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PubMed1996

Development of a canine chemotherapeutic model with ifosfamide.

The purpose of this study was to develop a canine experimental model for neoadjuvant chemotherapy of primary bone tumors with ifosfamide, which is safe and clinically relevant for use in human beings with bone tumors. Our study was divided into two steps, each with four dogs. In the first step ifosfamide was administered for 4 consecutive days in three cycles with 3-week intervals between each cycle. For this first step a daily dosage of 300 mg/m2 of body surface resulted in only moderate leukopenia, whereas a daily dosage of 450 mg/m2 caused severe leukopenia. Therefore, to determine the maximal dose tolerable and to verify the results from step 1, we administered the higher daily dosage of 450 mg/m2 in step 2 for four successive cycles with 3-week intervals. In each step one dog died acutely after the first cycle of chemotherapy. In addition during step 2 one dog died of overwhelming sepsis after the second cycle of ifosfamide. The remaining five dogs survived without other appreciable laboratory abnormalities. Neither hematuria nor proteinuria was observed throughout the course of study, and relevant findings were not observed at autopsy. We determined that 450 mg/m2 was the maximal tolerated dosage of ifosfamide for our regimen, with the dose-limiting factor being myelosuppression, specifically leukopenia. Using this canine model, we can estimate the effect of ifosfamide on bone graft incorporations and the fixation of biologic prostheses that is clinically the most important aspect of limb salvage surgery.

Animals↗
PubMed1997

Influence of mesna on urotoxic effects of selected bromosubstituted analogs of ifosfamide.

Bromofosfamides, the group of novel compounds closely related to ifosfamide, are currently in the stage of advanced preclinical evaluation. Ifosfamide, although itself the effective antineoplastic drug useful in situations which have proved refractory to cyclophosphamide therapy, has the side-effect toxicities caused by its metabolities that pose clinically a very real problem. One of their manifestations is the severe urinary tract toxicity which now could be adequately managed by conjunctive administration of mesna (sodium 2-mercaptoethane sulphonate). In this study we have compared the magnitude of urotoxic effects elicited by ifosfamide and two bromofosfamide compounds--racemate and S(-) isomer of chlorobromofosfamide (ClBrs)--selected previously on the base of their superior antitumor activity in advanced animal tumor models. The urotoxic effects, expressed by the increase of urinary bladder weight and histopathologically defined organ wall edema, were estimated in healthy mice 24 h following single intraperitoneal or oral administrations of tested compounds which were applied in amounts equal to curative, sublethal or lethal doses. It was found that the expression of toxic effects revealed by both ClBrs was statistically significantly lower as compared to ifosfamide. Mesna coadministration prevented urotoxic effects almost completely in mice treated with ifosfamide or racemic ClBr. Somewhat lower efficacy of uroprotection with mesna was observed in the case of S(-) isomer of ClBr.

Administration, Oral↗
PubMed1996

[High-dose ifosfamide in the treatment of patients with soft tissue sarcoma].

The increasing doses of 2.4-3.5 g/m2 ifosfamide, i/v, dropwise, were administered for 40 min, on days 1-5 each week, for 3 weeks, in 4 courses. Simultaneously, MESNA was given in a dose two-thirds of that of ifosfamide. The maximum single tolerable dose of ifosfamide was 3.2 g/m2. The dose of 3.5 g/m2 proved neurotoxic causing encephalopathy. The other toxic effects were stage III-IV neutropenia (47%), nausea and vomiting (91%) and weakness (33%). No clinical evidence of renal failure was attributed to the high dosage of the drug in the course of assays of biochemical components of the blood, blood- and urine-beta-2-microglobulins, N-acetyl-D-hexoaminidase (NAG) level in urine, creatinine clearance and complex renoscintigraphy data. On days 3-5, ifosfamide treatment was followed by increase in NAG and beta-2-microglobulin levels in urine which pointed to the toxic effect exerted on the epithelium of renal tubules. The antitumor effect was apparent in 5 (29%) patients for 6 months, which testifies to the high effectiveness of ifosfamide treatment for soft-tissue sarcoma.

Adult↗
PubMed1997

Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines.

The anticancer oxazaphosphorine prodrugs cyclophosphamide and ifosfamide are activated in human liver by a 4-hydroxylation reaction catalyzed by multiple cytochrome P450 (CYP) enzymes. In the present study, we used a cultured human hepatocyte model to identify possible inducers of the CYP-catalyzed activation of these two anticancer prodrugs. Treatment of primary cultures of human hepatocytes with phenobarbital, dexamethasone, or rifampin elevated hepatocyte microsomal oxazaphosphorine 4-hydroxylation by up to 200-400% of control for both drug substrates. These inductions were associated with corresponding increases in immunoreactive CYP2B6, CYP2C8, CYP2C9, and CYP3A4, all previously shown to catalyze oxazaphosphorine activation. Rifampin (1 microM, 96-h exposure) was a particularly potent inducer of ifosfamide and cyclophosphamide 4-hydroxylation, as well as of CYP3A protein levels and CYP3A-dependent testosterone 6beta-hydroxylation. CYP3A4, CYP2C8, and CYP2C9 protein levels were also increased by exposure of the hepatocytes to cyclophosphamide or ifosfamide (50 microM), which thereby enhanced their own rates of 4-hydroxylation in the cultured hepatocytes. In one human hepatocyte culture that contained the polymorphically expressed CYP3A5 in addition to the more widely expressed CYP3A4, only CYP3A4 was induced by cyclophosphamide, ifosfamide, and rifampin. These studies: (a) demonstrate an underlying metabolic basis for the clinically important oxazaphosphorine autoinduction pharmacokinetics seen with these drugs in cancer patients; and (b) identify rifampin and other CYP inducers as potentially useful for increasing the rates of cyclophosphamide 4-hydroxylation and ifosfamide 4-hydroxylation in human liver in a manner that could favorably impact the clinical pharmacokinetics of these anticancer prodrugs.

Adult↗
PubMed1997

Renal dysfunctions secondary to ifosfamide treatment in children.

With the increasing use of ifosfamide in pediatric tumors, nephrotoxicity became the point of interest since it may cause chronic morbidity. In this study, the renal glomerular and tubular functions of 25 cases with solid tumors aged between 2-17 years (median 9) who were treated with ifosfamide, were investigated. For this purpose, routine blood urea, creatinine, calcium, phosphorus, electrolytes, urinary creatinine, phosphorus, glucose, protein and urinary retinol binding protein as well as microglobulin were evaluated. Except for two patients who had hypophosphatemia, phosphaturia, and proteinuria, all the cases had normal blood biochemistry, creatinine clearance, tubular phosphate reabsorption; and none had proteinuria, hematuria, or glycosuria. In spite of these findings, urine beta 2 microglobulin and retinol binding protein were found to be high in 11 patients and this elevation persisted during the following one year in 8 cases whose treatments were stopped and their levels increased in three patients who continued to receive fosfamide therapy. In correlation with the increasing cumulative dose of ifosfamide (32-126 g/m2), urinary retinol binding protein or beta 2 microglobulin of patients who are treated with ifosfamide may predict the existence of renal toxicity even if other routine renal function tests are normal. Thus, the periodic evaluation of urinary beta 2 microglobulin and retinol binding protein in patients receiving chemotherapy containing ifosfamide is recommended.

Adolescent↗
PubMed1997

A phase I/II study of sequential, dose-escalated, high dose ifosfamide plus doxorubicin with peripheral blood stem cell support for the treatment of patients with advanced soft tissue sarcomas.

BACKGROUND: This Phase I/II study investigates increasingly high doses of ifosfamide combined with full dose doxorubicin chemotherapy supported with peripheral blood stem cells (PBSC) and granulocyte-colony stimulating factor (G-CSF) in patients with metastatic soft tissue sarcoma (STS). METHODS: Patients with histologically proven metastatic or advanced adult STS without prior treatment received doxorubicin, 75 mg/m2, on Day 1 followed by 4-day continuous infusion of ifosfamide at 5 consecutive dose levels starting with 8 g/m2 and escalating to 16 g/m2 in increments of 2 g/m2. Three patients per dose level and a maximum of 5 treatment cycles per level at 3-week intervals were planned. Each cycle was followed by G-CSF and retransfusion of PBSC. PBSC separation was performed prior to chemotherapy by steady state mobilization with G-CSF. RESULTS: Eighteen patients (median age, 45 years, range, 25-57 years) were included, with 4, 3, 4, 4, and 3 patients assigned to Levels 1-5, respectively. Metastatic sites included the lungs in 12 patients (67%), lymph nodes in 8 patients (44%), and the liver in 5 patients (28%). Nine patients (50%) achieved objective responses with 4 complete responses (22%) and 5 partial responses (28%). Lung metastases and a histology of synovial sarcoma or malignant fibrous histiocytoma were favorable features for response to therapy. The median survival for all patients was 13+ months (range, 3-19+ months). Hematotoxicity was manageable and treatment could be administered at a median interval of 24 days. One case of World Health Organization Grade 3 neurotoxicity occurred. Nephrotoxicity was dose-limiting, with 1 patient in Level 4 (WHO Grade 2) and 2 patients in Level 5 (WHO Grade 3). CONCLUSIONS: Multiple cycles of dose-intensive therapy with doxorubicin and high dose ifosfamide can be administered safely with PBSC support. Nephrotoxicity is dose-limiting for ifosfamide at total doses of 16 g/m2. Multiple cycles of high dose chemotherapy at short treatment intervals using ifosfamide at a dose of 14 g/m2 should be investigated further in a neoadjuvant setting in patients with STS.

Adult↗
PubMedDate not supplied

An overview of cyclophosphamide and ifosfamide pharmacology.

Cyclophosphamide and ifosfamide are alkylating agents administered to treat malignant disease. They are prodrugs and require activation by hepatic microsomal enzymes before being metabolized to their respective cytotoxic species, phosphoramide mustard and ifosfamide mustard. These species alkylate DNA, forming DNA-DNA cross-links that result in inhibition of DNA synthesis and cell death. Resistance to oxazaphosphorines is poorly understood, although increased aldehyde dehydrogenase activity may be a significant factor. Although both compounds share a common metabolic pathway, 4-hydroxylation of ifosfamide occurs at a slower rate and to a lesser extent than that of cyclophosphamide. This difference significantly alters the toxicity profile of ifosfamide. Leukopenia is the dose-limiting toxicity of cyclophosphamide, and neurotoxicity is the dose-limiting toxicity of ifosfamide when preventive measures are taken to reduce urotoxicity. With recent findings concerning their basic and clinical pharmacology, the therapeutic index of these compounds can be improved.

Animals↗
PubMed1998

Thiodiglycolic acid is excreted by humans receiving ifosfamide and inhibits mitochondrial function in rats.

Thiodiglycolic acid has been identified as a major metabolite of the anticancer drug ifosfamide in humans. Patients treated with 12-16 g ifosfamide/m2.day excreted thiodiglycolic acid ranging from 0.10 +/- 0.02 mmol on the first day of therapy, to a maximum of 3.27 +/- 0.15 mmol on the fourth day of ifosfamide infusion. This amounted to 5.4 +/- 0.2% of the administered dose of ifosfamide appearing as thiodiglycolic acid in urine during a 5 days' continuous ifosfamide infusion. Thiodiglycolic acid (50mg/kg) administered to rats inhibited the carnitine-dependent oxidation of [1-14C]palmitic acid by 55%, but affected neither the oxidation of [1-14C]octanoic acid, which is carnitine-independent, nor the oxidation of [1, 4-14C]succinic acid, a marker of Kreb's cycle activity. Additionally, thiodiglycolic acid (30 microM) inhibited oxidation of palmitic acid but not palmitoyl-L-carnitine in isolated rat liver mitochondria, indicating that it either sequesters carnitine or inhibits carnitine palmitoyltransferase I. This study elucidates a specific mitochondrial dysfunction induced by thiodiglycolic acid which may contribute to the adverse effects associated with ifosfamide chemotherapy.

Animals↗
PubMed1998

Ifosfamide and docetaxel in non-small cell lung cancer.

Ifosfamide has been in use for several decades and is generally considered to be one of the most effective drugs for the treatment of non-small cell lung cancer (NSCLC). At the same time, docetaxel is one of the new, promising drugs with high antitumor activity in various solid tumors. In NSCLC, an objective remission rate of 33% could be achieved in chemotherapy-naive patients. Currently, clinical research with docetaxel in NSCLC patients focuses on various combinations of this drug with radiotherapy and a number of different cytostatic chemicals. There are good reasons for combining docetaxel with ifosfamide. In addition to the promising antitumor activity in NSCLC displayed by both drugs, it is an advantage that docetaxel and ifosfamide have only minimal overlapping nonhematologic toxicity. Moreover, the combination seems to be well founded due to the lack of cross-resistance between docetaxel and alkylators such as ifosfamide of the oxazaphosphorine type, which have shown synergistic antitumor activity in vivo. Based on this background, two phase I studies of docetaxel and ifosfamide have been initiated.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Toxicity of chemotherapeutical protocols in the treatment of uterine sarcomas (Vincristine, actinomycin D, Cyclophosphamide VAC versus ifosfamide).

OBJECTIVE: Uterine sarcomas are rare tumors which account for 1% of all genital tract malignancies. They have a poor prognosis with an overall survival of under 50% at 2 years. The benefit of chemotherapy is unclear and different chemotherapy protocols are used for the treatment of uterine sarcomas. But there is little experience about their toxicity because of the limited case series. So we compared VAC protocol and ifosfamiide for toxic effects. MATERIAL AND METHOD: We reviewed 13 cases which were diagnosed as uterine sarcomas and treated with surgery plus chemotherapy at The Department of Obstetrics and Gynecology, Akdeniz University School of Medicine from 1990 to 1995. Data were obtained from patient files. RESULTS: Mean age was 55.7 (range 38-70), 7 (53.8%) patients had malignant mixed mullerian tumors and 6 (46.1) had leiomyosarcomas. A total of 32 courses of chemotherapy were given -20 ifosfamide and 12 VAC therapy. Leucopenia, hepatic dysfunction and peripheral neuropathy were more frequent in the VAC group as 75%, 16.6%, versus 30%, 0%, 0%, in the iFosfamide group respectively. However, urothelial toxicity (35%) was more common in the ifosfamide group. CONCLUSION: VAC protocol is more toxic for the liver, hematopoietic and peripheral neurologic system. On the other hand the major toxicity of ifosfamide was on the urinary tract. Ifosfamide may be a good choice with less toxicity than VAC therapy in the treatment of uterine sarcomas.

Adult↗
PubMed1999

A Phase II study of paclitaxel and ifosfamide for patients with advanced refractory carcinoma of the urothelium.

BACKGROUND: Cisplatin-based combination chemotherapy for patients with advanced transitional cell carcinoma (TCC) of the urothelium has limitations, and new therapies need to be evaluated. METHODS: Ifosfamide 1.0 gm/m2 on Days 1-4 and paclitaxel 135 mg/m2 by 24-hour infusion on Day 4 were administered to 26 patients with locally unresectable or metastatic TCC. Cycles were repeated every 21 days for a maximum of 6 cycles; dose escalation was dependent on whether Grade 3 or 4 toxicities occurred. RESULTS: There were 24 males and 2 females, with a median age of 66 years and a median Eastern Cooperative Oncology Group performance status of 0. The median number of cycles administered was 3. Twelve patients had Grade 3 or 4 hematologic toxicities, including 1 patient who died of a gastrointestinal hemorrhage while pancytopenic. There were no episodes of neutropenic fever. Two patients each had a complete response (CR) that lasted 5 and 28 months, respectively (response rate: 15%; 95% CI: 2-45%), among the 13 patients who had received prior chemotherapy. Of the 13 patients without prior chemotherapy, there were 3 with complete responses and 1 with a partial response ranging from 8 to 25+ months (RR: 30.7%; 95% CI: 9-61%). CONCLUSIONS: The combination of ifosfamide and paclitaxel is well tolerated and can produce objective responses in patients who are chemonaïve or have had prior therapy. For previously untreated patients, the addition of ifosfamide does not appear to result in a better response rate than single agent paclitaxel; and for previously treated patients, the addition of paclitaxel does not appear to result in a better response rate than single agent ifosfamide.

Adult↗
PubMedDate not supplied

Ifosfamide metabolite chloroacetaldehyde causes renal dysfunction in vivo.

Renal injury is a common side-effect of the chemotherapeutic agent ifosfamide. Current evidence suggests that the ifosfamide metabolite chloroacetaldehyde may be responsible for this nephrotoxicity. The present study examined the effect of increasing amounts of intrarenally infused chloroacetaldehyde on kidney function, glutathione content and malondialdehyde formation. The ability of the uroprotectant medication sodium 2-mercaptoethanesulfonate (mesna) to prevent chloroacetaldehyde-induced renal injury was also assessed. Intrarenal chloroacetaldehyde infusion caused dose-dependent declines in glomerular filtration rate and p-aminohippuric acid clearance and increases in urine flow rate, sodium, glucose and protein excretion. These abnormalities were associated with progressive kidney glutathione depletion and malondialdehyde accumulation. Mesna infusion did not affect renal function but did cause a significant fall in kidney glutathione content. Simultaneous administration of chloroacetaldehyde and mesna only partially corrected renal functional abnormalities and prevented malondialdehyde accumulation but not glutathione depletion. These results show that the ifosfamide metabolite chloroacetaldehyde causes kidney dysfunction, glutathione depletion and lipid peroxidation in vivo. Mesna provides limited protection against chloroacetaldehyde nephrotoxicity, potentially explaining its inability to completely prevent ifosfamide-related renal injury in clinical practice.

Acetaldehyde↗
PubMed1990

Interstitial pneumonitis associated with ifosfamide therapy.

Ifosfamide and cyclophosphamide have many toxicities in common. Interstitial pneumonitis has not been reported previously as a side effect of ifosfamide therapy. The authors report the case of a 58-year-old woman who was treated with ifosfamide for soft tissue sarcoma. After the fifth cycle of chemotherapy she developed clinical evidence of interstitial pneumonitis, a diagnosis that was later confirmed at autopsy. The authors suggest that ifosfamide therapy was directly related to this patient's fatal case of interstitial pneumonitis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

The role of ifosfamide plus cisplatin-based chemotherapy as salvage therapy for patients with refractory germ cell tumors.

A prospective study of four cycles of etoposide with ifosfamide and cisplatin (VIP) chemotherapy was conducted in 42 germ cell tumor (GCT) patients who were refractory to cisplatin with etoposide/vinblastine-based therapy. Forty patients were evaluable for response. Ten patients (25%) had a complete response: seven to chemotherapy alone and an additional three patients after surgical resection of viable GCT. With a median follow-up of 15 months, four complete responders relapsed, and six patients (15%) remain in remission. Hematologic and nephrotoxicity were moderately severe. Durable complete responses with VIP as second salvage were achieved and suggests that ifosfamide adds efficacy to standard first-salvage therapy. The observed nephrotoxicity and myelotoxicity are considerations in the design of ifosfamide-cisplatin-based regimens. Hematopoietic growth factors may be useful in ameliorating myelotoxicity. The early use of ifosfamide-based chemotherapy may reduce the nephrotoxicity exacerbated by prior cisplatin. A trial of VIP as first salvage after a relapse from a complete response to platinum-based induction therapy is warranted. The modest proportion of patients who achieve a durable remission to VIP as second salvage emphasizes the need for more efficacious salvage therapy for patients who do not achieve a durable complete response.

Adolescent↗
PubMed1994

Phase II study of ifosfamide and mesna in refractory adenocarcinoma of the endometrium. A Gynecologic Oncology Group study.

BACKGROUND: Ifosfamide has antitumor activity in previously treated ovarian epithelial tumors, squamous carcinomas of the cervix, trophoblastic disease, and untreated uterine sarcomas in Gynecologic Oncology Group (GOG) trials. Because cyclophosphamide and other alkylating agents are known to produce responses in adenocarcinoma of the endometrium, a Phase II trial of ifosfamide and the uroprotector, mesna, was undertaken. METHODS: Fifty-two patients with advanced adenocarcinoma of the endometrium recurrent after surgery and/or radiation therapy and refractory to first-line chemotherapeutic agents were treated with ifosfamide, 1.2 g/m2 intravenous daily for 5 days every 4 weeks, and mesna, 300 mg/m2 intravenous every 4 hours for 3 doses daily for 5 days. Two patients were ineligible--one due to prior therapy and one due to a second malignancy. Three patients had an inadequate trial, and 7 were inevaluable for response, leaving 47 patients evaluable for toxicity and 40 patients evaluable for response. Thirty-seven patients had undergone hysterectomy, 30 had received radiation therapy, and 32 had received prior cisplatin-based chemotherapy. All patients were GOG performance status 0, 1, or 2. RESULTS: Complete responses were observed in three (7.5%) and partial responses in three patients (7.5%), for a response rate of 15% (95% confidence interval for the true response rate was 5.5%-29.8%). Severe (Grade 3 or 4) leukopenia and anemia were seen in 25 and 4 patients, respectively. Severe thrombocytopenia was observed in 7 patients. Five patients had Grade 3 or 4 neurotoxicity, and one had Grade 3 renal impairment. Reversible alopecia was universal. CONCLUSIONS: This dose and schedule of ifosfamide and mesna is active in patients with adenocarcinoma of the endometrium failing platinum-based therapy. Phase II testing in untreated patients is under way.

Adenocarcinoma↗
PubMed2001

Phase II study of paclitaxel, ifosfamide, and carboplatin in patients with recurrent or metastatic head and neck squamous cell carcinoma.

BACKGROUND: In the current study the authors assessed the antitumor activity (including response rate, duration of response, and survival) and toxicity profile (including anorexia, fatigue, emesis, and peripheral neuropathy) of a combination of paclitaxel, ifosfamide, and carboplatin (TIC) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). The trial hypothesis was that the TIC therapeutic index would be as high as that of paclitaxel, ifosfamide, and cisplatin (TIP) in this setting, but with less toxicity. METHODS: Patients with recurrent or metastatic SCCHN were treated with 175 mg/m(2) of paclitaxel as a 3-hour infusion on Day 1, 1000 mg/m(2) of ifosfamide as a 2-hour infusion on Days 1-3, 600 mg/m(2) of mesna on Days 1-3, and carboplatin (area under the concentration-time curve of 6) as a 30-minute infusion on Day 1; the regimen was repeated every 3-4 weeks. All patients were premedicated with dexamethasone, diphenhydramine, and cimetidine before paclitaxel infusion. Prophylactic hematopoietic growth factors were not given. RESULTS: Among 56 patients entered onto the study, 55 patients were analyzed for survival rates (locoregional recurrence alone in 56% of patients and distant metastasis with or without locoregional recurrence in 44% of patients). Fifty-four patients were evaluable for tumor response and toxicity. A total of 32 patients (59%) had disease that responded to treatment; the complete response rate was 17% (9 of 54 patients). The median duration of the responses was 3.7 months (95% confidence interval [95% CI], 3.4-7.8 months) and that of complete responses was 9.7 months (95% CI, 7.4 months to date of last follow-up). The median duration of follow-up care in all patients was 13.5 months. The median survival time for all patients was 9.1 months (95% CI, 7.9-12.2 months). The regimen was well tolerated. Neutropenic fever developed in 30% of the patients; 1 patient died of neutropenia and sepsis. Other toxic effects included Grade 2-3 anorexia in 13% of patients, Grade 2-3 weight loss in 11% of patients, Grade 2-3 fatigue in 27% of patients, Grade 2-3 nausea/emesis in 13% of patients, and Grade 2-3 peripheral neuropathy in 9% of patients (toxicity grading based on the National Cancer Institute's Common Toxicity Criteria). Red blood cell and platelet transfusions were required in 13% and 7% of patients, respectively. CONCLUSIONS: The TIC regimen had high antitumor activity in patients with recurrent or metastatic SCCHN, with a 59% major response rate (17% complete response rate with relatively durable complete responses). Neutropenic fever developed in 30% of the patients, the incidence of which might have been decreased by prophylactic antibiotics or hematopoietic growth factor support. Other toxic effects included significantly lower rates and less severe instances of anorexia, emesis, fatigue, and peripheral neuropathy than those reported with the previously studied TIP regimen. The TIC regimen currently is being studied as an induction chemotherapy regimen in previously untreated patients with locally advanced SCCHN. The activity of TIC (a novel paclitaxel and ifosfamide-based regimen) in patients with recurrent or metastatic SCCHN should be confirmed in a Phase III randomized trial.

Adult↗
PubMed1985

Identification and quantification of metabolite conjugates of activated cyclophosphamide and ifosfamide with mesna in urine by ion-pair extraction and fast atom bombardment mass spectrometry.

The high bladder toxicity of the alkylating oxazaphosphorine anticancer drugs, cyclophosphamide and ifosfamide is effectively reduced by the concomitant administration of mesna (sodium 2-mercaptoethane sulphonate). The formation and rapid urinary excretion of conjugates of the activated (4-hydroxylated) oxazaphosphorine metabolites with mesna has been suggested as the pharmacological basis for the selective detoxification, but separation and identification of such metabolites in vivo have been extremely difficult due to their high polarity and chemical lability. In this study an ion-pair extraction procedure in combination with positive and negative ion fast atom bombardment mass spectrometry has been developed which enabled the identification and quantification of the conjugation products of activated oxazaphosphorine metabolites with mesna in urine. The conjugates extracted as the tetra-n-butylammonium salts are directly identified by their characteristic positive molecular ion adducts and fragment ions, and the corresponding abundant molecular anions. The pattern of molecular and fragment ion formation was established by comparison of the fast atom bombardment mass spectra of synthetic cyclophosphamide-mesna conjugates with various organic and inorganic counter ions. The ifosfamide-4-(2-thioethylsulphonate) (ifosfamide-mesna) conjugate was identified as a metabolite in the urine of rats, and in patients after administration of the combination, ifosfamide + mesna. By means of a two-step extraction and with the use of suitable analogues as internal standards, procedures for the quantification of parent oxazaphosphorine and of oxazaphosphorine-mesna conjugates by negative ion fast atom bombardment mass spectrometry have been developed, and first examples for the determination of excretion kinetics are described.

Acrolein↗
PubMedDate not supplied

Phase II trial of ifosfamide and mesna in previously treated patients with non-Hodgkin's lymphoma: Cancer and Leukemia Group B study 8552.

Ifosfamide (1.25 g/m2 intravenously/day x 5) with mesna (20 per cent of the ifosfamide dose x six doses on each day of ifosfamide therapy) was administered to 46 previously treated patients with non-Hodgkin's lymphoma of which 31 were eligible and evaluable. A 29 per cent response rate (9/31) was observed (two CR and seven PR) with a median duration of response of 2.5 months. Myelosuppression was dose-limiting. Hemorrhagic cystitis was observed in three patients (10 per cent). Nausea and vomiting was generally mild or moderate. One patient developed transient neurotoxic symptoms with confusion and disorientation. An additional patient developed an anaphylactic-type reaction with shortness of breath and respiratory stridor during the fourth course of therapy. Ifosfamide, as a single agent, produces remissions of limited duration in non-Hodgkin's lymphoma in patients in second or third relapse.

Adolescent↗