DNA-Damaging Agents

PHAR 7361

Chlorambucil (Leukeran)

Is a Nitrogen Mustard

oral absorption is adequate and reliable, though food decreases absorption

myelosuppressive effects are typically moderate, gradual and rapid reversible

carries a risk for developing secondary malignancies

Melphalan (Alkeran)

Is a Nitrogen Mustard

Is orally available, but absorption can be erratic

Melphalan hydrochloride is available for Iv administration

myelosuppression is a the major toxicity and similar to other mustard

Bendamustine (treanda)

Is a nitrogen Mustard

Given as a 30 minute IV infusion

• DNA damage is more extensive and less repairable than that observed with other nitrogen mustards

• Toxicity typical of DNA alkylating agents (myelosuppression and mucositis)

• Hypersensitivity/anaphylaxis and skin reactions have been noted; pretreatment with antihistamines and corticosteroids can help

Cyclophosphamide (cytoxan)

Is a Nitrogen Mustard

Administered either orally or IV

• Maximal concentrations in plasma are achieved approximately one hour post oral dose and plasma half-life is ~ 7 hours

• Metabolic activation is required for its alkylation activity and hepatic metabolism contributes to kidney and bladder toxicity

• Less effects on peripheral blood platelet counts and less mucosal damage than other DNA alkylating agents

Ifosfamide (ifex)

Is a Nitrogen Mustard

Bioactivation pathway similar to CP; however, N- dealkylation is a significant (~60%) metabolic pathway for ifosfamide (IFO)

• Increased chloroacetaldehyde leads to increased bladder toxicity and nephrotoxicity

• Adequate hydration can help reduce bladder toxicity

• Chloroacetaldehyde also contributes to neurotoxicity (mental status dysfunction, seizures, coma)— IFO is the most neurotoxic of the DNA alkylating agents

Mesna (Mesnex)

Acrolein is primarily formed in the liver and rapidly conjugated with glutathione (GSH)

• Delivery of the acrolein‒GSH conjugate to the bladder for excretion causes toxicity due to a variety of mechanisms

• Results include severe hemorrhage, sclerosis, induction of bladder cancer

• Acrolein also damages nephrons, especially in high doses, children, patients with one kidney, and those taking other nephrotoxic agents

• Mesna is employed as adjuvant or prophylactic therapy with IFO and high dose CP

Busulfan (Myleran, Busulfex)

Busulfan is the (bis)methylsulfonate ester of 1,4-butanediol

• One or both of the methylsulfonate esters can be displaced by the nucleophilic N7 of guanine, leading to monoalkylated and cross-linked DNA

• Busulfan can be administered either orally or IV

• With high doses, children clear the drug 2-4 times faster than adults

• Used in high-dose chemotherapy prior to stem cell transplant

• Can cause severe and prolonged pancytopenia, with recovery taking up to two years

• Pulmonary toxicity is a risk at high doses

Carmustine and Lomustine

Carmustine and lomustine are highly lipophilic nitrosoureas that cross the blood-brain

barrier → used in the treatment of a variety of brain tumors, but can cause CNS toxicity

at higher doses

These DNA methylating agents react with the O6 of guanine nucleobases

• Both dacarbazine and temozolomide (TMZ) form MTIC, the precursor to diazomethane (the methylating agent)

• Dacarbazine requires metabolic demethylation by CYP1A1 or CYP1A2 to generate MTIC

• Temozolomide generates MTIC via simple non-enzymatic hydrolysis

MGMT expression is associated with resistance to these agents

Darcarbazine (DTIC)

is a DNA-methylating Agent

Temozolomide (Temodar)

is a DNA-methylating Agent

Females clear the drug less effectively than males and have a higher incidence of neutropenia and thrombocytopenia

food decreases absorption

Procarbazine (Matulane)

Is a DNA-methylating Agent

Procarbazine is a hydrazine-containing molecule that is metabolically converted to diazomethane, which reacts with the O6 of guanine nucleobases

• MGMT expression is associated with resistance to this agent

rocarbazine is also a weak MAO inhibitor and blocks the metabolism of catecholamines →

Avoid tyramine-rich foods to prevent hypertensive crisis

Cisplatin

Cisplatin (and other platinum agents) react with aluminum and must not come into contact with

aluminum-containing infusion equipment

• It is photosensitive and packaged in amber bottles—must be protected from light. Elimination is primarily via the kidneys, but it is highly nephrotoxic, causing significant damage to the renal tubules

• Aggressive hydration with chloride-containing solutions prior to treatment can be used to help establish a chloride diuresis and mitigate renal toxicity

Co-administration of antiemetic therapy is almost always required to prevent nausea and vomiting

• Cisplatin causes mild to moderate, but transient myelosuppression. Electrolyte disturbances are common → routine measurement of plasma Mg2+ is recommended

Cisplatin can cause irreversible ototoxicity and is manifested by tinnitus and high-frequency hearing loss—more frequent and severe with repeated doses

• Treatment with amifostine (Ethyol®) is used to reduce renal toxicity, but its use for reducing ototoxicity is controversial

Carboplatin (paraplatin)

The mechanism of action of carboplatin is similar to cisplatin; however, formation of the cytotoxic hydrated intermediate is slower

Because carboplatin is less reactive, the majority of the drug in plasma remains in its parent form unbound to proteins

Side effect profile of carboplatin is significantly milder compared to cisplatin

Oxaliplatin (Eloxatin)

The DNA adduct formed through oxaliplatin treatment is different than that formed by cisplatin or carboplatin and results in different conformational changes

The conformation of the oxaliplatin–DNA adduct is much less likely to be recognized by MMR proteins, which is a mechanism of resistance for cisplatin and carboplatin

Oxaliplatin is also less dependent on CTR1 for intracellular access and often retains activity in patients who have stopped responding to other platinum agents

Oxaliplatin suppresses expression of thymidylate synthase (TS), the target of 5-FU, and is used in combination with 5-FU for the treatment of colon and rectal cancer

Dose-limiting toxicity is peripheral neuropathy, and an acute form is thought to be related to oxalate-based chelation of intracellular Ca2+ and/or Mg2+ → Acute neuropathy can be attenuated through infusion of Ca2+ or Mg2+ salts

Bleomycin (blenoxane)

Bleomycin hydrase is found in all tissues except skin and lung

Bleomycin—Fe2+ complex reacts with molecular oxygen to form a bleomycin ferric peroxide complex, which is the cytotoxic agent

The bleomycin ferric peroxide abstracts a hydrogen atom from deoxyribose to form a DNA free radical

The DNA free radical is unstable, and its formation initiates a cascade of events that leads to DNA strand breaks

5-10% of patients will experience potentially fatal pulmonary fibrosis, which can occur as late as several months after therapy has ceased

• Risk for pulmonary toxicity is related to total dose, and risk is enhanced in patients > 40-years-old

irinotecan

Pro-drug that is converted to its active metabolite SN-38 by hepatic carboxyl esterases

Conjugation of SN-38 by UGT1A1 at C10 yields an inactive metabolite

Polymorphisms in UGT1A1 may account for life-threatening toxicity— more prevalent in patients of Asian heritage

Dose-limiting toxicity is delayed diarrhea, which can be fatal if left untreated—vigorous loperamide therapy should be initiated immediately

Acute diarrhea is attributed to the drug’s anticholinesterase activity and is accompanied by “cholinergic syndrome”—these effects are short lived and can be treated with atropine

• Neutropenia is also a frequent side effect

• Antiemetic therapy should be given at least 30 minutes prior to administration of irinotecan

Camptothecin

Modifications at C10 (irinotecan) and C9 (topotecan) incorporate basic amines that permit salt formation and enhance solubility

Irinotecan and topotecan share camptothecin’s fused five-ring backbone and tertiary alcohol chiral center on lactone ring E, both of which are essential for activity

Etoposide

highly water insoluble and require solubility enhancers (e.g., polysorbate 80, polyoxyethylated castor oil) for IV dosing that can cause hypersensitivity reactions

CYP3A4 catalyzes O-demethylation

• Catechol metabolite oxidizes to a reactive orthoquinone metabolite

• Orthoquinone metabolite may be linked to therapy-induced leukemia in children

• CYP3A4 inducers and inhibitors have significant impacts on metabolism and represent a DDI risk

Serious side effects have been noted in children with acute lymphoblastic leukemia (ALL) treated with etoposide

• 2-12% of patients treated for childhood ALL develop acute myeloid leukemia

(AML) ~ 2 years after etoposide therapy

• Therapy-induced AML is thought to be related to a drug-induced chromosomal

translocation

Doxorubicin

Aldoketoreductase catalyzes the reduction of the C13 ketone to produce a secondary alcohol

metabolite linked to cardiotoxicity

Anthracyclines form semiquinone radical intermediates that react with oxygen to form superoxide anion radicals, which generate hydrogen peroxide (H2O2)

In the presence of Fe2+, H2O2 is converted to the highly toxic hydroxyl radical (•OH)

Anthracyclines are potent iron binders, and cardiac tissue has low levels of defensive enzymes to combat oxygen radicals

The iron-chelating drug dexrazoxane (Zinecard®) is used as a cardio-protective agent

Cardiomyopathy is the most important toxicity associated with doxorubicin and is found in both acute and chronic forms

The highly conjugated structure imparts a red-orange color to the drug, and patients should be warned that reddish urine is normal

Mitoxantrone

Mitoxantrone has limited ability to form semiquinone radicals and lacks the C13 ketone found in the anthracyclines, thus, it is less cardiotoxic than the anthracycline topoisomerase II inhibitors

Conjugated metabolites of the drug are blue and lead to blue-green feces and urine, and in some cases impart a bluish color to the skin and sclera

Arsenic Trioxide (Trisenox)

Arsenic trioxide (As2O3) is a heavy metal that is used for treating acute promyelocytic leukemia (APL), a cancer characterized by the reciprocal translocation of chromosomes 15 and 17

• Arsenic trioxide induces remission in APL through destruction of the fusion protein and induction of apoptosis in malignant cells

Antiemetics are used to control nausea and vomiting caused by As2O

Simultaneous treatment with other drugs that cause QT-prolongation should be avoided and serum electrolytes (especially Mg2+ and K+) should be monitored