Drugs that Disrupt DNA Flashcards
What are the three general types of drugs that disrupt DNA?
- crosslinking agents
- intercalating agents
- drugs that cause strand breaks
What is the major class of drugs that crosslink DNA?
alkylating agents
nitrogen mustards, nitrosoureas and others
What are the 5 nitrogen mustards?
chlorambucil cyclophosphamide ifosfamide mechlorethamine melphalan
What are the 2 nitrosoureas?
carmustine and lomustine
What antibiotic works as a crosslinking agent?
mitomycin
What are the platinum analogs that work as crosslinking agents?
carboplatin, cisplatin, oxaloplatin
Are cross-linking agents cell cycle specific or nonspecific?
They are NOT cell cycle specific, however, they are dependent on proliferation
reactions that initiate cell death can occur during any phase of the cell cycle, but primary toxicity occurs in late G1 and S phase
What’s the general mechanism for the alkylating agents?
They are strong electrophiles that will carry out nucleophile attack (like on the nitrogen of protein or DNA), causing cross-linking of the DNA strands.
This causes miscoding of DNA bases and DNA strand breakage form depurination
What is the method of selective toxicity for the alkylating agents?
- normal cells will stop the cell cycle and repair the damage caused by the alkylating agents
- cancer cells have mutated p53 in their cell cycle chekpoints, so they won’t repair the damage and will die
What are some common resistance mechanisms for the alkylating agents? Are they susceptible to MDR?
- increased production of nucleophilic substances like glutathione
- increased DNA repair (increased repair enzymes)
3 decreased activation of oral agents
They are susceptible to MDR
What’s the major distinguishing feature among alkylating agents that determines whether they can be given IV or orally?
the rate at which they’re converted to a strong electrophile
if it happens instantaneously (mechlorethamine), you have to give IV to minimize blistering
If it has to be activated in various tissues (busulfan, cyclophosphamide) they can be given orally
What alkylating agent is instantaneously activated upon contact with water?
mechlorethamine
What is the derivative of mechlorethamine that needs to be activated by liver CYP450 enzymes?
cyclophosphamide
Since cyclophosphamide requires the liver enzymes, what effect will induction or inhibition of CYP2B6 have on drug concentration?
It will be the opposite of conventional drug/drug interactions:
induction of the enzymes will increase drug effectiveness
inhibition of the enzymes will decrease drug effectiveness
The final steps of cyclophosphamide activation results in the creation of what active metabolite and what toxic metabolite?
active = phosphoramide mustard toxic = acrolein
What toxicity is associated with the acrolein from cyclophosphamide?
hemorrhagic cystitis
What drugs do you co-administer with cyclophosphamide to counteract the hemorrhagic cystitis? How does it work?
Mesna - it binds to acrolein, inhibiting its toxic effects
What are the therapeutic uses for alkylating agents?
They’re pretty much used for every type of cancer
What are the toxicities common to all cross linking agents?
- moderate to severe myelosuppression
- severe N/V
- strong vesicant properties for the IV meds - when escapes from the vein it’s being injected to
- immunosuppression
- gonadal failure
- carcinogenesis (leukemias esp AML)
- mutagenesis
- teratogenesis
What are two drugs/drug types among the cross linking agents that can be used for brain tumors?
the nitrosoureas: carmustin and lomustine
temozolamide
What’s the specific toxicity of busulfan?
busulfan tan hyperpigmentation, lung and hepatotoxicity
What’s the main therapeutic use of busulfan?
CML
What’s hte main use of melphalan?
multiple myeloma
What’s the main use of dacarbazine?
hodgkin’s
What’s the general mechanism for the anthracycline antibiotics?
they cause intercalation in the major groove DNA, causing several cytotoxic actions including inhibition of topo 2 and causing strand breaks or chromatid exchange
also alters fluidity of membranes and react with CYP450 reductase to form ROS
Are the intercalating agents cell cycle specific or nonspecific?
nonspecific, but maximal toxicity is S phase
How does resistance to the intercalating agents typically arise?
increased P-glycoprotein efflux, leading to MDR
also changes in target proteins (decreased topo 2) and increased inactivation with glutathione peroxidase activity
How are the intercalating agents administered?
IV (so they’re vesicants)
What’s the major toxicity of the intercalating agents?
cardiomyopathy that is often irreversible and related to the total DOSE of the drug (likely from the ROS formed by interaction with cytochrome p450 reductase)
How are the intercalating agents eliminated?
metabolic conversion and biliary excretion - deoendent on liver function
What are the therapeutic uses for intercalating agents?
like the alkylating agents, they’re among the most comonly used antineoplastic agents
Doxorubicin wins the prize for what?
broadest spectrum antineoplastic agent
For the cardiomyopathy that occurs with the intercalating agents, what’s the presentation acutely? chronically?
acutely: increased heart rate, conduciton abnormalities, arrhythmias
chronic: CHF unresponsive to digitalis
Besides the cardiomyopathy, what are the symptoms common to the intercalating agents?
extravasation necrosis - vesicant myelosuppression 4. N/V 5. alopecia 6. mutagenic, carcinogenic 7. radiation recall reaction 8. hand-foot syndrome 9. RED URINE!
What’s the exception to the rule that anthracycline antibiotics cause red urin?
mitoxantone - it turns the urine and whites of eyes blue!
What antibiotic causes DNA strand breaks?
bleomycin
What plant alkaloids cause DNA strand breaks?
etoposide, irinotecan, and topotecan
What alkylating agent will cause DNA strand breaks as a primary mechanism?
procarbazine
Are DNA strand breakers CCS or CCNS?
all are CCS
What machinery is required for the DNA strand breakers to completely kill the cell?
apoptotic machinery - especially p53
Why is bleomycin special and included in so many regimens?
It has a unique mechanism - binds to DNA (not RNA) thorugh it’s amin-terminal peptide and generates free radicals that cut the DNA
it will cause accumulation of cells in G2 that have chromosomal aberrations
How do etoposide, irinotecan and topotecan cause DNA strand breaks?
They inhibit topoisomerase
1 - irinotecan and topotecan, 2 - etoposide
Etoposide causes ___ strand breaks while irinotecan and topotecan cause ___ strand breaks.
etoposide = double strand (topo 2) irinotecan/topotecan = single strand (topo1)
How does resistance develop to bleomycin?
increased inactivation (increased hydrolase activity) or increased DNA repair
How does resistance develop to the topo inhibitors?
- decreased accumulation bia increase in P-glyc
- change in target proteins - mutations in topo 2
- decreased activation of topotecan and iriotecan
What’s the main therapeutic uses for bleomycin?
testicular cancer, lymphomas and squamous cell carcinoma
What are the unique side effects to bleomycin?
hypersensitivity, GI, pulmonary fibrosis, alopecia, edema of hands
Irinotecan and topotecan commonly cause diarrhea - what can you treat the early diarrhea with?
atropine
