Enzyme preparations: L-asparaginase
The active substance is an enzyme obtained through the vital activity of Escherichia coli or Erwinia chrysanthemi bacteria.
Mechanism of action is based on the principle of "metabolic starvation". Unlike healthy cells, malignant cells are unable to independently synthesize the amino acid asparagine and are completely dependent on its supply from the bloodstream. The drug deaminates asparagine circulating in the blood, breaking it down into aspartic acid and ammonia. The tumor experiences an acute deficiency of building material, causing intensively growing cells to die.
Application features:
- Indications: acute lymphoblastic leukemia (often combined with prednisolone or vincristine).
- Administration: exclusively parenterally, since the protein molecule of the enzyme is completely destroyed in the gastrointestinal tract.
Adverse effects:
- Allergic reactions to foreign bacterial protein.
- Neurotoxicity (seizures, coma) due to poisoning with ammonia, a byproduct of breakdown.
- Decreased blood clotting due to suppression of protein-synthetic function.
- Damage to internal organs (pancreatitis, liver dysfunction).
Topoisomerase I inhibitors
This group includes irinotecan and topotecan. These are semi-synthetic derivatives of the camptothecin alkaloid, which was originally isolated from the Camptotheca acuminata tree. A complex lactone ring is responsible for the pharmacological activity of the molecule.
The drugs are phase-specific and work strictly in the S-phase of the cell cycle. They selectively block the topoisomerase I enzyme, which leads to critical disruption of DNA repair processes and arrest of division.
They are administered intravenously as infusions. The main danger during therapy is pronounced hematotoxicity, which manifests as neutropenia, anemia, and thrombocytopenia. Systemic reactions such as alopecia, nausea, vomiting, and diarrhea are also possible.
Topoisomerase II inhibitors
The group is represented by etoposide and teniposide—semi-synthetic derivatives of podophyllotoxin. The initial alkaloid is extracted from the plant Mayapple (Podophyllum peltatum).
Mechanism of action: the drug molecule binds simultaneously to the DNA strand and the topoisomerase II enzyme, forming a stable ternary complex. This blocks the normal operation of the enzyme, provokes DNA strand breaks, and subsequent cell death.
Indications for prescription and routes of administration:
- Etoposide: used for small cell lung cancer (oat cell carcinoma, prone to rapid and aggressive metastasis), as well as testicular carcinoma (as part of combination therapy with cisplatin and bleomycin). The drug can be administered parenterally and taken orally.
- Teniposide: indicated for acute leukemias and solid tumors of the central nervous system (neuroblastomas, gliomas). Administered exclusively intravenously.
Among the adverse effects of the entire group, myelosuppression (severe bone marrow suppression), dyspeptic disorders, immune allergic reactions, and dermatological problems (hair loss) predominate.
Arsenic compounds
In modern oncology, arsenic trioxide is used. Historically, arsenic compounds were widely used in traditional Chinese medicine to treat psoriasis and syphilis, but were later successfully repurposed to combat malignant neoplasms.
The drug is administered intravenously in the treatment of leukemias. It induces the degradation of a specific leukemic oncoprotein (PML/RAR-$\alpha$) and triggers the mitochondrial apoptotic pathway through the activation of intracellular enzymes—caspases.
Due to its high toxicity, arsenic trioxide is used with great caution. The main adverse reactions include:
- Cardiotoxicity: severe arrhythmias, pathological QT interval prolongation, ECG changes.
- Systemic manifestations: pronounced fluid retention in the body, dyspnea, fever.
- Skin reactions: various types of rashes.
The logical chain will help remember the toxicity of L-asparaginase: it is a foreign protein $\rightarrow$ risk of allergy; the enzyme breaks down the amino acid with the release of ammonia $\rightarrow$ intoxication and neurotoxicity (seizures, coma); synthesis of own proteins is disrupted $\rightarrow$ blood clotting drops.
Class and exam questions
Why can't L-asparaginase be taken in pills?
Since the drug is an enzyme (protein), when taken orally it will be completely destroyed by the enzymes of the gastrointestinal tract. Therefore, it is administered exclusively parenterally.
In which phase of the cell cycle do camptothecin derivatives act?
Irinotecan and topotecan are phase-specific drugs. They exhibit their cytotoxic activity strictly in the S-phase of the cell cycle.
What is the difference in indications between etoposide and teniposide?
Etoposide is more often used in small cell lung cancer and testicular carcinoma, whereas teniposide is indicated for acute leukemias and central nervous system tumors.
What else to study on this topic
- Polychemotherapy regimens including L-asparaginase (combinations with vincristine and prednisolone).
- The role of caspases and the mitochondrial pathway in the induction of apoptosis during the use of arsenic trioxide.
- Features of the chemical structure of the lactone ring of camptothecin derivatives.
- The mechanism of formation of the "drug — DNA — topoisomerase II" ternary complex.
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