior radiation therapy
What is the MOA for bleomycin?
Binds to DNA (not RNA) through its amino-terminal peptide, and generates free radicals that cut the DNA
What are the two mechanisms of resistance for bleomycin?
Increased inactivation - increased hydorlase activity
Increased DNA repair
What is the MOA of Etoposide?
Forms complex with topo II and DNA that results in DOUBLE-strand breaks- remains bound to enzyme so that repair cannot occur
What are the two main mechanisms of resistance for Etoposide?
Decreased accumulation via increased p-glycoprotein
Mutation or decreased expression of topo II or decreased apoptosis due to mutation in p53
What is MOA of Irinotecan and topotecan?
Inhibitor of TOPO I and causes SINGLE strand breads
What is the BIG difference in elimination between Irinotecan and topotecan?
Irinotecan - eliminated by LIVER
Topotecan - eliminated by KIDNEY
Main forms of resistance of Irinotecan/topotecan?
Decreased accumulation via increased P-glycoprotein
What is the MOA of for Vinlastine/Vincristine?
Bind to tubulin at the forming end of the microtubules and TERMINATE (disrupt) spindle assembly
What is the main difference in toxicities between vinlastine and vincristine?
Vinlastine- bone marrow suppression
Vincristine- CNS toxicity, fatal if given intrathecally (mainly because of the requirement for microtubules in axon transport)
What is the mechanism of paclitaxel?
Binds to tubulin and ENHANCES and STABILIZES spindle assembly
Main mechanism of resistance for paclitaxel?
Decreased accumulation via increased P-glycoprotein expression
What is the MOA for ixabepilone?
Antibiotic that binds to tubulin and ENHANCES and STABILIZES spindle assembly (similar to paclitaxel)