mesna and Kidney-Diseases

Platinum-type drugs have proven to be valuable in the treatment of a variety of solid tumors, beginning with the commercial approval of cisplatin 18 years ago. There are several clinically important toxicities commonly associated with the administration of these drugs. Despite the extensive use of cisplatin and carboplatin, the fundamental chemical transformations and mechanisms that underlie their antitumor and toxic effects have not been fully characterized. Several first-generation protective thiols have been clinically studied in an attempt to reduce the toxicity of platinum-type drugs; while some of these agents appear to protect against certain toxicities, nearly all platinum-protecting drugs have their own intrinsic toxicities, which can be additive to the toxicity of platinum-type drugs. Tumor protection by platinum-protecting drugs is an additional untoward effect that is associated with certain types of agents and must be addressed with care. Recent advances in theoretical and laboratory methods and the use of supercomputers have extended our understanding of the possible major mechanisms underlying platinum drug antitumor activity and toxicity; we present strong evidence that there are two classes of chemical species of platinum drug. One class appears to predominantly account for the antitumor activity, and the other class of chemical species produces many of the toxic effects of platinum drugs. We have discovered a new nontoxic, second-generation platinum-protecting agent, known as BNP7787, which appears to selectively inactivate and eliminate toxic platinum species. BNP7787 has recently entered phase I clinical testing in cancer patients.

Topics: Amifostine; Animals; Antineoplastic Agents; Cisplatin; Drug Interactions; Humans; Kidney Diseases; Mesna; Platinum Compounds; Protective Agents; Sulfhydryl Compounds

Nephrotoxicity is a relatively common and potentially serious adverse effect of treatment with certain cytotoxic drugs (especially ifosfamide). The patient may develop severe chronic proximal tubular toxicity. It is therefore very important to attempt to reduce the frequency and severity of acute and chronic nephrotoxicity resulting from chemotherapy. A logical approach is described, with particular reference to ifosfamide and cisplatin, involving improved evaluation of the important clinical features of nephrotoxicity and a greater understanding of its pathogenesis. This approach will facilitate the development of logical preventive strategies, or less toxic analogues, or both. The methods used may also enable prediction of the potential nephrotoxicity of newly developed cytotoxic agents.

Topics: Adult; Antineoplastic Agents; Cell Line; Chelating Agents; Child; Child, Preschool; Cisplatin; Humans; Ifosfamide; Kidney; Kidney Diseases; Kidney Tubules; Mesna; Neoplasms; Prognosis; Risk Factors; Thiosulfates

With the increasing use of ifosfamide in pediatric malignancies, nephrotoxicity has emerged as a potentially serious adverse effect, which may be dose-limiting or may cause severe chronic morbidity, including glomerular impairment and/or Fanconi's syndrome. The purpose of this review was (1) to improve the documentation of ifosfamide nephrotoxicity in children, and (2) to consider the possible causative role of ifosfamide metabolites.. (1) A grading system was developed that allowed documentation of the nature and severity of published reports of ifosfamide-induced nephrotoxicity, and evaluation of patient and treatment-related risk factors. (2) The relationship between the pharmacology of ifosfamide/mesna and nephrotoxicity was investigated by examination of published data, especially that concerning the quantitative differences in the metabolism of ifosfamide and its nonnephrotoxic structural isomer, cyclophosphamide.. (1) Examination of 16 published reports (with assessable data from 40 children) demonstrated that ifosfamide-induced nephrotoxicity was associated with a wide range of patient ages and ifosfamide cumulative doses given by different administration schedules. (2) Chloroacetaldehyde, a major metabolite of ifosfamide only, may be at least partly responsible for the renal toxicity of this drug. Although mesna may be capable of detoxifying the toxic metabolite(s), delivery to the renal tubule may not be sufficient to provide adequate protection of tubular glutathione from depletion by the metabolite(s), which results in a failure to prevent nephrotoxicity.. Increased understanding of the interindividual variability in the extent and nature of ifosfamide metabolism, which may be a major determinant of susceptibility to renal damage, may lead to improved use of the drug with less nephrotoxicity.

Topics: Child; Humans; Ifosfamide; Kidney Diseases; Mesna; Risk Factors

Renal dysfunction and urinary disorders are the most troublesome adverse reaction to anticancer agents such as cisplatin (CDDP) and ifosfamide (IFM). A number of antidotes such as sodium thiosulfate (STS), WR-2721, thiourea, diethyldithiocarbamate and bismuth subnitrate have been tested to reduce the nephrotoxicity of CDDP. One notable method previously reported by Baba et al. and Pfeifle et al involves the i.v. administration of STS to prevent the nephrotoxicity of CDDP given locally. Since STS has been proven clinically effective in reducing such side effects, we initiated a study of STS in patients with advanced non-small-cell lung carcinoma who were given a combination of CDDP and vindesine (VDS) systemically. Urinary levels of beta 2-microglobulin (BMG) and N-acetyl-beta-D-glucosaminidase (NAG) were measured as an index of proximal tubular function. Analysis of both levels indicated that STS suppressed CDDP nephrotoxicity to a minimal level. Therefore, the present study clearly demonstrates that systemic administration of STS reduces the side effects of CDDP to a minimal level without impairing its antitumor activity and that STS treatment is applicable in a repeated chemotherapy using CDDP alone or in combination with other antitumor agents. Furthermore, it has been reported that urinastatin and fosfomycin may exert potent effects to reduce untoward nephrotoxicity of CDDP. IFM causes urinary disorders such as hematuria, reducing its clinical usefulness, Sodium 2-mercaptoethane sulfonate (mesna) is the thiol compound which binds specifically to the urinary toxic metabolites of IFM, and thereby decreases the undesirable effect of IFM on the lower urinary tract, especially on the bladder. Recently, it was reported by a Osaka mesna study group that mesna is useful for the prevention of IMF-induced urinary disorders. It was considered that above new treatments were required in repeating chemotherapy which induced urogenital toxicity.

Topics: Antidotes; Antineoplastic Agents; Cisplatin; Humans; Ifosfamide; Kidney Diseases; Mesna; Thiosulfates

Topics: Biotransformation; Cisplatin; Cyclophosphamide; Humans; Kidney Diseases; Mesna; Urinary Bladder Diseases

The purpose of this study was to examine the efficacy of sodium 2-mercaptoethanesulfonate (MESNA), a reactive oxygen scavenger, in at-risk patients given radiographic contrast agents. Contrast-induced nephropathy (CIN) is a common complication of radiographic procedures; reactive oxygen species (ROS) could play a key role.. We conducted a randomized, double-blinded, placebo-controlled trial in 100 patients with stable serum creatinine levels ≥ 150 µmol/l. They received an infusion of either 1,600 mg of MESNA (n = 51) or placebo (n = 49) plus 0.9% saline prior to and after contrast administration. CIN was defined as a ≥ 25% increase in serum creatinine after 48 h compared to baseline.. CIN occurred in 7 patients in the placebo group and none in the MESNA group (p = 0.005). The adjusted odds ratio for CIN was 0.17 (95% confidence interval 0.03 - 0.80, p = 0.026) in the MESNA group compared to the placebo group. Cystatin C concentrations decreased slightly in the MESNA group but increased in the control group (p < 0.05).. MESNA plus volume expansion before and during contrast exposure was effective in this single-center study for preventing CIN compared to volume expansion alone.

Topics: Aged; Contrast Media; Double-Blind Method; Female; Humans; Kidney Diseases; Kidney Function Tests; Male; Mesna; Middle Aged; Placebos; Protective Agents; Statistics, Nonparametric; Treatment Outcome

BNP7787 (disodium 2,2'-dithio-bis-ethane sulphonate; Tavocept) is a novel agent developed to protect against cisplatin (cis-diammine-dichloroplatinum(II))-associated chronic toxicities. In this study, we determined the recommended dose of BNP7787 when preceding a fixed dose of cisplatin, the pharmacokinetics (PKs) and the possible reduction of saline hydration. Patients with advanced solid tumours received BNP7787 in escalating doses of 4.1-41 g m(-2) as a 15-min intravenous (i.v.) infusion followed by cisplatin 75 mg m(-2) as a 60-min i.v. infusion together with pre- and postcisplatin saline hydration in a volume of 2200 ml; cycles were repeated every 3 weeks. PK was carried out using BNP7787, cisplatin and the combination. Twenty-five patients were enrolled in stage I of the study to determine the recommended dose of BNP7787. No dose-limiting toxicity was reached. The highest dose level of 41 g m(-2) resulted in a low incidence of grade 2 toxicities, being nausea and vomiting, dry mouth or bad taste and i.v. injection site discomfort. Doses of BNP7787 > or = 18.4 g m(-2) did not show a drug interaction between BNP7787 and cisplatin. In stage II of the study, patients received a fixed dose of BNP7787 of 18.4 g m(-2) preceding cisplatin and were entered in prespecified reduced saline hydration steps. A total of 21 patients in cohorts of six to nine patients received reduced saline hydration of 1600 ml (step A), 1000 ml (step B) and 500 ml (step C). In step C, two out of six evaluable patients experienced grade 1 nephrotoxicity. Cisplatin acute toxicities in all 46 patients were as expected. Only five patients complained of paresthesias grade 1 and six developed slight audiometric changes. Partial tumour response was observed in four patients and stable disease in 15 patients. In conclusion, BNP7787 was tolerated well up to doses of 41 g m(-2). The recommended dose of 18.4 g m(-2) enabled safe reduction of the saline hydration schedule for cisplatin to 1000 ml. Further studies will assess whether BNP7787 offers protection against platinum-related late side effects.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Dehydration; Female; Humans; Kidney Diseases; Male; Mesna; Middle Aged; Neoplasms

The nephrotoxicity induced by contrast media remains a serious clinical problem, and the underlying mechanism has not been completely understood. Experimental and clinical investigations suggest that reactive oxygen species (ROS) are critical determinants of radiocontrast nephropathy (RCN), and that antioxidants can prevent this damage.. Cultured human proximal renal tubule cells (HK-2) were exposed to hydrogen peroxide (H2O2) at different concentrations. H2O2-induced tubular DNA damage was examined in the presence of the antioxidant MESNA (sodium-2-mercaptoethane sulphonate). The induction of DNA damage was measured with the alkaline comet assay (single cell gel electrophoresis). We also studied 12 patients with stable renal impairment (median baseline creatinine 296 micromol/l; range: 203-495 micromol/l) undergoing cardiac catheterization/intervention prospectively. Patients received 800 mg MESNA intravenously 30 min before exposure to the contrast agent in addition to 0.9% saline hydration.. In the cell cultures, oxidative stress on HK-2 cells induced increased DNA migration in the comet assay. Treatment of tubular cells with the antioxidant MESNA prior to the addition of H2O2 significantly reduced DNA migration in the comet assay. In the clinical study, treatment of the patients with MESNA prevented the adverse renal effect of contrast media (median serum creatinine 293; range: 187-433 micromol/l) 48 h after coronary angiography/intervention.. Both the in vivo and the in vitro studies suggest that the ROS-mediated renal injury could be inhibited by a potent antioxidant such as MESNA.

Topics: Antioxidants; Cardiac Catheterization; Cell Line, Transformed; Contrast Media; Creatinine; Humans; Hydrogen Peroxide; Kidney Diseases; Kidney Tubules, Proximal; Mesna; Oxidants; Prospective Studies; Reactive Oxygen Species

There is evidence that continuous infusion allows the delivery of higher doses of a drug while reducing the incidence of neurologic and renal toxicity. To verify prior to phase II testing the feasibility of ambulatory treatment with high-dose ifosfamide/mesna by continuous infusion in adult solid tumours, the maximum tolerated dose (MTD) and the non-haematological dose-limiting toxicities for the achievement of 2 courses of therapy were determined.. Thirty-two patients with advanced solid tumours were given continuous-infusion ifosfamide, from 9 to 16 g/m2, over 4 consecutive days, with equidose mesna uroprotection and granulocyte colony-stimulating-factor support; courses were repeated every 3 weeks. Total dose/course was escalated by 1 g/m2, in cohorts of 3 to 5 patients until the MTD was determined.. At 16 g/m2, the dose-limiting toxicity was renal, with 2 of the 5 patients treated developing renal failure. Haematological toxicity was dose-related and significant at higher dosages, but generally surmountable. Ifosfamide at 15 g/m2/course with mesna uroprotection was identified as the MTD.. The present study shows that high-dose continuous-infusion ifosfamide, administered by portable infusion pumps, is feasible in an ambulatory regimen, with acceptable non-haematological toxicity and good patient compliance.

Topics: Adult; Aged; Ambulatory Care; Female; Granulocyte Colony-Stimulating Factor; Humans; Ifosfamide; Immunologic Factors; Infusions, Intravenous; Kidney Diseases; Male; Mesna; Middle Aged; Neoplasms; Neutropenia; Recombinant Proteins; Remission Induction; Treatment Outcome

Forty three patients with histologically confirmed malignant mesothelioma were entered onto an Eastern Cooperative Oncology Group phase II study of ifosfamide given with mesna. Eligibility criteria included adequate performance status, hemogram and renal functions. Ifosfamide was given at 1.5 g/m2 in 200 ml of normal saline over 30 minutes by intravenous infusion on days 1 to 5 of each 21 day cycle. Mesna was given at 300 mg/m2 on each day of ifosfamide at 0, 4 and 8 hours. Two patients were cancelled and one patient was ineligible. The most common toxicity was haematologic. More than 50% of the patients had at least one episode of severe or life threatening toxicity and 2 patients had lethal toxicity (1 renal and 1 pulmonary oedema attributed to treatment), and an additional 4 patients died while on study (2 of cardiac and 2 of cerebral vascular disease not considered directly related to treatment). Of the 40 eligible patients one was unevaluable for response, and one patient had a partial response lasting 6.3 months. Twenty four patients had a no change status with a median duration of 5 months. The median time to treatment failure for all eligible patients was 2.5 months. The median overall survival time (from registration) for all eligible patients was 6.9 months. In multi variable models, factors that predicted for a statistically significant poorer survival were age > or = 62, stage > or = 3, performance status poorer than 0 to 1 and prior surgery (i.e.: more than biopsy).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Drug Administration Schedule; Female; Humans; Ifosfamide; Infusions, Intravenous; Kidney Diseases; Male; Mesna; Mesothelioma; Middle Aged; Peritoneal Neoplasms; Pleural Neoplasms; Proportional Hazards Models; Survival Analysis

The dose-limiting toxicity in two separate phase I trials of the high-dose single agents ifosfamide and carboplatin was renal insufficiency at 18 g/m2 and hepatic and ototoxicity at 2,400 mg/m2, respectively. In this phase I study, 16 adults were treated with ifosfamide at 75% of the single-agent maximum-tolerated dose (MTD) (12 g/m2) and escalating doses of carboplatin (400 to 1,600 mg/m2) to determine the nonhematologic dose-limiting toxicity and the maximum-tolerated dose of the combination. Both drugs as well as mesna for uroprotection were given by continuous infusion over 4 days with an additional day of mesna (total dose per course, 15 g/m2). Autologous bone marrow support was stipulated for subsequent dose levels once granulocytes remained less than 500/microL for more than 14 days in two of three to five patients entered at a given dose level. Autologous bone marrow support was used at doses above the 400 mg/m2 carboplatin dose level. At the maximum-tolerated dose level of 1,600 mg/m2 of carboplatin, renal toxicity precluded further dose escalation. Of the five patients entered at this dose level, reversible creatinine elevation greater than 2 mg/dL (median peak, 2.6 mg/dL) was observed in three patients, and irreversible renal failure occurred in an additional patient (peak creatinine, 6.9 mg/dL. Transient gross hematuria appeared more common with the combination than with ifosfamide alone. Two patients developed severe somnolence and confusion associated with a rising creatinine. There were two complete (CRs) and four partial responses (PRs) in 14 heavily pretreated assessable patients (including four partial or complete responses in eight assessable patients with advanced refractory sarcoma, and one CR in two patients with germ cell carcinoma). Carboplatin and ifosfamide appear to have overlapping renal toxicity. Nevertheless, carboplatin and ifosfamide can be combined at 80% and 75% of the single-agent maximum-tolerated doses, respectively, with acceptable nonhematologic toxicity. Ifosfamide and carboplatin are an attractive core combination for further studies in the treatment of sarcoma, germ cell, ovarian, and lung carcinomas.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carboplatin; Combined Modality Therapy; Creatinine; Drug Administration Schedule; Drug Evaluation; Female; Hematologic Diseases; Humans; Ifosfamide; Kidney Diseases; Male; Mesna; Middle Aged; Neoplasms; Neoplasms, Germ Cell and Embryonal; Nervous System Diseases; Sarcoma; Survival Rate

In two sequential trials, 154 patients were treated with dosages of ifosfamide, ranging between 8 and 18 g/m2 divided over 4 days, with mesna uroprotection. The first was a phase II efficacy trial in 125 advanced sarcoma patients (Antman et al: J Clin Oncol 7:126-131, 1989), while the second was a dose escalation trial involving 29 patients (Elias et al: J Clin Oncol 8:170-178, 1990). In the first trial, patients received 8 to 10 g/m2 ifosfamide either by bolus or continuous infusion. The response rate for the 64 patients receiving bolus administration was 23% compared with 12% for the 60 patients receiving a continuous infusion schedule (P = .09). Of the 154 patients, 144 had sarcoma and had failed at least one previous regimen. Of these 144, 4% responded completely and 23% had a complete or partial response. The maximum tolerated dose of ifosfamide was 16 g/m2 in the second trial. Dose-limiting renal toxicity was observed at 18 g/m2 ifosfamide (Elias et al: J Clin Oncol 8:170-178, 1990). The duration of myelosuppression and the frequency and severity of mucositis and renal tubular acidosis were dose-dependent. A median of 11 days (range, 8 to 18) of granulocytopenia (less than 500/microL) were observed. Thus, autologous bone marrow reinfusion was not required. Severe central nervous system toxicity (transient confusion, hallucinations, and somnolence) was observed sporadically at both low- and high-dose levels. The first four patients on the standard-dose study did not receive mesna because it was unavailable; three developed gross hematuria. In patients who received mesna, hematuria was uncommon. Hematuria in the group as a whole was significantly associated with a lack of uroprotection, but was not associated with prior cyclophosphamide, pelvic radiotherapy, age, or bolus versus a continuous infusion schedule. Patients receiving ifosfamide with mesna uroprotection can tolerate considerable dose escalation over the usual prescribed doses before nonhematologic toxicity becomes dose-limiting. Ifosfamide, with its broad activity in solid tumors, may prove to be an important addition to high-dose combination-chemotherapy regimens (Elias et al: J Clin Oncol 8:170-178, 1990).

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Child; Child, Preschool; Cystitis; Drug Administration Schedule; Drug Evaluation; Hematologic Diseases; Humans; Ifosfamide; Kidney Diseases; Mesna; Middle Aged; Pulmonary Fibrosis; Sarcoma

Previous studies from our laboratory have identified a role for gamma-glutamyl transpeptidase (GGT) in BNP7787 (disodium 2,2'-dithio-bis ethane sulfonate, dimesna, Tavocept™)-mediated cisplatin nephroprotection. Dekant has proposed that gamma-glutamyl transpeptidase (GGT), aminopeptidase N (APN) and cysteine-conjugate-β-lyase (CCBL) comprise a multi-enzyme pathway that acts on xenobiotic-glutathione conjugates converting them to nephrotoxic metabolites. We report modulation of APN activity within this pathway by BNP7787-derived mesna-disulfide heteroconjugates.. A fluorimetric assay was used to determine the effect of BNP7787, BNP7787-derived mesna-disulfide heteroconjugates, and the BNP7787 metabolite, mesna (sodium 2-mercaptoethane sulfonate), on the initial velocity and overall progress curve of the human APN reaction in vitro.. Neither BNP7787 nor mesna-cysteinyl-glutamate inhibited human APN. Select BNP7787-derived mesna-disulfide heteroconjugates (mesna-cysteine, mesna-glutathione, mesna-cysteinyl-glycine) and high concentrations of mesna inhibited APN activity. Allosteric effects on the enzyme progress curve outside of the linear initial velocity region were observed for mesna-cysteinyl-glycine, mesna-glutathione and mesna-cysteinyl-glutamate and appeared to be a function of having both mesna and di- or tri-peptide functionalities in one molecule. In situ-generated mesna-cisplatin conjugates were not a substrate for human APN.. BNP7787-mediated prevention or mitigation of cisplatin-induced nephrotoxicity may involve APN inhibition by certain BNP7787-derived mesna-disulfide heteroconjugates and appears correlated to the presence of a glycinate moiety and/or an anionic group. Two general mechanisms for BNP7787-mediated nephroprotection of cisplatin-induced nephrotoxicity involving the GGT, APN and CCBL nephrotoxigenic pathway are proposed which acting in a concerted and/or synergistic manner, and thereby prevent or mitigate cisplatin-induced renal toxicity.

Topics: Allosteric Regulation; Biocatalysis; CD13 Antigens; Cisplatin; Cysteine; Dipeptides; Glutathione; Glycine; Humans; Kidney Diseases; Kinetics; Mesna; Models, Biological; Protective Agents; Recombinant Proteins

Chloroacetaldehyde (CAA) is the putative metabolite responsible for ifosfamide-induced nephrotoxicity. Whereas evidence suggests that sodium 2-mercaptoethanesulfonate (mesna) and amifostine protect renal cells against CAA toxicity in vitro, their efficacy in clinical studies is controversial. To better understand the discrepancy between in vivo and in vitro results, we combined the in vivo intraperitoneal administration of either saline or mesna (100 mg/kg) or amifostine (200 mg/kg) in rats and the in vitro study of CAA toxicity to both proximal tubules and precision-cut renal cortical slices. The measured renal cortical concentrations of mesna and amifostine were 0.6+/-0.1 micromol/g and 1.2+/-0.2 micromol/g, respectively; these drugs did not cause renal toxicity. Despite this, none of the adverse effects of 0.5 mM CAA was prevented by the previous in vivo administration of mesna or amifostine. Toxicity of 0.5 mM CAA to rat proximal tubules was shown by the fall of cellular adenosine triphosphate (ATP), total glutathione and coenzyme A + acetyl-coenzyme A levels and by the altered metabolic viability of renal cells. Long-term exposure of cortical slices to CAA concentrations > or =30 microM caused severe cell toxicity (i.e. decrease in cellular ATP, total glutathione, and coenzyme A + acetyl-coenzyme A levels), which was not prevented by the in vivo administration of mesna or amifostine.

Topics: Acetaldehyde; Acetyl Coenzyme A; Adenosine Triphosphate; Amifostine; Animals; Disease Models, Animal; Drug Therapy, Combination; Glutathione; Glutathione Disulfide; Injections, Intraperitoneal; Kidney; Kidney Diseases; Kidney Tubules, Proximal; Male; Mesna; Organ Culture Techniques; Radiation-Protective Agents; Rats; Rats, Wistar

Ifosfamide is an oxazophosphorine widely used in the treatment of cancer in children and adults. Nephrotoxicity and neurotoxicity are major side effects. The aim of this study was to use high-resolution proton nuclear magnetic resonance (1H NMR) spectroscopy of urine to identify novel biochemical markers of ifosfamide-induced toxicity. Urine samples were collected from 10 nonencephalopathic patients (who had not previously received nephrotoxic chemotherapy) immediately prior to the first ifosfamide dose and at timed intervals for up to four treatment cycles. The findings were compared with those for urine samples collected from five patients during acute encephalopathic episodes. 1H NMR urinalysis identified a series of characteristic time-related changes in the excretion profiles of low molecular weight endogenous metabolites during ifosfamide therapy. These changes included a decreased excretion of hippurate and an increased excretion of glycine, histidine, glucose, lactate, and trimethylamine-N-oxide. Two nonencephalopathic patients had marked but transient glutaric or adipic aciduria during the second cycle of ifosfamide treatment. Urinary retinol-binding protein rose acutely after each treatment cycle but usually returned to baseline levels. Maximum renal toxicity was observed by the fourth treatment cycle. The ratio of the urinary excretion of the uroprotectant mesna (active form) to dimesna (inactive form) correlated with the degree of renal toxicity. For the encephalopathic patients, the ifosfamide-induced changes in the urinary low molecular weight metabolite profile were similar to those for the nonencephalopathic group. In contrast to previous reports, none of the encephalopathic group developed glutaric aciduria, and i.v. methylene blue did not reverse neurotoxicity in the two patients who received it. The results suggest that ifosfamide nephrotoxicity involves both cortical and medullary regions of the nephron and that the urinary mesna:dimesna ratio may be important in assessing the degree of cytoprotection. This study demonstrates that 1H NMR can provide novel biochemical information on ifosfamide-induced toxicity and will be of value in the optimization of ifosfamide therapy.

Topics: Adult; Amino Acids; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Brain Diseases; Dicarboxylic Acids; Humans; Ifosfamide; Kidney Cortex; Kidney Diseases; Kidney Function Tests; Kidney Medulla; Magnetic Resonance Spectroscopy; Mesna; Methylene Blue; Molecular Weight; Neoplasms; Protons; Retinol-Binding Proteins; Urinalysis

Ferric nitrilotriacetate (Fe-NTA) is a renal toxicant and carcinogen in rats and mice. We found that its administration results in formation of 4-hydroxy-2-nonenal (HNE) in the renal proximal tubule cells of rats, and 8-hydroxydeoxyguanosine (8-OHdG) adducts in their DNA, suggesting a role for oxidative stress. Since 2-mercaptoethane sulfonate (MESNA) and N-acetylcysteine (NAC), administered orally, have been shown to increase the kidney levels of free thiol groups, their influence on the renal toxicity and carcinogenicity induced by Fe-NTA was examined in the present study. Male Wistar rats were intraperitoneally injected with Fe-NTA (12 mg Fe/kg), and MESNA (100 mg/kg) or NAC (200 mg/kg) was given orally 1 h before and 1 h after this treatment. The animals were killed for tissue analyses 3 h after the Fe-NTA exposure. In accord with our previous reports, HNE-modified protein was detected in the proximal tubules of Fe-NTA-treated rats by means of immunohistochemistry. Likewise, levels of 8-OHdG in the renal nuclear DNA, lipid peroxides as thiobarbituric acid-reactive substances in the kidneys, and blood urea nitrogen and creatinine in the serum were significantly increased by the Fe-NTA treatment. All of these changes were completely inhibited by oral administration of MESNA or NAC. These results suggest that both of these compounds can prevent the oxidative stress induced by Fe-NTA.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetylcysteine; Aldehydes; Animals; Antioxidants; Carcinogens; Deoxyguanosine; DNA; DNA Damage; Ferric Compounds; Kidney; Kidney Diseases; Kidney Tubules, Proximal; Lipid Peroxidation; Male; Mesna; Nitrilotriacetic Acid; Oxidative Stress; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances

Platinum, copper, and zinc concentrations in kidney and liver were monitored following administration of cis-diamminedichloroplatinum (Cisplatin, CDDP) alone or in combination with diethyldithiocarbamate (DDC) or mercaptoethanesulfonate (mesna). Compounds were administered in saline to F344 female rats as single bolus ip doses: 7.5 mg CDDP/kg body wt; 500 mg DDC/kg body wt 1 hr after CDDP; and 100 mg mesna/kg body wt 1 hr before CDDP, at the same time as CDDP, or 1 hr after CDDP. Tissues were collected at 4 hr, 1 day, 4 days, and 7 days post-CDDP dosing. CDDP alone produced significant increases in blood urea nitrogen (fourfold) and plasma creatinine (threefold) concentrations by Day 4. Concurrent with the toxicity, CDDP lowered kidney copper (-71%) by Day 4, but had little effect on liver copper except in copper-pretreated rats. Copper-pretreated rats initially had a twofold higher kidney copper concentration and a fourfold higher liver copper concentration, but by Day 4, CDDP lowered copper concentrations in both organs to near the noncopper-treated levels. Platinum in kidney and liver rose 72-100% of peak levels within 4 hr post-CDDP and was relatively stable throughout the 7-day test period. Kidney zinc rose significantly by day 4 only in CDDP-treated rats. DDC protected against the kidney toxicity of CDDP and markedly changed kidney copper loss. Within 4 hr, DDC reduced kidney copper 60% while increasing kidney platinum to the highest concentration of any of the treatments. By Day 4, DDC-treated rats had approximately 50% lower kidney platinum while copper returned toward control levels. A single dose of mesna did not significantly protect against CDDP nephrotoxicity and had little effect on kidney platinum, copper, or zinc. The patterns of copper loss and toxicity from CDDP alone or with DDC suggest that copper be further evaluated for its role in the mechanism of CDDP cytotoxicity.

Topics: Animals; Blood Urea Nitrogen; Body Weight; Cisplatin; Copper; Creatinine; Ditiocarb; Female; Kidney; Kidney Diseases; Mesna; Platinum; Rats; Rats, Inbred F344; Zinc

The effect of three ifosfamide/mesna regimens on urinary N-acetyl-beta-D-glucosaminidase (NAG) activity and beta-2-microglobulin (beta 2 M) was studied. All regimens produced significant increases in these urinary proteins, indicating nephrotubular damage. In regimen A (n = 15), plasma nitrobenzylpyridine (NBP) alkylating activity area under the curve (AUC) on day 1 correlated with the percentage increase above baseline of maximum urinary NAG activity (r2 = 0.538, P = 0.0022) and maximum beta 2 M concentration (r2 = 0.413, P = 0.0097). In regimen B (n = 5), plasma NBP alkylating activity AUC correlated with the percentage increase above baseline of maximum NAG activity (r2 = 0.843, P = 0.03) and beta 2 M (r2 = 0.78, P = 0.046). In these two regimens the renal exposure to ifosfamide metabolites correlated with the increases in urinary NAG and beta 2 M. The relation of these urinary protein abnormalities to longer term effects on renal function with different ifosfamide/mesna schedules requires further study.

Topics: Acetylglucosaminidase; Adult; Aged; beta 2-Microglobulin; Creatinine; Female; Humans; Ifosfamide; Kidney Diseases; Male; Mesna; Middle Aged; Neoplasms

To characterize the excretion of 2-mercaptoethanesulfonate sodium (mesna) administered by intermittent infusion, urinary concentrations of mesna and its corresponding inactive disulfide were measured during 50 courses of ifosfamide (1.6 g/m2 for 5 days) and mesna (400 mg/m2 at 0.25, 4, and 6 h after each ifosfamide dose) administered i.v. to 19 patients. Some patients had previously received nephrotoxic therapy that might influence the excretion of mesna and its associated uroprotective effects. The median urinary free thiol concentration increased to 3 mM by 1 h after mesna infusion, declining to background levels by 4 h. The rate of mesna excretion correlated with the creatinine clearance rate in a subset of six patients. The proportion of mesna recovered in urine within 4 h after infusion was lower (P less than 0.05) in children who had evidence of preexisting renal tubular damage. Ifosfamide-induced tubular proteinuria was associated with lower urinary mesna recovery. Low urinary mesna concentrations indicated potentially subtherapeutic renal tubular levels. However, ifosfamide nephrotoxicity was subclinical and is not necessarily linked to differences in mesna excretion.

Topics: Adolescent; Adult; Child; Child, Preschool; Creatinine; Female; Humans; Ifosfamide; Kidney Diseases; Male; Mercaptoethanol; Mesna; Neoplasms; Proteinuria

Topics: Adolescent; Adult; Aged; Drug Evaluation; Female; Humans; Ifosfamide; Kidney Diseases; Male; Mercaptoethanol; Mesna; Mesothelioma; Middle Aged; Pleural Neoplasms

Twenty-one patients with refractory germ cell tumors were treated with a chemotherapy regimen containing etoposide (VP-16) (V) 75 mg/m2/day (days 1 to 5), ifosfamide (I) 3 g/m2/day (days 1 and 2) with a 3.6 g/m2 continuous infusion of mesna (days 1 and 2), and high-dose cisplatin (hP) 40 mg/m2/day (days 1 to 5). The regimen is referred to as VIhP. Nineteen patients were evaluable for response. Five patients (26%) achieved a complete remission (CR) with chemotherapy alone, and three patients (16%) were in CR after resection of a residual nonactive tumoral mass (e.g., necrosis and/or fibrosis and/or mature teratoma). Thus, a CR rate of 42% was achieved with the entire treatment. One additional patient achieved a CR after resection of active, bulky disease. Among the responders, five patients (26%) are still alive and disease-free at 6, 7, 9, 10, and 18 months after the initiation of the chemotherapy. However, toxicity was heavy in this protocol. Severe myelosuppression was observed with 10 patients developing aplasia and six patients documented sepsis. Reversible Grade 1-2 renal toxicity occurred in 14 patients, and Grade 2-3 peripheral neurotoxicity occurred in six patients. No hemorrhagic cystitis was encountered. We conclude that a VIhP regimen seems to play an active role in refractory germ cell tumors although the presence of high-dose cisplatin in this regimen does not appear to improve the response rate compared to that of a conventional dose. Toxicity, which seems to be enhanced, is currently under detailed study. However, the contribution of VIhP as a first-line treatment in poor prognosis, advanced germ cell tumors warrants further study.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Choriocarcinoma; Cisplatin; Etoposide; Evaluation Studies as Topic; Humans; Ifosfamide; Kidney Diseases; Leukopenia; Male; Mesna; Mesonephroma; Nausea; Sepsis; Teratoma; Testicular Neoplasms

We monitored acute tubular damage in 16 patients who received a 5-day course of ifosfamide (1.6 g/m2/day) and mesna (1.2 g/m2/day) therapy. Urinary concentrations of alanine aminopeptidase, N-acetyl-beta-D-glucosaminidase, and total protein increased in every patient, but the extent of tubular toxicity varied widely among patients. Evidence of toxicity was greatest in patients whose tumors involved the kidneys. The time course of enzymuria and proteinuria indicated tubular cell necrosis. We observed this acute toxic effect despite the administration of sufficient mesna to prevent hemorrhagic cystitis. Urinary marker concentrations returned towards pre-dose levels, and there were no increases in serum creatinine concentrations measured 3 weeks after treatment.

Topics: Acetylglucosaminidase; Adolescent; Adult; Aminopeptidases; CD13 Antigens; Child; Child, Preschool; Creatinine; Drug Evaluation; Female; Humans; Ifosfamide; Kidney Diseases; Kidney Tubules; Male; Mercaptoethanol; Mesna; Proteinuria

Topics: Animals; Cisplatin; Kidney Diseases; Kidney Neoplasms; Mercaptoethanol; Mesna; Rats

Early results with ifosfamide plus mesna in soft tissue sarcoma showed an initial response rate of 38% in 42 patients. All these patients treated at The Royal Marsden Hospital plus 30 more (total 67) have now been analysed. Single doses of 5 or 8 g/m2 ifosfamide were given over 24 h by infusion in dextrose saline together with 400 mg/m2 or 600 mg/m2, respectively, of mesnum every 4 h to give a total of 9 doses. A diuresis of 200 ml/hour was maintained during therapy. Treatment was repeated 3-weekly. CR was seen in 6 and PR in 10 patients. More recently doxorubicin was added to ifosfamide therapy in an attempt to improve on these results. At first only 20 mg/m2 doxorubicin was given but this was escalated to 40 mg/m2 and 60 mg/m2. Mesna has been given in higher dosage (5 g/m2 over 24 h), but otherwise the schedule is as above. In all 60 patients have been treated and most are now evaluable for response. Encephalopathy has been seen with both regimens. The incidence and patient characteristics are reported.

Topics: Adolescent; Adult; Aged; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Doxorubicin; Female; Humans; Ifosfamide; Kidney Diseases; Leukopenia; Male; Mesna; Middle Aged; Nausea; Sarcoma; Soft Tissue Neoplasms; Vomiting

Topics: Animals; Cisplatin; Dose-Response Relationship, Drug; Kidney; Kidney Diseases; Mercaptoethanol; Mesna; Rats

Topics: Cyclophosphamide; Humans; Ifosfamide; Infusions, Parenteral; Kidney Diseases; Mercaptoethanol; Mesna

Sodium 2-mercaptoethane sulfonate (mesna, Uromitexan) is oxidized in the organism of rats to 2,2'-dithiodi-(ethane sodium sulfonate) (dimesna). Dimesna is partially reduced to the mercapto compound mesna (kidneys); both compounds are eliminated via the urine. Even after administration of dimesna mesna can be detected in the urine. Accordingly dimesna also proved to be an effective antidote against the urotoxic actions of cyclophosphamide and ifosfamide.

Topics: Animals; Cyclophosphamide; Ifosfamide; Kidney Diseases; Mercaptoethanol; Mesna; Oxidation-Reduction; Rats; Rats, Inbred Strains

Thirty-two patients with advanced cancer were treated in a phase I-II trial with ifosfamide plus mesnum. At doses up to 300 mg ifosfamide/kg the administration of mesnum prevented most of the expected kidney and bladder toxicity. With this high dose range hemopoietic dose-limiting. Only one of twelve evaluable patients with breast cancer showed definite therapeutic benefit. Complete remission or partial remission was seen in three patients with non-Hodgkin lymphoma and one patient with Hodgkin's disease.

Topics: Adult; Aged; Cyclophosphamide; Female; Humans; Ifosfamide; Kidney Diseases; Leukopenia; Male; Mercaptoethanol; Mesna; Middle Aged; Neoplasms; Urinary Bladder Diseases