Asparaginase

Asparaginase (L-asparaginase) is sometimes used as an antitumor agent in the treatment of certain cancers. It works as an enzyme that breaks down asparagine, one of the amino acids needed for the growth and survival of certain types of tumors.

Asparaginase-based drugs, such as Ervase (Erwinia asparaginase) or asparaginase, can be used to treat different types of cancer, including acute lymphoblastic leukemia in children and adults. Asparaginase may also be used to treat other types of lymphomas and tumors.

The mechanism of action is that tumor cells, especially certain types of leukemia, cannot synthesize enough of their own asparaginase to meet their asparagine needs. When an externally produced asparaginase such as Ervase is used, the asparagine required for tumor growth is destroyed, starving the tumor cells and causing them to die.

However, it should be noted that the use of asparaginase may cause undesirable side effects, including allergic reactions, liver dysfunction, changes in the blood (such as anemia or thrombocytopenia) and others. Treatment with asparaginase is carried out under strict medical supervision and control.

Indications Asparaginase

1. Acute lymphoblastic leukemia (ALL): Asparaginase is often used in the treatment of acute lymphoblastic leukemia in children and adults. It may be part of combination therapy, including chemotherapy and other anticancer drugs.
2. Lymphomas: Asparaginase may also be used in the treatment of various types of lymphomas, including diffuse large B-cell lymphoma (DLBCL) and others.
3. Other types of leukemia: In some cases, asparaginase may be used to treat other forms of leukemia, such as acute myeloblastic leukemia (AML).

Release form

Injectable forms:

• Powder for preparation of solution for injection: This form of asparaginase is intended for intramuscular or intravenous injection. The powder must be dissolved in a special solvent before use. This form of release is the most common for hospital treatment.
• Pre-preparedsolution for injection: In some cases, asparaginase may be supplied as a pre-mixed solution that is also used for intramuscular or intravenous administration. This form is convenient because it does not require additional preparation before administration.

Examples of asparaginase preparations

• L-asparaginase: The standard form of asparaginase used in many OLL treatment protocols.
• Pegaspargase (Pegaspargase): This is a pegylated form of L-asparaginase that has a longer half-life and can be administered less frequently than regular L-asparaginase. Pegaspargase is usually a ready-to-use solution for injection.
• Erwinase (Erwinase): This is a form of asparaginase derived from the bacteria Erwinia chrysanthemi, and is used as an alternative for patients who develop an allergy to E. Coli derivatives of asparaginase. It is also available as a powder for injection.

Pharmacodynamics

1. Asparagine Deprivation: The main mechanism of action of asparaginase is to break down asparagine in the blood. This leads to a deficiency of asparagine in tumor cells, which normally depend on this amino acid for their growth and division.
2. Inhibition of tumor growth: Since tumor cells cannot synthesize asparagine on their own and depend on its supply from outside, asparagine deficiency caused by the action of asparaginase may slow down tumor growth and development.
3. Selectivity to tumor cells: Normal tissues can synthesize asparagine on their own, so they are less sensitive to the action of asparaginase. However, tumor cells, which normally have an increased requirement for asparagine, are more sensitive to a deficiency of this amino acid.
4. Decreased survival of tumor cells: Asparagine deficiency can lead to apoptosis (programmed cell death) in tumor cells, which decreases their survival rate.

Pharmacokinetics

1. Absorption: Asparaginase is usually administered into the body by injection, often into the muscle. Absorption from the injection site into the bloodstream is relatively rapid.
2. Distribution: After absorption, asparaginase is distributed to tissues and organs of the body. It can penetrate cell membranes and reach its target, the cancer cells.
3. Metabolism: Asparaginase is a protein drug, so it does not undergo the usual metabolic processes. It can be broken down in the body, but its functionality is retained for a period of time.
4. Excretion: Excretion of asparaginase from the body occurs mainly through the kidneys, like other proteins.

Dosing and administration

Method of Application:

Asparaginase is administered intramuscularly or intravenously to patients. The route of administration may depend on the specific drug formulation and clinical protocol.

1. Intramuscular injection:

   • The drug is slowly injected into the muscle, which allows you to achieve the desired concentration of the substance in the blood without sharp peaks that can occur with intravenous administration.

2. Intravenous administration:

   • The drug is injected directly into a vein, usually for a faster effect or if intramuscular injections are not well tolerated by the patient.

Dosage:

Asparaginase dosage can vary greatly depending on the age of the patient, the type and stage of the disease, and whether the drug is used in monotherapy or in combination with other medications. Here are general dosing recommendations:

For adults and children:

• Thestandard dose for L-asparaginase (derived from E. Coli) is 6000 to 10000 international units (IU) per m^2 of body surface area, administered 2 to 3 times per week.
• Thedose for Pegaspargase (a pegylated form of asparaginase) is usually 2500 IU per m^2 of body surface area, administered every 2 weeks.

The dosage can be adapted:

• Depending on the patient's response to treatment and the occurrence of side effects.
• Consideration of liver and other organ function, as asparaginase may cause toxic reactions.

Use Asparaginase during pregnancy

The use of asparaginase during pregnancy can be problematic because chemotherapy can adversely affect fetal development.

Contraindications

1. Hypersensitivity: People with known hypersensitivity to asparaginase or any other components of the drug should avoid its use.
2. Severe hepatic or renal impairment: Because asparaginase is metabolized in the liver and excreted via the kidneys, its use may be limited in patients with severe hepatic or renal impairment.
3. Blood problems: Asparaginase may affect the blood, so its use may be limited in patients with thrombocytopenia or other hematopoietic disorders.
4. Pregnancy and lactation: Information on the safety of asparaginase use during pregnancy and lactation is limited, so use should be evaluated by a physician.
5. Pediatric age: The use of asparaginase in children requires caution and may require special dosage.

Side effects Asparaginase

1. Allergic reactions: Including skin rash, itching, urticaria, facial edema, difficulty breathing, or anaphylactic shock.
2. Liver damage: Increased blood levels ofliver enzymes (ALT, AST) and jaundice.
3. Decreased blood cell count: Including anemia (decreased hemoglobin level), thrombocytopenia (decreased platelet count), and leukopenia (decreased white blood cell count).
4. Hypercoagulability: Increased tendency to clot formation and associated thrombosis.
5. Hyperbilirubinemia: Increased bilirubin levels in the blood, which may be associated with liver dysfunction.
6. Abdominal discomfort: Including nausea, vomiting, pain or discomfort in the abdominal area.
7. Myalgias and arthralgias: Muscle and joint pain.
8. Hypersensitivity to light: Increased sensitivity to sunlight.
9. Osteoporosis: Rare cases of osteoporosis or osteopenia, especially with prolonged treatment.

Overdose

1. Increased risk of toxicity: It is possible that administration of excessive amounts of asparaginase may result in an increased risk of toxicity and undesirable side effects.
2. Disorders of hematopoiesis: Since asparaginase is used in the treatment of leukemia and other blood tumors, its excessive administration may cause disturbances in the process of hematopoiesis and lead to anaemia, thrombocytopenia and other disorders of blood function.
3. Allergic Reactions: Overdose may increase the risk of allergic reactions such as skin rash, itching, edema, and anaphylactic shock.
4. Other Possible Side Effects: It is possible that administration of excessive amounts of asparaginase may cause other unwanted effects such as increased body temperature, generalized weakness, nausea, vomiting, and diarrhea.

Interactions with other drugs

1. Drugs that may increasethe risk of allergic reactions: Drugs that may increase the risk of allergic reactions may increase the risk of unwanted effects with asparaginase. These may be other chemotherapy drugs or drugs that cause allergies.
2. Drugs that affect liver and kidney function: Such drugs may affect the metabolism and excretion of asparaginase from the body, which may affect its efficacy and safety.
3. Antineoplastic drugs and drugs to relieve side effects: Interactions may occur with other antineoplastic drugs or drugs intended to relieve side effects of chemotherapy, such as antiemetics or blood thinners.
4. Drugs that reduce the immune response: Drugs that reduce the immune response may reduce the effectiveness of asparaginase by reducing the body's immune response to the tumor.