Comparative activity of ifosfamide and cyclophosphamide

Abstract

Antitumor activity (increase in lifespan and cure) was greater for ifosfamide (IFO) in several experimental tumors, some of which were primarily resistant to cyclophosphamide (CYC). IFO has been shown to be active in anthracycline-resistant and in adriamycin/cisplatin-resistant sublines of an Ehrlich ascites tumor, as well as in tumor cells primarily resistant to CYC. The few comparative controlled clinical trials available suggest superior single-agent activity of IFO compared with CYC in soft tissue sarcoma and ovarian cancer. Combination chemotherapy with IFO has been effective in second-line treatment of sarcomas, malignant lymphomas, lung cancer, and testicular cancer, most of them pretreated with or refractory to CYC. Although it is difficult to obtain clinical proof that there is no cross-resistance between IFO and CYC, IFO has been shown to be active in multirefractory malignant lymphomas, in small cell lung cancer not responding to adriamycin, vincristine, and etoposide, and in soft tissue and bone sarcomas. Testicular cancer and pancreatic cancer are some of the tumors in which IFO activity is currently being evaluated and in which CYC has so far failed to show sufficient clinical activity. More comparative controlled clinical trials are needed in ovarian cancer, breast cancer, malignant lymphomas, sarcomas and cervical cancer, in which IFO has already shown sufficient single-agent activity. Due to its lower level of cross-resistance with a variety of heterocyclic products, but also with other alkylating agents, in addition to its use in induction chemotherapy, IFO is an important second-line agent in many clinical situations.

The effect of age on the pharmacokinetics of ifosfamide.

“…This occurs mainly in the liver (Brock & Hohorst, 1963) by the action of a mixed function oxidase, producing the active metabolites 4-hydroxyifosfamide (Connors et al, 1974) and isophosphoramide mustard (Brock, 1983). Ifosfamide is less myelosuppressive than cyclophosphamide (Brade et al, 1986) but is more urotoxic (Teufel & Pfleiderer, 1986). However, with the introduction of the uroprotector Mesna (uromitexan) in 1982 (Bryant et al, 1980) urotoxicity is now largely avoidable.…”

The Pharmacologic Basis of Ifosfamide Use in Adult Patients with Advanced Soft Tissue Sarcomas

“…tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide], first synthesized in the 1960s, is a member of the oxazaphosphorine family of alkylating agents [24,25]. It was introduced as a chemical modification of cyclophosphamide with a different position of its two chloroethyl groups on the central ring, providing a structure with greater water solubility and antitumor activity and a better toxicity profile [26].…”

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

“…1A). 5,7 With the co-administration of mesna uroprotection, the primary dose-limiting toxicity of ifosfamide is myelosuppression. 8 To improve the selectivity of tumor cell killing and the sparing of normal tissue, prodrug forms that can be selectively activated in tumor tissue have been widely investigated.…”