Ifosfamide in Advanced/Disseminated Breast Cancer

Sorio, Roberto; Lombardi, Davide; Spazzapan, Simon; Mura, N. La; Tabaro, Gianna; Veronesi, Andrea

doi:10.1159/000073360

Cited by 10 publications

(6 citation statements)

References 30 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 andN-Dechloroethylation of Ifosfamide and Deuterated Ifosfamide by the Human Cytochrome P450s and Their Commonly Occurring Polymorphisms

et al. 2015

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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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“…Moreover, other factors like the greater cross-linking arm length of IFO and its longer half-life may be contributing to this difference [39]. IFO has shown antitumor activity against a variety of tumors, including small-cell and non-small-cell lung carcinoma [40][41][42][43], breast cancer [44][45][46], ovarian cancer [47,48], bladder cancer [49][50][51], cervical cancer [52], osteosarcoma [53], neuroblastoma [54,55], leukaemia [56,57], multiple myeloma [58], and lymphomas [59,60]. 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: Pharmacology Of Oxazaphosphorines Antitumor Activity and Mecmentioning

confidence: 99%

Reversal of Resistance to Oxazaphosphorines

Zhang¹,

Tian²,

Zhu³

et al. 2006

CCDT

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The oxazaphosphorines including cyclophosphamide (CPA), ifosfamide (IFO) and trofosfamide are one important group of alkylating agents. However, resistance is the major hindrance for success of oxazaphosphorine chemotherapy. The mechanism of resistance to oxazaphosphorines is not fully identified, but recently some novel insights into these aspects have been generated by using sensitive analytical techniques and powerful pharmacogenetic techniques. Potential mechanisms for oxazaphosphorine resistance include decreased activation by cytochrome P450s (e.g. CYP3A4, CYP2C9 and CYP2B6), increased deactivation of the agents by deactivating enzymes such as aldehyde dehydrogenases (ALDHs), increased cellular thiol level, increased DNA repair capacity, and altered cellular apoptotic response to DNA repair, e.g. deficient apoptosis due to lack of cellular mechanisms to result in cell death following DNA damage. In addition, decreased cellular accumulation of cytotoxic species of oxazaphosphorines may also play a role in the resistance. This review highlights the pharmacology of oxazaphosphorine anticancer drugs and possible agents that reverse the resistance to these agents. Possible agents that can overcome oxazaphosphorine resistance include inducers of CYPs, modulators of GSTs and ALDHs, modulators of DNA repair process, antisense oligonucleotides against genes encoding various enzymes and signalling proteins, and novel gene delivery systems. Most of these agents have been investigated in preclinical studies and promising results have been observed. To date, several types of these agents are being evaluated in Phase III trials in cancer patients. Further studies are needed to identify the molecular targets associated with resistance to oxazaphosphorines.

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Ifosfamide in Advanced/Disseminated Breast Cancer

Cited by 10 publications

References 30 publications

Clinical Pharmacology of Cyclophosphamide and Ifosfamide

Clinical Pharmacology of Cyclophosphamide and Ifosfamide

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

Reversal of Resistance to Oxazaphosphorines

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