Ifosfamide/Mesna

Abstract

Ifosfamide is an oxazaphosphorine alkylating agent with a broad spectrum of antineoplastic activity. It is a prodrug metabolised in the liver by cytochrome P450 mixed-function oxidase enzymes to isofosforamide mustard, the active alkylating compound. Mesna, a uroprotective thiol agent, is routinely administered concomitantly with ifosfamide, and has almost eliminated ifosfamide-induced haemorrhagic cystitis and has reduced nephron toxicity. Therapeutic studies, mostly noncomparative in nature, have demonstrated the efficacy of ifosfamide/mesna alone, or more commonly as a component of combination regimens, in a variety of cancers. In patients with relapsed or refractory disseminated nonseminomatous testicular cancer, a salvage regimen of ifosfamide/mesna, cisplatin and either etoposide or vinblastine produced complete response in approximately one-quarter of patients. As a component of both induction and salvage chemotherapeutic regimens, ifosfamide/mesna has produced favourable response rates in small cell lung cancer, paediatric solid tumours, non-Hodgkin's and Hodgkin's lymphoma, and ovarian cancer. Induction therapy with ifosfamide/mesna-containing chemotherapeutic regimens has been encouraging in non-small cell lung cancer, adult soft-tissue sarcomas, and as neoadjuvant therapy in advanced cervical cancer. As salvage therapy, ifosfamide/mesna-containing combinations have a palliative role in advanced breast cancer and advanced cervical cancer. Ifosfamide/mesna can elicit responses in patients refractory to numerous other antineoplastic drugs, including cyclophosphamide. With administration of concomitant mesna to protect against ifosfamide-induced urotoxicity, the principal dose-limiting toxicity of ifosfamide is myelosuppression; leucopenia is generally more severe than thrombocytopenia. Reversible CNS adverse effects ranging from mild somnolence and confusion to severe encephalopathy and coma can occur in approximately 10 to 20% of patients after intravenous infusion, and the incidence of neurotoxicity may be increased to 50% after oral administration because of differences in the preferential route of metabolism between the 2 routes of administration. Other adverse effects of ifosfamide include nephrotoxicity, alopecia, and nausea/vomiting. In general, intravenously administered mesna is associated with a low incidence of adverse effects; however, gastrointestinal disturbances are common following oral administration. Thus, ifosfamide/mesna is an important and worthwhile addition to the currently available range of chemotherapeutic agents. It has a broad spectrum of antineoplastic activity and causes less marked myelosuppression than many other cytotoxic agents. At present, the role of ifosfamide/mesna in refractory germ cell testicular cancer is clearly defined; however, its overall place in the treatment of other forms of cancer awaits delineation in future well-controlled comparative studies.

Pharmacology of Ifosfamide

“…Renal tubular epithelial cells reconvert dimesna to mesna by means of glutathione reductase. Due to their hydrophilic characteristics, both mesna and dimesna are unable to enter the cells (with the exception of the renal tubular and intestinal ones) so that they do not interfere with antineoplastic activity of IFO [43]. Mesna should be given concomitantly with and after IFO because of its short half-life.…”

New investigations into the stability of Mesna using LC-MS/MS and NMR

“…(1)(2)(3)(4)(5)(6)(7)(8) Previous studies have confirmed that Mesna does not react with Ifosfamide, obstruct the tumour response to treatment or enter the cancer cells at all. This could be due to its hydrophilic properties, which prevents it from passing through the lipid biological membranes.…”

“…(1,(11)(12)(13) Upon entering the bloodstream, Mesna is oxidised to form its less active dimer Dimesna (dithiobis-mercaptoethanesulphonate). (1,2) Similarly to Mesna, Dimesna is a hydrophilic compound which does not transfer across the lipid biological membrane through passive diffusion. (14) Upon reaching the kidneys, Dimesna is reduced back to Mesna and rapidly excreted due to its high solubility in water.…”

Comparison of hypoxia-activated prodrug evofosfamide (TH-302) and ifosfamide in preclinical non-small cell lung cancer models

“…3,4 Ifosfamide (3-(2-chloroethyl)-2-[(2-chloroethyl)-amino] tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide) is a prodrug which is metabolized in the liver by hepatic cytochrome P450 (CYP)-catalyzed 4-hydroxylation to produce the active DNAalkylating agent isophosphoramide mustard (IPM). 5 It is approved for the treatment of testicular cancer 6 and also used as a treatment for a variety of other cancers, including breast cancer, lymphoma, soft tissue sarcoma, osteosarcoma, bone tumor, lung cancer, cervical cancer, and ovarian cancer. 5 The main acute side effects of ifosfamide include those commonly seen with other antineoplastic agents such as neutropenia, thrombocytopenia, nausea and vomiting, alopecia, and hypersensitivity reactions.…”