Drugs that Disrupt DNA Flashcards
What groups do drugs that disrupt DNA fall into?
- Crosslinking agents (alkylating agents & misc. others)
- Intercalating agents (esp. anthracycline antibiotics)
- Drugs that cause Strand Breaks/Prevent Replication
- -These drugs fall into several chemical classes including alkylating agents, natural products (antibiotics and plant alkaloids) and misc. drugs.
What is hemorrhagic cystitis (toxicity) unique to?
Cyclophosphamide
What chemical class of agents is associated with cardiomyopathy?
Anthracycline antibiotics (doxorubicin)
What do most drugs that disrupt DNA cause (side effects)?
-Bone marrow suppression
-Gastritis
-Alopecia
(bc these drugs target rapidly dividing cells)
Are cross linking agents CCS?
NO - CCNS - reactions that initiate cell death can occur at any time but primary toxicity occurs at late G1 and S phase
-However, they are dependent upon proliferation
Which alkylating agents are converted to a strong electrophile fast?
MECHLORETHAMINE - virtually instantaneous
-Given IV to minimize blistering and GI effects
What alkylating agents are converted to a strong electrophile slowly?
BUSULFAN, CYCLOPHOSPHAMIDE, IFOSFAMIDE, MELPHALAN
- Must be activated in the liver and other tissues
- Can be given orally!
What is the anthracycline antibiotic?
Doxorubicin!
What is important about doxorubicin?
- CCNS drug
- Intercalates DNA
- Major toxicity is unusual cardiomyopathy that is often irreversible and related to the total dose of the drug
What is important about Bleomycin?
- Unique MOA and spectrum of toxicities
- Included in many combination therapies
- Generates free radicals that cut through DNA strands
- Does not cause significant myelosuppression (unlike other drugs)
- It does cause skin and lung damage – because those tissues do not have the enzyme (hydrolase) required to metabolize BLEOMYCIN.
What are the three functional grouping of drugs that disrupt DNA?
- Drugs that crosslink DNA (esp. alkylating agents)
- includes alkylating agents, natural products (antibiotics) and misc. - Drugs that intercalate and form adducts with DNA
- natural products (esp. anthracycline antibiotics) - Drugs that cause strand breaks
- natural products (antibiotics and plant alkaloids) and misc.
What are the three chemical types of cross-linking agents?
- Alkylating agents
- Antibiotics
- Misc.
What are the two groups of alkylating agents?
- Nitrogen mustards
2. Nitrosoureas
What are the nitrogen mustards we need to know?
(discovered due to bone marrow suppression seeing soldiers after being exposed to mustard gas)
-Chlorambucil, Cyclophosphamide, Ifosfamide, Mechlorethamine (not used much anymore - often causes cancer), Melphalan
What are the nitrosoureas you need to know?
Carmustine (BCNU), Lomustine (CCNU)
What antibiotic cross-linker should you know?
Mitomycin
What misc. cross linkers should you know?
Carboplatin, cisplatin, oxaloplatin, BUSULFAN, DACARBAZINE, PROCARBAZINE, TEMOZOLAMIDE
What is the mechanism for alkylating agents?
- Drug activation
- N7 guanine - Neutrophilic attack
- DNA Damage
How are alkylating agents selectively toxic?
- 50% of human cancers have a mutation in p53, so the cancer cells can’t stop the cell cycle, accumulate errors and this leads to cell death
- Normal cells will be able to stop the cell cycle
What are common resistance mechanisms to alkylating agents?
- Inc. DNA repair (Inc. expression of guanine 06 alkyl transferase)
- Inc. glutathione production (trapping agent)
- Oral = Dec. activation
How is cyclophosphamide activated?
- Derivative of mechlorethamine that must be activated by LIVER CYP450 enzymes as the first step in a multistep activation process
- Induction/inhibition of CYP2B6 by other drugs will have the opposite effect on CYCLOPHOSPHAMIDE than conventional drug/drug interactions (induction of the enzyme increases activity)
How is mechlorethamine activated?
Immediate activation upon H2O exposure!!
What are the most common cross linking agents used?
- Cyclophosphamide
- Cisplatin
- Subtyping cancer to identify the best drug is common!
What are common toxicities of cross linking agents?
- Cytotoxic side effects
- Particularly strong nausea & vomiting - esp. Mechlorethamine & Cisplatin! - Vesicant – will cause blistering (Dec. oral agents)
- Mutagenic, Carcinogenic (AML especially), Teratogenic
What cross linking agents are taken orally?
- Cyclophosphamide, Ifosfamide
- Busulfan
- Melphalan
- Chlorambucil
What cross linking drug methylates DNA?
Temozolomide (TMZ)
What cross linking drugs are lipid soluble (cross BBB)?
Temozolomide (TMZ), Nitrosoureas (Carmustine, Lomustine)
What cross linking agent causes a tan appearance?
Busulfan-tan!
What cross linking agent causes nausea (emetic), oto and renal toxicity?
Cisplatin, Carboplatin, oxaloplatin
What cross linking drug causes hemorrhagic cystitis?
Cyclophosphamide, Ifosfamide
What crossing linking drug is a vesicant and emetic?
nausea & burning (must be IV)
-Mechlorethamine
What are the intercalating agents?
Anthracycline Antibiotics: Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantone
What are antrhacycline antibiotics important in treating?
Breast cancer!!
When is doxorubicin most toxic?
Its CCNS but its most toxic during S phase!
How does resistance develop to antracycline antibiotics?
- Inc. accumulation due to Inc. P-glycoprotein expression
- Dec. Topo II activity (temporarily)
- Inc. inactivation
What is the pharmacokinetics of intercalating agents?
- Given IV (vesicant)
- Metabolized in the liver –> excreted in the bile!
What is the most commonly used antineoplastic?
DOXORUBICIN!! = Adriamycin
-Athracycline antibiotics = 1st line treatment for breast cancer
What toxicity is associated with intercalating agents?
- Cytotoxic (bone marrow suppression)
- Unusual cardiomyopathy (causes you to stop a drug & start a different one)
- Damage DNA
- Radiation Recall Reaction
- Red urine (not blood though)
What is the reason you stop and give a break in intercalating agents?
Bone marrow suppression (cytotoxic)
-You stop and let normal cells recover for a bit and then you restart!
What causes the unusual cardiomyopathy?
- Often irreversible
- Related to total dose in lifetime
- Acute: Inc. HR, arrhythmia
- Delayed: CHF (congestive heart failure) years after treatment stopped - unresponsive to standard treatment (digitalis)
What does mitoxantone cause?
-Blue urine, turns fingernails & sclera of the eyes blue
What is “radiation recall reaction”?
Erythema and desquamation of the skin at sites of prior radiation therapy
What do all drugs that cause strand breaks and prevent DNA replication have in common?
-All are CCS - work in G2/M
What antibiotic causes strand breaks and/or prevents DNA Replication?
Bleomycin
What plant alkaloids cause strand breaks and/or prevent DNA Replication?
- Etoposide (epipodophyllotoxin)
- Irinotecan
- Topotecan (camptothecins)
What are the misc drugs that cause strand breaks and/or prevent DNA Replication?
Procarbazine (alkylating agent!)
What does bleomycin do to DNA?
BLEOMYCIN BLASTS!
- Binds to DNA
- Generates free radicals
- Cuts DNA into pieces
- Cells accumulate in G2 and die
What do the MOA for drugs that cause strand breaks and/or prevent DNA replication require?
Apoptic machinery –> i.e. where p53 is NOT mutated
What does Etoposide target?
It’s a Topoisomerase II inhibitor (more effective drug!)
- -More specific for rapidly dividing cells
- -Harder to repair
What does Irinotecan and Topotecan target?
It’s a Topoisomerase I inhibitor
What are the -TECANS (IRINO and TOPO) metabolized?
In the liver. They are also activated here!!
What is the mechanisms of Procarbazine?
Alkylating
-More effects on RNA & protein synthesis than others and more strand breaks
How is resistance developed against Bleomycin?
- Inc. DNA repair
2. Inc. Inactivation (HYDROLASE - skin & lungs –> side effects)
How has resistance developed against Etoposide?
- Inc. P-glycoprotein => MDR
2. Dec. activation
How has resistance developed against Irinotecan/Topotecan?
- Inc. P-glycoprotein => MDR
2. Dec. activation
What is Bleomycin’s therapeutic use?
-In combination (unique mechanism of action)
What is Irinotecan/Topotecan’s therapeutic use/
Metastatic colon cancer
What’s unique about the toxicity of drugs that cause strand breaks and/or prevent DNA replication?
(topoisomerase inhibitors)
-Less cytotoxic side effects!
What toxicity develops with Bleomycin?
- Skin & lung damage (no hydrolase)
- Hypersensitivity reactions
- Edema
What toxicity develops with Etoposide?
Cardiovascular - CV (hypotension)
What toxicity develops with Irinotecan/Topotecan?
- Excreted in the Bile
—> causes severe diarrhea
A) Acute phase: cholinergic –> treat with atropine
B) Late phase: dehydration, electrolyte imbalances => opiates (Loperamide)
