Ifosfamide

Ifosfamide can be synthesized through several routes. One method involves reacting an this compound intermediate with a chlorinating agent, followed by cyclization under the action of an organic base . Another method uses aziridine as the starting material, which undergoes cyclization and subsequent reactions to form this compound . Industrial production methods often involve optimizing these synthetic routes to ensure high yield and purity while minimizing the use of toxic and explosive chemicals .

Ifosfamide undergoes various chemical reactions, including oxidation, reduction, and substitution. It is metabolized in the liver by cytochrome P450 enzymes, leading to the formation of active and inactive metabolites . Common reagents used in these reactions include mixed-function oxidases and organic bases . Major products formed from these reactions include chloroacetaldehyde and other metabolites that contribute to the drug’s therapeutic and toxic effects .

FDA-Approved Indications

Ifosfamide is utilized in several FDA-approved settings:

• Germ Cell Tumors : Administered at a dose of 1.2 g/m²/day for 5 days in combination with mesna, it has shown complete remission rates of 21% to 26% when paired with cisplatin or etoposide .
• Soft Tissue Sarcomas : Combination therapy with this compound and mesna yields objective response rates around 40% as induction therapy .
• Lymphomas : It serves as salvage therapy in non-Hodgkin lymphoma and is part of the RICE regimen for relapsed Hodgkin lymphoma .
• Ovarian Cancer : Particularly in platinum-resistant cases, this compound has demonstrated response rates exceeding 40% when combined with other agents .

Off-Label Uses

This compound's versatility extends to several off-label applications:

• Ewing Sarcoma : High-dose this compound has been shown to extend survival compared to other regimens like topotecan .
• Cervical Cancer : Administered alongside mesna at 1500 mg/m²/day, response rates range from 18% to 45% when combined with paclitaxel and cisplatin .
• Bladder Carcinoma : Utilized for advanced bladder cancer cases .
• Lung Cancer : More beneficial than standard regimens as maintenance or consolidation therapy for both small-cell and non-small-cell lung cancer .

Delayed Encephalopathy

A notable case involved a 19-year-old female patient with Hodgkin lymphoma who developed neurotoxicity 16 days post-ifosfamide infusion. She recovered rapidly after treatment with methylene blue, highlighting the importance of recognizing delayed effects of this compound .

Acute Kidney Injury

Another case study documented a 44-year-old woman with leiomyosarcoma who experienced acute kidney injury following this compound treatment. This case emphasizes the need for monitoring renal function during therapy .

Comparative Efficacy Data

Ifosfamide requires biotransformation in the liver by the cytochrome P450 system before it becomes active . The active metabolites of this compound form DNA crosslinks at the guanine N-7 position, leading to cellular damage and death . This disruption of DNA replication and RNA production inhibits cancer cell growth and proliferation . The exact molecular targets and pathways involved in this compound’s cytotoxicity are still being studied, but it is known to interfere with DNA and RNA synthesis .

Ifosfamide is chemically related to other nitrogen mustards, such as cyclophosphamide, trofosfamide, mafosfamide, sufosfamide, and glufosfamide . Compared to these compounds, this compound has unique pharmacokinetic properties, including a longer half-life and different metabolic pathways . Its ability to form DNA crosslinks and its effectiveness in treating a wide range of cancers make it a valuable chemotherapeutic agent .

Ifosfamide is a nitrogen mustard alkylating agent used primarily in the treatment of various cancers, including sarcomas and lymphomas. As a prodrug, it requires metabolic activation to exert its therapeutic effects. This article explores the biological activity of this compound, focusing on its pharmacokinetics, mechanisms of action, gene expression alterations, and clinical efficacy based on diverse research findings.

This compound acts primarily through DNA alkylation , leading to the formation of cross-links that inhibit DNA replication and transcription. The active metabolite, isophosphoramide mustard, predominantly interacts with the N-7 position of guanine residues in DNA, causing both intra- and inter-strand cross-links. This mechanism ultimately leads to cell death, particularly in rapidly dividing cancer cells .

Metabolism and Pharmacokinetics

The metabolism of this compound involves several cytochrome P450 (CYP) enzymes, including CYP2B6, CYP2C8, CYP2C9, and CYP3A4. In vitro studies using human hepatocyte cultures have demonstrated that these enzymes catalyze the 4-hydroxylation of this compound, which is crucial for its activation . Notably, rifampin has been identified as a potent inducer of this compound metabolism, enhancing its pharmacokinetic profile in patients .

Gene Expression Changes Induced by this compound

Research has shown that this compound administration significantly alters gene expression in liver and kidney tissues. A study identified 2,672 differentially expressed genes (DEGs) in the liver after treatment with 100 mg/kg body weight per day. Of these, 1,283 genes were upregulated while 1,389 were downregulated. In the kidneys, 401 DEGs were observed with a similar trend of downregulation predominating . These changes indicate potential toxicity and organ-specific responses to this compound.

Table 1: Differential Gene Expression Induced by this compound

Clinical Efficacy: Case Studies and Trials

This compound has been evaluated in numerous clinical settings. A notable phase II trial assessed the efficacy of this compound combined with lenvatinib and etoposide in children with high-grade osteosarcoma. Results indicated improved outcomes compared to this compound alone . Similarly, another study reported a progression-free rate (PFR) of 66% at three months for patients treated with sorafenib plus this compound for advanced soft tissue sarcoma .

Case Study: Efficacy in Small Cell Lung Cancer (SCLC)

This compound monotherapy has shown a response rate of approximately 42% in SCLC patients. However, a recent phase II study indicated that its efficacy diminishes in heavily pre-treated populations, leading to an early termination due to futility . This underscores the importance of considering prior treatment history when evaluating therapeutic options.

Toxicity Profile

While effective, this compound is associated with various toxicities. Common adverse effects include myelosuppression, neurotoxicity (notably encephalopathy), and renal toxicity. The alteration of gene expression related to immune cell localization and organ development suggests that careful monitoring is required during treatment to mitigate these risks .

Basic Research Questions

Q. What experimental techniques are critical for studying the alkylation kinetics of ifosfamide metabolites?

• Answer: ³¹P NMR spectroscopy is a key method for tracking the kinetics of this compound's active metabolites, such as isophosphoramide mustard, to quantify bisalkylation rates and compare them to cyclophosphamide analogs. This technique helps elucidate structural differences impacting DNA cross-linking efficiency .

Q. How does this compound-induced glutathione depletion influence therapeutic efficacy, and how is this monitored in clinical studies?

• Answer: Intracellular glutathione (GSH) levels in peripheral blood lymphocytes are measured via HPLC or enzymatic assays to assess this compound's oxidative stress effects. Depletion correlates with reduced detoxification capacity and may predict treatment resistance. Mesna co-administration is critical to mitigate bladder toxicity but does not fully restore systemic GSH .

Q. What are the standard protocols for mitigating nephrotoxicity in pediatric this compound regimens?

• Answer: Hydration (≥2 L/day) and mesna are mandatory. Tubular dysfunction (e.g., Fanconi syndrome) is monitored via urinary β2-microglobulin and serum bicarbonate. Dose adjustments are required for patients with pre-existing renal impairment or retroperitoneal tumors .

Advanced Research Questions

Q. How can preclinical models elucidate the synergy between this compound and immunomodulators like interferon?

• Answer: Murine Ewing sarcoma models demonstrate that interferon-α/β enhances this compound's DNA damage response by upregulating pro-apoptotic pathways. Tumor volume regression and survival metrics are compared between monotherapy and combination arms. RNA-seq analysis identifies IFN-regulated genes (e.g., STAT1) as biomarkers for synergy .

Q. What methodological considerations are critical for designing trials testing high-dose this compound (HDI) in refractory soft tissue sarcomas?

• Answer: HDI (4 g/m²/day ×3 days) requires granulocyte colony-stimulating factor (G-CSF) support due to grade 3–4 neutropenia. Response evaluation uses RECIST criteria, with emphasis on distinguishing SDI-resistant (progression on ≤4 cycles) vs. SDI-refractory (no response) subgroups. Pharmacokinetic monitoring of chloroacetaldehyde (CAA) levels informs renal toxicity risk .

Q. How do metabolic differences between this compound and cyclophosphamide explain their distinct toxicity profiles?

• Answer: this compound generates higher CAA, a neurotoxic and nephrotoxic metabolite, due to slower 4-hydroxylation. Comparative LC-MS/MS studies of hepatic CYP3A4/5 activity and urinary CAA excretion rates clarify interpatient variability. Glutathione S-transferase (GST) polymorphisms further modulate detoxification efficiency .

Q. What statistical approaches resolve contradictions in survival outcomes for this compound combinations across sarcoma subtypes?

• Answer: Meta-analyses (e.g., Cochrane Review) stratify by histology (leiomyosarcoma vs. synovial sarcoma) and prior therapy. For uterine carcinosarcoma, weighted log-rank tests show a 1.82 odds ratio favoring this compound-cisplatin over monotherapy, but toxicity-adjusted benefit-risk ratios must account for neurotoxicity (RR = 1.59) and febrile neutropenia .

Q. How can microencapsulation technologies improve this compound's therapeutic index in pancreatic cancer?

• Answer: Cell-in-a-Box® microencapsulation allows localized this compound activation via cytochrome P450 enzymes. Phase II trials use a 33% dose reduction (1.6 g/m² vs. 2.4 g/m²) with CT-based tumor response criteria. RNA-seq of tumor biopsies post-treatment identifies hypoxia-related genes (e.g., HIF1A) as predictors of encapsulation efficacy .

Q. Methodological Guidelines

Q. What pharmacokinetic parameters should be prioritized in phase I this compound trials?

• Answer: Area under the curve (AUC) for 4-hydroxy-ifosfamide and CAA, renal clearance rates, and half-life (t½ = 6–7 hours). Population PK models incorporate creatinine clearance and albumin levels to predict neurotoxicity risk (e.g., serum bicarbonate <20 mmol/L) .

Q. How are zebrafish models used to study this compound's environmental impact and genomic toxicity?

• Answer: Zebrafish larvae exposed to 1–100 µg/L this compound for 7 days undergo RNA-seq to assess dysregulated miRNAs (e.g., miR-297) and DNA repair pathways. Comparative analysis with in vitro human hepatocyte models validates conserved toxicity mechanisms .