Antitumor Antibiotics

Antitumor antibiotics, also known as antineoplastic antibiotics, are the product of soil microbes, Streptomyces bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview. The commonly used types of antitumor antibiotics—bleomycin, dactinomycin, and anthracyclines—have a wide spectrum of activity against hematologic malignancies and solid tumors. Bleomycin differs from the rest of the drugs owing to its cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle–specific action during the G2 phase. Mechanisms of actions of these drugs include free radical damage to DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure, topoisomerase II inhibition, binding of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure via intercalation, and alteration of cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane fluidity and transport of ions. Important adverse effects include cardiotoxicity (acute and chronic) and myelosuppression.

Last update:

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Overview

Antitumor antibiotics, agents isolated from strains of Streptomyces, are used for cancer treatment owing to their ability to interfere with DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and/or RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure synthesis, thus leading to cancer cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death. The effects of these drugs are too toxic for use in bacterial infections.

Agents within this class include:

  • Cell cycle–specific: bleomycin
  • Cell cycle–nonspecific:
    • Dactinomycin
    • Mitomycin
    • Anthracyclines

Bleomycin

Description

  • Cell cycle–specific drug that acts on the G2 phase of the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle
  • Mechanism of action: 
    • Contains a DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure-binding site and an iron-binding site → binds DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure, forming a complex ( DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure–bleomycin–Fe(II)) 
    • Effect: DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure double- and single-stranded breaks
  • Pharmacokinetics:
    • IV, IM, SC, intrapleural
    • Metabolism: inactivated enzymatically by bleomycin hydrolase (not found in significant amounts in skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin and lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs)
    • Half-life: 2 hours (IV)
    • Excretion: renal 
  • Indications (labeled): 
    • Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma
    • Head and neck cancer
    • Testicular cancer Testicular cancer Testicular cancer is the most common solid malignancy affecting men 15-35 years of age. Most of the testicular cancers are of the germ cell tumor type, and they can be classified as seminomas and nonseminomas. The most common presentation of testicular cancer is a painless testicular mass. Testicular Cancer
    • Malignant pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion (sclerosing agent)
Structure of bleomycin

Structure of bleomycin

Image: “Bleomycin A2” by Yikrazuul. License: Public Domain

Adverse effects

  • Pulmonary toxicity presenting as pneumonitis:
    • Most severe toxicity
    • May lead to pulmonary fibrosis Pulmonary Fibrosis Idiopathic pulmonary fibrosis is a specific entity of the major idiopathic interstitial pneumonia classification of interstitial lung diseases. As implied by the name, the exact causes are poorly understood. Patients often present in the moderate to advanced stage with progressive dyspnea and nonproductive cough. Pulmonary Fibrosis
  • Hepatotoxicity
  • Renal toxicity
  • Idiosyncratic reaction (↓ blood pressure, wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, chills)
  • Dermatologic: 
    • Rash
    • Hyperpigmentation
    • Alopecia Alopecia Alopecia is the loss of hair in areas anywhere on the body where hair normally grows. Alopecia may be defined as scarring or non-scarring, localized or diffuse, congenital or acquired, reversible or permanent, or confined to the scalp or universal; however, alopecia is usually classified using the 1st 3 factors. Alopecia

Contraindications and drug interactions

  • Contraindications: 
    • Hypersensitivity to the drug
    • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care (1st trimester)
  • If there are pulmonary changes, treatment should be withheld and relation to bleomycin should be investigated.
  • Dose adjustment in impaired renal function
  • Drug interactions (↑ pulmonary toxicity of bleomycin):
    • Brentuximab
    • Gemcitabine
    • Granulocyte colony-stimulating factors
    • Oxygen

Dactinomycin

Description

  • Dactinomycin (actinomycin D)
  • Chromopeptide from Streptomyces
  • Mechanism of action: 
    • Forms a bond with DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure, intercalating between base pairs (cytosine and guanine)
    • Prevents the activity of RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure polymerase, blocking transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure
    • Also produces single-stranded breaks in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure
  • Pharmacokinetics:
    • IV
    • Does not cross blood–brain barrier
    • Minimal metabolism
    • Half-life: 36 hours
    • Excretion: urine and feces, 30%
  • Indications (labeled):
    • Solid tumors
    • Wilms tumor Wilms tumor Wilms tumor is a malignancy caused by proliferation of metanephric blastema in the kidneys and is the most common renal malignancy in children. Wilms tumor usually arises sporadically, but it can also occur as a result of a specific congenital anomaly like WAGR syndrome, Denys-Drash syndrome, or Beckwith-Wiedemann syndrome. Wilms tumor commonly presents as a firm, nontender, smooth mass that does not cross the midline. Wilms Tumor
    • Ewing sarcoma Ewing Sarcoma Ewing sarcoma (ES) is a primary bone malignancy derived from primitive round cells affecting primarily children and teenagers. Ewing sarcoma commonly presents with a painful mass, swelling, and pathologic bone fractures. Ewing Sarcoma
    • Gestational trophoblastic neoplasia
    • Rhabdomyosarcoma
Structure of dactinomycin

Structure of dactinomycin

Image: “Actinomycin D” by Edgar181. License: Public Domain

Adverse effects

  • Myelosuppression
  • Mucocutaneous toxicity (such as Stevens-Johnson syndrome Stevens-Johnson syndrome Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome, toxic epidural necrolysis)
  • Hepatotoxicity (such as ↑ bilirubin, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes)
  • Nephrotoxicity
  • GI toxicity: nausea, vomiting, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Extravasation (causes local tissue damage)
  • Secondary malignancy (such as leukemia)

Contraindications and drug interactions

  • Avoid live vaccines before and during dactinomycin treatment.
  • Dactinomycin:
    • ↑ Toxicity when combined with radiation therapy
    • ↓ Effects of inactivated and live vaccines
    • ↑ Toxic effects of live vaccines

Mitomycin

Description

  • Mitomycin: isolated from Streptomyces caespitosus
  • Mitomycin is activated into mitosene.
  • Mechanism of action:
    • Mitosene alkylates DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure cross links DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure
    • Prevents DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure synthesis
  • Pharmacokinetics:
    • Metabolism: liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
    • Half-life: < 1 hour
    • Excretion: mainly in feces (some through renal excretion)
  • Indications:
    • Gastric cancer Gastric cancer Gastric cancer is the 3rd-most common cause of cancer-related deaths worldwide. The majority of cases are from adenocarcinoma. The modifiable risk factors include Helicobacter pylori infection, smoking, and nitrate-rich diets. Gastric Cancer
    • Pancreatic cancer
    • Off-label: anal cancer Anal cancer Anal cancer accounts for 2.7% of all gastrointestinal tract cancers. Squamous cell carcinoma is the most common type of anal cancer. The patient can present with rectal bleeding (most common), change in bowel habits, perianal pruritic mass, or perianal painful ulceration. Anal Cancer, bladder cancer, esophageal cancer Esophageal cancer Esophageal cancer is 1 of the most common causes of cancer-related deaths worldwide. Nearly all esophageal cancers are either adenocarcinoma (commonly affecting the distal esophagus) or squamous cell carcinoma (affecting the proximal two-thirds of the esophagus). Esophageal Cancer, cervical cancer Cervical cancer Cervical cancer, or invasive cervical carcinoma (ICC), is the 3rd most common cancer in women in the world, with > 50% of the cases being fatal. In the United States, ICC is the 13th most common cancer and the cause of < 3% of all cancer deaths due to the slow progression of precursor lesions and, more importantly, effective cancer screening. Cervical Cancer, vulvar cancer Vulvar cancer There are multiple different types of malignancies that can affect the vulva. The most common histologic type is squamous cell carcinoma (SCC), which accounts for approximately 75%-85% of all vulvar cancers. Vulvar Cancer
Structure of mitomycin

Structure of mitomycin

Image: “Mitomycin” by Fvasconcellos. License: Public Domain

Adverse effects

  • Myelosuppression
  • Myocardial toxicity (heart failure)
  • Hemolytic uremic syndrome and renal failure
  • Bladder fibrosis (with intravesical administration)
  • Pulmonary toxicity
  • GI toxicity: nausea, vomiting, mucositis
  • Extravasation

Contraindications and drug interactions

  • Contraindications:
    • Hypersensitivity
    • Bleeding tendency
    • Discontinue medication with significant organ toxicity
  • Drug interactions:
    • Concurrent vinca alkaloid treatment can cause bronchospasm.
    • ↓ Effects of inactivated and live vaccines
    • ↑ Toxic effects of live vaccines

Anthracyclines

Description

  • Anthracyclines or anthracycline antibiotics are derived from Streptomyces peucetius var. caesius.
  • Chemotherapy agents frequently used for different types of cancers (hematologic cancers and solid tumors)
  • Mechanisms of action:
    • Inhibit topoisomerase II and impede DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure repair
    • Form oxygen free radicals, which bind to single- and double-stranded DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure → cause damage
    • Intercalate with DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure to block transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription and replication
    • Bind to cellular membranes and alter ion transport
  • Pharmacokinetics:
    • IV
    • Metabolism: liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver via hydrolysis of the anthracycline ring
    • Elimination: mostly in feces through biliary excretion
  • Indications:
    • Doxorubicin:
      • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
      • Ovarian cancer Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). Ovarian Cancer 
      • ALL, AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia
      • Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma, non- Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma
      • Bladder cancer
      • Bone sarcoma, soft tissue sarcoma
      • Bronchogenic carcinoma
      • Gastric cancer Gastric cancer Gastric cancer is the 3rd-most common cause of cancer-related deaths worldwide. The majority of cases are from adenocarcinoma. The modifiable risk factors include Helicobacter pylori infection, smoking, and nitrate-rich diets. Gastric Cancer
      • Neuroblastoma Neuroblastoma Neuroblastoma is a malignancy that arises from the neural crest cell derivatives along the sympathetic chain (neuroblasts) and is most commonly located in the adrenal medulla. The tumor often presents in childhood with a flank mass that crosses the midline. Neuroblastoma
      • Thyroid carcinoma
      • Wilms tumor Wilms tumor Wilms tumor is a malignancy caused by proliferation of metanephric blastema in the kidneys and is the most common renal malignancy in children. Wilms tumor usually arises sporadically, but it can also occur as a result of a specific congenital anomaly like WAGR syndrome, Denys-Drash syndrome, or Beckwith-Wiedemann syndrome. Wilms tumor commonly presents as a firm, nontender, smooth mass that does not cross the midline. Wilms Tumor
    • Daunorubicin:
      • ALL
      • AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia
    • Idarubicin: AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia
    • Epirubicin: breast cancer
    • Mitoxantrone:
      • Advanced prostate cancer Prostate cancer Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. Prostate Cancer 
      • AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia
      • Multiple sclerosis Multiple Sclerosis Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease that leads to demyelination of the nerves in the CNS. Young women are more predominantly affected by this most common demyelinating condition. Multiple Sclerosis
Structure of doxorubicin

Structure of doxorubicin

Image: “Doxorubicin2” by NEUROtiker. License: Public Domain

Adverse effects

  • Cardiotoxicity:
    • Acute: ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) disturbances, pericarditis Pericarditis Pericarditis is an inflammation of the pericardium, often with fluid accumulation. It can be caused by infection (often viral), myocardial infarction, drugs, malignancies, metabolic disorders, autoimmune disorders, or trauma. Acute, subacute, and chronic forms exist. Pericarditis, myocarditis Myocarditis Myocarditis is an inflammatory disease of the myocardium, which may occur alone or in association with a systemic process. There are numerous etiologies of myocarditis, but all lead to inflammation and myocyte injury, most often leading to signs and symptoms of heart failure. Myocarditis, elevated troponin level
    • Chronic: 
      • Dilated cardiomyopathy Dilated Cardiomyopathy Dilated cardiomyopathy (DCM) is the most common type of non-ischemic cardiomyopathy and a common cause of heart failure (HF). The cause may be idiopathic, familial, or secondary to a variety of underlying conditions. The disease is characterized by the enlargement of 1 or both ventricles and reduced systolic function. Dilated Cardiomyopathy (dose-dependent) leading to congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure
      • Results from free oxygen radicals damaging the myocardium
      • Dexrazoxane: given to prevent anthracycline-induced cardiotoxicity (metastatic breast cancer) 
    • Liposomal formulations of anthracyclines have reduced incidence of cardiotoxicity.
  • Myelosuppression
  • Secondary malignancy
  • Hepatic impairment
  • Extravasation
  • Radiation recall: Erythema and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin desquamation can develop in areas treated with radiation. 
  • Tumor lysis syndrome Tumor lysis syndrome Tumor lysis syndrome is a potentially lethal group of metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly. The lysed cells release their intracellular contents into the bloodstream, resulting in the development of hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. Tumor Lysis Syndrome
  • Mucositis

Contraindications and drug interactions

  • Contraindications:
    • Hypersensitivity to the medication
    • Impaired cardiac function or severe cardiac disease or arrhythmia
    • Impaired liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver function
    • Severe myelosuppression
    • Active infection 
  • Drug interactions (particularly doxorubicin):
    • The following ↑ risk of cardiotoxicity:
      • Trastuzumab
      • Taxanes
      • Cyclophosphamide
    • ↓ Effects of inactivated and live vaccines
    • ↑ Toxic effects of live vaccines

Comparison with other chemotherapeutic agents

Various chemotherapy drugs and their effects on the cell cycle

Various chemotherapy drugs and their effects on the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle

Image by Lecturio.
Table: Comparison of the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle–independent chemotherapy drugs
Drug class Mechanism
Antitumor antibiotics:
  • Dactinomycin
  • Mitomycin
Intercalate between bases, leading to blockage of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure or RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure synthesis and prevention of DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication
Anthracyclines
  • Inhibition of topoisomerase II
  • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure intercalation, leading to DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure inhibition
  • Promote reactive oxygen species formation
Alkylating agents
  • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis due to alkylation of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure
  • DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication, protein synthesis
Table: Comparison of the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle–dependent chemotherapy drugs
Drug class Cell cycle phase affected Mechanism of action
Antifolates Cell cycle arrest at S phase Inhibit:
  • Dihydrofolate reductase
  • Thymidylate synthase
Bleomycin Cell cycle arrest at G2 phase Binds DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure, leading to single- and double-stranded breaks
Fluoropyrimidines Cell cycle arrest at S phase Inhibit thymidylate synthase
Deoxycytidine analogs Cell cycle arrest at S phase Inhibit:
  • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase
  • Ribonucleotide reductase
Purine analogs Cell cycle arrest at S phase Inhibition of de novo purine synthesis
Topoisomerase II inhibitors Cell cycle arrest at S and G2 phases Inhibit topoisomerase II
Taxanes Cell cycle arrest at metaphase of the M phase Hyperstabilization of microtubules
Vinca alkaloids Cell arrest during metaphase of the M phase Binds to beta-tubulin and prevents microtubule polymerization

References

  1. Chu E. (2021). Cancer chemotherapy. Chapter 54 in Katzung B. G., Vanderah T. W. (Eds.),  Basic & Clinical Pharmacology, 15th ed. McGraw-Hill. Retrieved September 22, 2021, from https://accessmedicine.mhmedical.com/content.aspx?bookid=2988&sectionid=250603422
  2. Gao, Y., Shang, Q., Li, W., et al. (2020) Antibiotics for cancer treatment: a double-edged sword. J Cancer 11, pp. 5135–5149. Retrieved September 22, 2021, from doi:10.7150/jca.47470
  3. Hollingshead, L.M., Faulds, D. (1991) Idarubicin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the chemotherapy of cancer. Drugs 42, pp. 690–719. Retrieved September 22, 2021, from doi.org/10.2165/00003495-199142040-00010
  4. Johnson-Arbor, K., Dubey, R. (2021) Doxorubicin. StatPearls. Retrieved September 22, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK459232/
  5. Saleem, T., Kasi, A. (2020) Daunorubicin. StatPearls. Retrieved September 22, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK559073/
  6. Thorn, C. F., Oshiro, C., Marsh, S., et al. (2011) Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics 21, pp. 440–446. Retrieved September 22, 2021, from doi.org/10.1097/FPC.0b013e32833ffb56
  7. Bleomycin. (2021). UpToDate. Retrieved September 22, 2021, from https://www.uptodate.com/contents/bleomycin-drug-information
  8. Dactinomycin. (2021). UpToDate. Retrieved September 22, 2021, from https://www.uptodate.com/contents/dactinomycin-drug-information
  9. Epirubicin. (2021). UpToDate. Retrieved September 22, 2021, from https://www.uptodate.com/contents/epirubicin-drug-information
  10. Idarubicin. (2021). UpToDate. Retrieved September 22, 2021, from https://www.uptodate.com/contents/idarubicin-drug-information
  11. Mitomycin. (2021). UpToDate. Retrieved September 22, 2021, from https://www.uptodate.com/contents/mitomycin-intravenous-and-intravesical-systemic-drug-information
  12. Mitoxantrone. (2021). UpToDate. Retrieved September 22, 2021, from https://www.uptodate.com/contents/mitoxantrone-drug-information
  13. Wellstein, A., Giaccone, G., Atkins, M. B., Sausville, E. A. (2017). Cytotoxic drugs. Chapter 66 in Brunton, L. L., Hilal-Dandan, R., Knollmann B. C. (Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13th ed. McGraw-Hill. Retrieved September 22, 2021, from https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=172486857

USMLE™ is a joint program of the Federation of State Medical Boards (FSMB®) and National Board of Medical Examiners (NBME®). MCAT is a registered trademark of the Association of American Medical Colleges (AAMC). NCLEX®, NCLEX-RN®, and NCLEX-PN® are registered trademarks of the National Council of State Boards of Nursing, Inc (NCSBN®). None of the trademark holders are endorsed by nor affiliated with Lecturio.

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

User Reviews

0.0

()

¡Hola!

Esta página está disponible en Español.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details