Antitumor antibiotics

Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)


Anthracyclines

Anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin) are closely structurally related and have similar mechanisms of action and resistance, but they have different patterns of clinical activity and toxicity.

Pharmacology

The anthracyclines have several effects, and their specific mode of action is unclear.

  • Complexes with DNA by intercalating between DNA base pairs, which interferes with strand elongation; results in inhibition of DNA and RNA synthesis.
  • There are direct effects at the cell surface and also on signal transduction, specifically, activation of protein kinase C-mediated cell signaling pathways. The role of these actions in mediating anthracycline cytotoxicity is undefined.
  • Their ability to undergo reduction to highly reactive compounds and to generate free radicals has clinically important implications. Characteristic cardiotoxicity of anthracyclines appears to be due to generation of free radicals in the heart, where defense systems are less active.
  • The major target of anthracyclines is the enzyme topoisomerase ii. During cell division, topoisomerase ii binds to DNA, forming a “cleavable complex” that makes transient “nicks” in DNA, allowing torsional strain in DNA to be released, after which strands rejoin. Anthracyclines bind to the cleavable complex, disrupting this process, leading to DNA strand breaks and cell death.

Drug resistance

  • Some tumors are inherently resistant to anthracyclines, whereas others initially respond but later become resistant.
  • The MDR1 gene codes for a p-170 glycoprotein (Pgp) that is a naturally occurring cell-surface pump. Its physiological function appears to be a protective mechanism, expelling toxic substances from the cell. Although expression is increased in some human cancers before treatment or at relapse, attempts to manipulate Pgp have had limited success.
  • A second efflux pump associated with expression of multidrug resistance-associated protein (MRP) gene has been implicated in anthracycline resistance in the laboratory.

Toxicity

The dose-limiting acute toxicities are as follows:

  • Myelosuppression and mucositis, both occurring 5 –10 days after treatment.
  • Alopecia occurs but is reversible.
  • Extravasation injury can be severe; dexarazoxane may result in effective treatment.

Cumulative cardiotoxicity is specific to anthracyclines and appears to be caused by accumulation of free radicals in the heart. It typically presents with heart failure, the risk of which is dose related.

At doxorubicin doses below 450 mg/m2, the risk is less than 5% but increases substantially at higher doses. In most cases, this threshold allows a full course of anthracycline to be given without risk. Irradiation of the heart increases risk of cardiotoxicity, as does preexisting cardiac disease. liposomal encapsulation of doxorubicin reduces cardiotoxicity. Epirubicin, daunorubicin, and idarubicin have less effect on the myocardium than doxorubicin.

Doxorubicin

  • Clinical use: Doxorubicin plays a strong role in the management of breast, lung, gastric, and ovarian cancers, Hodgkin’s disease, non-Hodgkin’s lymphoma, sarcoma, myeloma, acute lymphocytic leukemia, and Kaposi’s sarcoma.

Dosing

  • Conventional: 15 –75 mg/m2 per dose
  • Liposomal: 20 –50 mg/m2 every 3 – 4 weeks

Adverse events

  • Bone marrow suppression
  • Nausea and vomiting
  • Tissue necrosis (conventional formulation is a vesicant; liposomal formulation is an irritant)
  • Cardiotoxicity: heart failure (cumulative); arrhythmias
  • Mucositis
  • Alopecia
  • Radiation recall
  • Nail and skin discoloration
  • Urine discoloration
  • Palmar-plantar erythrodysesthesia (hand –foot syndrome) (with liposomal formulation)
  • Anaphylactoid reactions
  • Bronchospasm (with liposomal formulation)
  • Secondary malignancies
  • Impaired fertility

Additional comments

  • The dose should be reduced in patients with hyperbilirubinemia.
  • The incidence of cardiotoxicity increases significantly once a cumulative dose of 450 mg/m2 is reached (for conventional formulation). Risk factors include previous cardiovascular disease, radiation to chest, bolus administration, and age; risk is lower with liposomal formulation.
  • Dexrazoxane may be given to reduce incidence of cardiotoxicity.
  • Substrate of CYP2D6 and 3A4.

Daunorubicin

  • Clinical use: Acute leukemias, Kaposi’s sarcoma

Dosing

  • Conventional: 30 – 60 mg/m2 IV daily for 2–3 days
  • Liposomal: 40 mg/m2 IV every 2 weeks or 100 –140 mg/m2 IV every 3 weeks

Adverse events

  • Bone marrow suppression
  • Nausea and vomiting
  • Tissue necrosis (conventional formulation is a vesicant; liposomal formulation is an irritant)
  • Cardiotoxicity: heart failure (cumulative); arrhythmias
  • Mucositis
  • Alopecia
  • Radiation recall
  • Nail and skin discoloration
  • Urine discoloration
  • Anaphylactoid reactions
  • Secondary malignancies
  • Impaired fertility

Additional comments

  • The dose should be reduced in patients with hyperbilirubinemia or severe renal impairment.
  • The incidence of cardiotoxicity increases significantly once a cumulative dose of 450 mg/m2 is reached (for conventional formulation). Risk factors include previous cardiovascular disease, radiation to the chest, bolus administration, and age; risk is lower with liposomal formulation.
  • Dexrazoxane may be given to reduce the incidence of cardiotoxicity.

Epirubicin

  • Clinical use: breast cancer, bladder cancer, gastric cancer, lung cancer, multiple myeloma, ovarian cancer, head and neck cancer, hepatocellular cancer, soft tissue sarcoma

Dosing

  • 100 mg/m2 IV on day 1 in combination with fluorouracil and cyclophosphamide every 21 days OR
  • 60 mg/m2 IV on days 1 and 8 in combination with oral cyclophosphamide and fluorouracil every 28 days for adjuvant treatment of breast cancer
  • Adjust dose for hepatic impairment
  • Maximum cumulative dose of 900 mg/m2

Adverse event

  • Bone marrow suppression
  • Nausea and vomiting
  • Tissue necrosis (vesicant)
  • Cardiotoxicity: heart failure (cumulative); arrhythmias
  • Mucositis
  • Alopecia
  • Radiation recall
  • Nail and skin discoloration
  • Urine discoloration
  • Anaphylactoid reactions
  • Secondary malignancies
  • Impaired fertility

Additional comments

  • The dose should be reduced in patients with hyperbilirubinemia or severe renal impairment.
  • The incidence of cardiotoxicity increases significantly once a cumulative dose of 900 mg/m2 is reached. Risk factors include previous cardiovascular disease, radiation to the chest, bolus administration, and age.
  • Dexrazoxane may be given to reduce the incidence of cardiotoxicity.

Idarubicin

  • Clinical use: Acute myelogenous leukemia (AMl), acutelymphoblastic leukemia (All), chronic myelogenous leukemia (CMl), myelodysplastic syndrome (MDS), breast cancer, non-Hodgkin’s lymphoma (Nhl)
  • Dosing: 8 –12 mg/m2 IV once daily for 3 days in combination with cytarabine for AMl

Adverse events

  • Bone marrow suppression
  • Nausea and vomiting
  • Tissue necrosis (vesicant)
  • Cardiotoxicity: heart failure (cumulative); arrhythmias
  • Mucositis
  • Alopecia
  • Radiation recall
  • Nail and skin discoloration
  • Urine discoloration
  • Secondary malignancies
  • Impaired fertility

The dose should be reduced in patients with hyperbilirubinemia or severe renal impairment.

Mitoxantrone

Mitoxantrone is a synthetic anthracycline derivative called an anthracenedione. It exhibits less cardiotoxicity than that of classic anthracyclines and is not generally considered to be a vesicant. Mitoxantrone does not form oxygen free radicals, which is a feature that distinguishes this agent from traditional anthracyclines.

  • Clinical indications: Acute myelogenous leukemia, prostate cancer, multiple sclerosis, other leukemias and lymphomas
  • Dosing: 12 mg/m2 IV daily for 3 days in combination with cytarabine (for AMl); reduce dose for hyperbilirubinemia

Adverse events

  • Bone marrow suppression
  • Nausea and vomiting
  • Cardiotoxicity: heart failure (cumulative); arrhythmias
  • Mucositis
  • Alopecia
  • Radiation recall
  • Nail and skin discoloration
  • Injection site reactions, tissue necrosis
  • Anaphylactoid reactions
  • Urine discoloration
  • Conjunctivitis
  • Secondary malignancies
  • Impaired fertility

Additional comments

  • This agent binds to DNA and interacts with topoisomerase ii but appears less potent in generating free radicals. It is also a substrate for Pgp.
  • The main clinical use of mitoxantrone has been as an alternative to doxorubicin in advanced breast cancer, because it is substantially less cardiotoxic and less vesicant, and causes less alopecia.
  • However, mitoxantrone is less effective than doxorubicin. It has some activity against other solid tumors, including non-Hodgkin’s lymphoma and nonlymphocytic leukemia.

Dactinomycin (actinomycin D)

  • Clinical use: Testicular cancer, melanoma, choriocarcinoma, Wilm’s tumor, neuroblastoma, retinoblastoma, sarcomas
  • Dosing: 500 µg IV daily for a maximum of 5 days (should not exceed 15 µg/kg per day or 400 – 600 µg/m2 per day for 5 days in adults)

Adverse events

  • Bone marrow suppression
  • Nausea and vomiting (severe)
  • Fatigue, malaise, fever
  • Mucositis
  • Hepatotoxicity
  • Hypocalcemia
  • Alopecia
  • Radiation recall
  • Tissue necrosis (vesicant)
  • Anaphylactoid reactions
  • Secondary malignancies
  • Impaired fertility

Additional comments

  • Actinomycin D binds strongly to DNA by intercalation and inhibits synthesis of RNA and proteins. It also appears to be a substrate for the Pgp pump. It is especially active against childhood tumors.

Mitomycin C

Mitomycin acts as an alkylating agent and has proper ties similar to other antitumor antibiotics

  • Clinical use: Adenocarcinoma of the stomach or pancreas, bladder cancer, colorectal cancer, and as a radiation sensitizer
  • Dosing: 10 mg/m2 IV (combination therapy) or 20 mg/m2 IV (single-agent therapy) every 6 – 8 weeks. Adjust dose in renal impairment; may be administered intravesicularly for bladder cancer

Adverse events

  • Bone marrow suppression (delayed and cumulative)
  • Nausea and vomiting
  • Tissue necrosis (vesicant)
  • Cardiotoxicity: heart failure (higher doses)
  • Fever
  • Mucositis
  • Alopecia
  • Radiation recall
  • Nail banding and discoloration
  • Paresthesias
  • Interstitial pneumonitis
  • Secondary malignancies
  • Impaired fertility
  • Hemolytic-uremic syndrome (rare)
  • Renal failure (rare)

Additional comments

  • Mitomycin C (MMC) is active against a range of solid tumors but is also used as a radiosensitizer in chemoirradiation.
  • Mitomycin C is used in combination with other cytotoxics to treat breast cancer, non-small– cell lung cancer, and GI cancer.
  • It is used as a radiosensitizer in the treatment of anal cancer.
  • The most important toxicity of mitomycin C is myelosuppression, especially thrombocytopenia, which is delayed and can be cumulative. Accordingly, it is given systemically every 6 weeks, in contrast to the 3-weekly schedules usually used for other antitumor antibiotics.
  • Hemolytic-uremic syndrome, pulmonary fibrosis, and cardiac complications are all uncommon side effects.
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