Role of Ifosfamide in Cervical Cancer: An Overview

Buda, Alessandro; Dell’Anna, Tiziana; Signorelli, Mauro; Mangioni, Costantino

doi:10.1159/000073362

Cited by 18 publications

(6 citation statements)

References 24 publications

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“…The second arm in phosphoramide mustard can react with a second guanine moiety in an opposite DNA strand or in the same strand to form crosslinks. non-small-cell lung carcinoma (NSCLC) [313][314][315][316], breast cancer [317][318][319], ovarian cancer [320,321], bladder cancer [322][323][324], cervical cancer [325], osteosarcoma [326], neuroblastoma [327,328], leukemia [329,330], multiple myeloma [331], and lymphomas [332,333]. IFO could be used in both single agent and combination therapy with many other cytotoxic agents in clinical practice, such as etoposide, doxorubicin and mitomycin.…”

Section: Antitumor Activitymentioning

confidence: 99%

Clinical Pharmacology of Cyclophosphamide and Ifosfamide

Zhang¹,

Tian²,

Zhou³

2006

CDTH

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The oxazaphosphorine cyclophosphamide (CPA) and ifosfamide (IFO) are two commonly used DNAalkylating agents in cancer chemotherapy. This review highlights the pharmacokinetics and pharmacodynamics of the two important agents. As alkylating agents, CPA and IFO are usually combined with other anticancer drugs in the chemotherapy of solid tumors and hematological malignancies to obtain synergistic or additive anticancer effect due to complementary mechanism of action. Both compounds are prodrugs that are activated via 4-hydroxylation by cytochrome P450s such as CYP2B6 and CYP3A4 to generate alkylating nitrogen mustards (phosphoramide mustard and ifosforamide mustard) and the byproduct acrolein. The resultant mustards can alkylate DNA to form DNA-DNA cross-links, leading to inhibition of DNA synthesis and cell apoptosis. Both CPA and IFO are also inactivated by N-dechloroethylation, resulting in N-dechloroethylated metabolites and the byproduct chloroacetaldehyde. Acrolein is the causative agent for hemorrhagic cystitis, whereas chloroacetaldehyde induces nephrotoxicity and neurotoxicity. Pharmacokinetics of CPA and IFO is markedly influenced by route of administration and duration of treatment, age, comedication, liver and renal function. Large interpatient variability in pharmacokinetics, clinical response rate and toxicity has been observed in cancer patients treated with CPA or IFO. Resistance to CPA or IFO occurs due to decreased activation by CYP3A4 and CYP2B6, increased deactivation of the agents, decreased entry into or increased efflux from tumor cells, increased cellular thiol level, increased DNA repair capacity, and/or deficient apoptotic response to DNA damage. A full understanding of factors affecting the pharmacokinetics, pharmacodynamics, toxicology and pharmacogenetics of CPA and IFO is important to optimize the dose and regimens of CPA and IFO in cancer chemotherapy.

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Section: Antitumor Activitymentioning

confidence: 99%

Clinical Pharmacology of Cyclophosphamide and Ifosfamide

Zhang¹,

Tian²,

Zhou³

2006

CDTH

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“…It is the structural isomer of the more commonly used antineoplastic and immunosuppressive agent cyclophosphamide (CPA) (Zhang et al, 2006). Toxicities associated with IFO treatment limit its use, even though the drug has proven more effective than CPA in a wide range of malignant diseases (Buda et al, 2003;Sorio et al, 2003;Donfrancesco et al, 2004;Pocali et al, 2004;Biagi et al, 2005;Kosmas et al, 2007). IFO-induced toxicities include moderate-to-severe nephrotoxicity, which occurs in ;30% of the patient population, and neurotoxicities, which occur in ;20% of the patient population (Loebstein et al, 1999;Klastersky, 2003;McCune et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Hydroxylation and N-Dechloroethylation of Ifosfamide and Deuterated Ifosfamide by the Human Cytochrome P450s and Their Commonly Occurring Polymorphisms

Calinski

Zhang

Ludeman

et al. 2015

Drug Metabolism and Disposition

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The hydroxylation and N-dechloroethylation of deuterated ifosfamide (d4IFO) and ifosfamide (IFO) by several human P450s have been determined and compared. d4IFO was synthesized with deuterium at the alpha and alpha' carbons to decrease the rate of N-dechloroethylation and thereby enhance hydroxylation of the drug at the 4' position. The purpose was to decrease the toxic and increase the efficacious metabolites of IFO. For all of the P450s tested, hydroxylation of d4IFO was improved and dechloroethylation was reduced as compared with nondeuterated IFO. Although the differences were not statistically significant, the trend favoring the 4'-hydroxylation pathway was noteworthy. CYP3A5 and CYP2C19 were the most efficient enzymes for catalyzing IFO hydroxylation. The importance of these enzymes in IFO metabolism has not been reported previously and warrants further investigation. The catalytic ability of the common polymorphisms of CYP2B6 and CYP2C9 for both reactions were tested with IFO and d4IFO. It was determined that the commonly expressed polymorphisms CYP2B6*4 and CYP2B6*6 had reduced catalytic ability for IFO compared with CYP2B6*1, whereas CYP2B6*7 and CYP2B6*9 had enhanced catalytic ability. As with the wild-type enzymes, d4IFO was more readily hydroxylated by the polymorphic variants than IFO, and d4IFO was not dechloroethylated by any of the polymorphic forms. We also assessed the use of specific inhibitors of P450 to favor hydroxylation in human liver microsomes. We were unable to separate the pathways with these experiments, suggesting that multiple P450s are responsible for catalyzing both metabolic pathways for IFO, which is not observed with the closely related drug cyclophosphamide.

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“…For example, systemic chemotherapy is typically the last or strictly concurrent option, after surgery and radiotherapy, for treatment of cervical cancer (3,4). In addition, systemic medications can lead to significant adverse side effects when high drug concentrations in the circulation are required to elicit a therapeutic response in the CV tract (5).…”

mentioning

confidence: 99%

Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus

Lai¹,

O’Hanlon

Harrold

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

905

1,012

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Nanoparticles larger than the reported mesh-pore size range (10 -200 nm) in mucus have been thought to be much too large to undergo rapid diffusional transport through mucus barriers. However, large nanoparticles are preferred for higher drug encapsulation efficiency and the ability to provide sustained delivery of a wider array of drugs. We used high-speed multiple-particle tracking to quantify transport rates of individual polymeric particles of various sizes and surface chemistries in samples of fresh human cervicovaginal mucus. Both the mucin concentration and viscoelastic properties of these cervicovaginal samples are similar to those in many other human mucus secretions. Unexpectedly, we found that large nanoparticles, 500 and 200 nm in diameter, if coated with polyethylene glycol, diffused through mucus with an effective diffusion coefficient (D eff) only 4-and 6-fold lower than that for the same particles in water (at time scale ‫؍‬ 1 s). In contrast, for smaller but otherwise identical 100-nm coated particles, D eff was 200-fold lower in mucus than in water. For uncoated particles 100 -500 nm in diameter, D eff was 2,400-to 40,000-fold lower in mucus than in water. Much larger fractions of the 100-nm particles were immobilized or otherwise hindered by mucus than the large 200-to 500-nm particles. Thus, in contrast to the prevailing belief, these results demonstrate that large nanoparticles, if properly coated, can rapidly penetrate physiological human mucus, and they offer the prospect that large nanoparticles can be used for mucosal drug delivery. drug delivery ͉ mucosal tissues ͉ particle tracking ͉ PEG

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Role of Ifosfamide in Cervical Cancer: An Overview

Cited by 18 publications

References 24 publications

Clinical Pharmacology of Cyclophosphamide and Ifosfamide

Clinical Pharmacology of Cyclophosphamide and Ifosfamide

Hydroxylation and N-Dechloroethylation of Ifosfamide and Deuterated Ifosfamide by the Human Cytochrome P450s and Their Commonly Occurring Polymorphisms

Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus

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