Trofosfamide

Abstract: The development of the oxazaphosphorine cytostatics cyclophosphamide, ifosfamide, and trofosfamide was based on the idea of applying the transport form/active form principle to the highly reactive nitrogen mustard group. A critical analysis and synopsis of the available results and knowledge will include examination of the extent to which the hypotheses on which this concept is based have been confirmed by experimental and clinical findings: 1. Chemical synthesis succeeded in converting the reactive nitrogen mustard into an inactive transport form (latentiation). 2. The requirement that the transport form be enzymatically activated to the active form in the target organ (the cancer cell) has been achieved by a sequence of metabolic reactions. 3. The aim of considerably increasing the therapeutic index of alkylating agents has been achieved by the oxazaphosphorine cytostatics. The greater cancerotoxic selectivity is closely correlated with the cytotoxic specificity of their activated primary metabolites. 4. The cancerotoxic selectivity of oxazaphosphorines was further increased when mesna was introduced as a regional uroprotector. Mesna eliminates the risk of therapy-limiting urotoxic side effects of oxazaphosphorines. With mesna protection, these cytostatics can be given in higher doses with increased safety, and their therapeutic efficacy can be enhanced. 5. Stabilization of the primary oxazaphosphorines, e.g., by attaching 2-mercaptoethanesulfonic acid (mafosfamide), opens up new possibilities in preclinical investigations and in therapy, e.g., for the clonogenic stem cell assay, for in vitro purging in autologous bone marrow transplantation, for regional perfusion of tumors, and, in small doses, for immunomodulation, where appropriate, in conjunction with "biological response modifiers."

Abstract: Purpose We prospectively studied the efficacy of high dose therapy (HDT) versus an oral maintenance treatment (OMT) in patients with stage IV soft tissue sarcoma (STS). Patients and Methods Both groups were pretreated with the CEVAIE combination consisting of carboplatin, etoposide, vincristine, actinomycin D, ifosfamide, and epirubicin. HDT consisted of a tandem cycle of thiotepa (600 mg/m2) plus cyclophosphamide (4,500 mg/m2) and melphalan (120 mg/m2) plus etoposide (1,800 mg/m2). This treatment was compared with OMT, consisting of four cycles trofosfamide (10 days 2 × 75 mg/m2/day) plus etoposide (10 days 2 × 25 mg/m2/day), and 4 cycles trofosfamide (10 days 2 × 75 mg/m2/day) plus idarubicin (10 days 4 × 5 mg/m2). Eligibility criteria were: diagnosis confirmed by reference pathology, primary stage IV, below 22 years of age, and having completed the study therapy. Results From 96 patients 45 were treated with HDT and 51 with OMT. The main risk parameters were equally distributed in both arms. After a median follow-up of 57.4 months, 11/45 (24.4%) patients in the HDT-arm and 26/51 (57.8%) patients in OMT-arm were alive. Kaplan–Meier analysis demonstrated an overall survival for the whole group of 0.27 (OMT group: 0.52, HDT group 0.27, log rank P = 0.03). The proportional hazard analysis for patients with rhabdomyosarcoma (RMS) or “RMS-like” tumors (77.1% of all patients) demonstrated an independent benefit of OMT on outcome. Conclusion Oral maintenance therapy seems to be a promising option for patients with RMS-like stage IV tumors. Pediatr Blood Cancer 2008;50:739–745. © 2008 Wiley-Liss, Inc.

Abstract: In studies on a model of induced pulmonary metastasis in mice a tumour host system was analysed which was not affected by immunogenicity of the tumour for the host; neither intensive immunosuppression nor immunization caused a significant change in the quantity of pulmonary metastatic nodules. In contrast the application of cytostatic drugs and of Corynebacterium parvum could modify the pulmonary resistance to the formation of tumour nodules by a factor greater than 100 in either direction. This finding confirms the observation of others that major modification of the resistance to metastatic tumour formation can occur independently of classical immunological mechanisms. Special attention is drawn to the fact that cyclophosphamide enhances the formation of metastatic nodules in this model by factors of 100 to more than 1,000, whereas other cytostatic drugs include the cyclophosphamide congeners iphosphamide and trophosphamide are active only by factors between 2 and 12. The possible practical significance of these findings is discussed. Chemicals/CAS: cyclophosphamide, 50-18-0; ifosfamide, 3778-73-2; trofosfamide, 22089-22-1; Alkylating Agents; Antineoplastic Agents; Busulfan, 55-98-1; Globulins; Mitolactol, 10318-26-0; Nitrogen Mustard Compounds