All alkylating agents have alkyl groups, and they can transfer this alkyl group to a suitable receptor site. Alkylating agents in neutral or alkaline solution form highly reactive carbonium ions, which are quaternary ammonium derivatives. This carbonium ion is highly reactive and can react with groups like NH₂, SH, OH, or PO₄ in physiologically important molecules in cells and render them unavailable for normal metabolic reactions. One more property of this carbonium ion is its nucleophilicity; it can react with nucleic acid bases and inhibit DNA synthesis. The nitrogen at guanine position 7 is especially more susceptible. So, this results in
- Cross-linking inhibits DNA replication.
- Abnormal base pairing (alkylated guanine pairs with thymine instead of cytosine) results in production of defective protein
- DNA strand breakage—decreased cell proliferation
- Alkylation also damages RNA and proteins
- Non cycle specific
Myelosuppression is the major dose-limiting toxicity for most alkylating agents.
Cyclophosphamide/Ifosfamide
Cyclophosphamide is usually administered as a single-dose bolus or in fractionated doses over 2 to 5 days. Ifosfamide is administered in a fractionated schedule over 5 days because, in the initial trials, the single-dose schedule produced intolerable nephrotoxicity, cystitis, and neurotoxicity.
Cyclophosphamide and ifosfamide are eliminated primarily by hepatic biotransformation to active and inactive metabolites, which are excreted mainly in the urine.
Adverse effects:
- Myelosuppression
- Alopecia
- Nausea & Vomiting
- SIADH
- Nephrotoxicity
- Secondary malignancy-AML
- Hemorrhagic cystitis, dysuria, and increased urinary frequency occur in 5%–10% of patients for cyclophosphamide and 20% to 40% for ifosfamide. Time of onset is variable and may begin within 24 hours of therapy or may be delayed for up to several weeks. This effect is dose-related and caused by the activated metabolites such as acrolein, which causes chemical cystitis.
Hemorrhagic cystitis can be prevented by
- Hydration
- Frequent emptying of bladder
- Bladder irrigation
- Administration of MESNA (2-mercaptoethane sulfonate Na).
Ifosfamide Toxicity:
| Commonly happens to 21-100 children out of every 100 | Occasional Happens to 5-20 children out of every 100 | Rarely happens to < 5 children out of every 100 | |
| Immediate: Within 1-2 days of receiving drug | Nausea & vomiting (acute and delayed) | CNS toxicity (somnolence, depressive psychosis and confusion) | Anorexia, diarrhea, constipation, encephalopathy, which may progress to coma (L), seizure, SIADH, phlebitis, hypokalemia |
| Prompt: Within 2-3 weeks, prior to next course | Leukopenia, alopecia, immune suppression | Thrombocytopenia, anemia, cardiac toxicities (arrhythmia, asymptomatic ECG changes), microscopic hematuria, metabolic acidosis | ↑ liver enzymes, ↑ bilirubin, hemorrhagic cystitis with macroscopic hematuria, dysuria, cystitis, and urinary frequency (<5% with mesna and vigorous hydration) (L), bladder fibrosis |
| Delayed: Any time later during therapy | Gonadal dysfunction: azoospermia or oligospermia (prolonged or permanent) 1 (L) | Renal failure, acute or chronic; renal tubular acidosis; Fanconi-like syndrome gonadal dysfunction; ovarian failure (L); CHF | |
| Late: Any time after completion of treatment | Moderate nephrotoxicity (↓ in glomerular filtration rate, renal tubular threshold for phosphate, and serum bicarbonate) | Secondary malignancy, hypophosphatemic rickets |
Ifosfamide neurotoxicity – the role of Methylene blue
Methylene blue should be considered for all patients with grade 2 neurocortical toxicity grading and is indicated for patients with grade 3 and 4 toxicity.
Methylene blue is contraindicated in patients with
- Glucose-6-phosphate dehydrogenase deficiency
- Pregnancy & Lactation
- Known sensitivity to the drug
- Severe renal impairment
Mechanism of action
Whilst the exact mechanisms for Ifosfamide-induced encephalopathy are not known, various metabolic pathways have been suggested. Methylene blue may act by counteracting some of these pathways
Treatment of Ifosfamide-induced encephalopathy: Pediatrics: 1 mg/kg/dose – 4 hourly
Prophylaxis of Ifosfamide-induced encephalopathy: Pediatrics: 1 mg/kg/dose – 6 hourly
Administration Either as a slow IV bolus—given over several minutes—or in 100 mL normal saline over 15–30 min. The methylene blue should be filtered before use using a 0.45 micron filter.
Available Brands of Cyclophosphamide in Bangladesh:
Cyclotox by Beacon Pharma. Endoxan by Synovia Pharma (not easily available). Neoclomide by Healthcare Pharma.
Available formulations: 200mg, 500mg, 1000 mg, or 1 gm.
Ifosfamide: Xifos by Beacon Pharma. Ifodex by Healthcare.
Platinum Compounds
Cisplatin/Carboplatin/Oxaliplatin
Cisplatin, carboplatin, and oxaliplatin are heavy metal coordination complexes that exert their cytotoxic effects by platination of DNA. Reactive intermediate compounds are formed in solution.
- Chloride is the leaving group replaced by a water molecule in cisplatin.
- Di-carboxy-cyclo-butane is the leaving group in carboplatin, and
- Oxalate is the leaving group in oxaliplatin.
These reactive intermediates covalently bind to DNA (N7 position of adenine and guanine) and form intra-strand and inter-strand DNA cross-links.
The toxicity profiles of the platinum analogs are strikingly different. Cisplatin is associated with only mild myelosuppression but produces significant and potentially irreversible nephrotoxicity, ototoxicity, and neurotoxicity.
The dose-limiting toxicity of carboplatin is hematologic toxicity, primarily thrombocytopenia.
Adverse effects
- Emesis***: Two forms are observed—acute (within the first 24 hours) and delayed (24 hours). Early form begins within 1 hour of starting cisplatin therapy and may last for 8–12 hours. The delayed form can present 3–5 days after drug administration.
- Nephrotoxicity: reduction in renal blood flow and GFR and a loss of tubular function. primarily in the renal proximal and distal tubule epithelium and collecting ducts.
- Electrolyte abnormalities, mainly hypomagnesemia, hypocalcemia, and hypokalemia, are common
- Peripheral neuropathy
- Ototoxicity: High-frequency irreversible hearing loss, more common in children below 5 years.
- Hypersensitivity
- Myelosuppression
- Alopecia
IV fluid hydration with normal saline before and after the infusion of cisplatin reduces the severity of nephrotoxicity. Diuresis with mannitol and furosemide has been used in an effort to decrease cisplatin-induced nephrotoxicity.
Precautions:
Cisplatin is a potent emetogenic agent. Prophylaxis against delayed emesis (24 hours after the drug administration) is also recommended. A combination of a 5-HT3 antagonist (e.g., ondansetron or granisetron) and dexamethasone is standard therapy for prevention of nausea and vomiting.
Patients must be hydrated before, during, and post-drug administration with potassium, calcium, and magnesium. Diuresis may be used. Concurrent administration of nephrotoxic medications should be avoided in patients receiving cisplatin.
Cisplatin causes a reversible sensory peripheral neuropathy (i.e., numbness, tingling, and paresthesias) at cumulative doses of 300 to 600 mg/m2. Lhermitte sign (an electric shock sensation when the neck is flexed) is common at high cumulative doses of cisplatin.
Carboplatin’s myelosuppressive effects are delayed. Platelet nadirs are typically seen up to 3 weeks after the dose, and milder granulocyte nadirs are observed 3 to 4 weeks after carboplatin administration.
Thanks, all.
Here is a quick link to previous topics.
Chemotherapy drugs: Things you need to know
Chemotherapy Drugs for Childhood Cancer Part 2 Basics
