Ifosfamide

异环磷酰胺可以通过多种途径合成。 一种方法是在有机碱的作用下，使异环磷酰胺中间体与氯化剂反应，然后环化 . 另一种方法是以氮丙啶为起始原料，通过环化和后续反应形成异环磷酰胺 . 工业生产方法通常涉及优化这些合成路线，以确保高产率和纯度，同时最大限度地减少有毒和爆炸性化学物质的使用 .

异环磷酰胺会发生各种化学反应，包括氧化、还原和取代。 它在肝脏中由细胞色素 P450 酶代谢，形成活性代谢产物和非活性代谢产物 . 这些反应中常用的试剂包括混合功能氧化酶和有机碱 . 这些反应形成的主要产物包括氯乙醛和其他代谢产物，它们对药物的治疗作用和毒性作用都有贡献 .

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

异环磷酰胺需要在肝脏中由细胞色素 P450 系统生物转化才能发挥作用 . 异环磷酰胺的活性代谢产物在鸟嘌呤 N-7 位形成 DNA 交联，导致细胞损伤和死亡 . 这种对 DNA 复制和 RNA 生成的破坏抑制了癌细胞的生长和增殖 . 异环磷酰胺的细胞毒性涉及的具体分子靶点和途径仍在研究中，但已知它会干扰 DNA 和 RNA 的合成 .

异环磷酰胺在化学上与其他氮芥类药物有关，如环磷酰胺、曲磷酰胺、马磷酰胺、苏磷酰胺和谷磷酰胺 . 与这些化合物相比，异环磷酰胺具有独特的药代动力学特性，包括更长的半衰期和不同的代谢途径 . 它形成 DNA 交联的能力及其在治疗多种癌症方面的有效性使其成为一种有价值的化疗药物 .

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 .