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© 2000 American Society for Clinical Oncology Phase I Trial of 6-Hour Infusion of Glufosfamide, a New Alkylating Agent With Potentially Enhanced Selectivity for Tumors That Overexpress Transmembrane Glucose Transporters: A Study of the European Organization for Research and Treatment of Cancer Early Clinical Studies GroupFrom the Department of Medical Oncology, University of Ioannina, School of Medicine, Ioannina, Greece; and Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, Belmont, Sutton, United Kingdom, members of the European Organization for Research and Treatment of Cancer, Early Clinical Studies Group; NDDO Oncology, Amsterdam, the Netherlands; and Department of Biological Research Biochemistry, ASTA Medica AG, Frankfurt, Germany. Address reprint requests to Evangelos Briasoulis, MD, Department of Medical Oncology, School of Medicine, University of Ioannina, 451 10 Ioannina, Greece; email ebriasou{at}otenet.gr
PURPOSE: To determine the maximum-tolerated dose (MTD), the principal toxicities, and the pharmacokinetics of 6-hour infusion of glufosfamide (beta-D-glucosylisophosphoramide mustard; D-19575), a novel alkylating agent with the potential to target the glucose transporter system. PATIENTS AND METHODS: Twenty-one patients (10 women and 11 men; median age, 56 years) with refractory solid tumors were treated with doses ranging from 800 to 6,000 mg/m2. Glufosfamide was administered every 3 weeks as a two-step (fast/slow) intravenous infusion over a 6-hour period. All patients underwent pharmacokinetic sampling at the first course. RESULTS: The MTD was 6,000 mg/m2. At this dose, two of six patients developed a reversible, dose-limiting renal tubular acidosis and a slight increase in serum creatinine the week after the second and third courses of treatment, respectively, whereas three of six patients experienced short-lived grade 4 neutropenia/leukopenia. Other side effects were generally mild. Pharmacokinetics indicated linearity of area under the time–versus-concentration curve against dose over the dose range studied and a short elimination half-life. There was clear evidence of antitumor activity, with a long-lasting complete response of an advanced pancreatic adenocarcinoma and minor tumor shrinkage of two refractory colon carcinomas and one heavily pretreated breast cancer. CONCLUSION: The principal toxicity of 6-hour infusion of glufosfamide is reversible renal tubular acidosis, the MTD is 6,000 mg/m2, and the recommended phase II dose is 4,500 mg/m2. Close monitoring of serum potassium and creatinine levels is suggested for patients receiving glufosfamide for early detection of possible renal toxicity. Evidence of antitumor activity in resistant carcinomas warrants further clinical exploration of glufosfamide in phase II studies.
GLUFOSFAMIDE IS A new alkylating agent in which isophosphoramide mustard, the alkylating metabolite of ifosfamide, is linked to beta-D-glucose (ß-D-Glu-IPM). In vitro data suggest that cellular uptake of glufosfamide is mediated by the transmembrane transport system of glucose. Initial studies demonstrated a direct cytotoxicity that was reducible by the inhibitors of transmembrane glucose transporters, phlorizin and phloretin.1 Recently it was found that glufosfamide is conveyed into tumor cells by SAAT1, a low-affinity sodium/glucose cotransporter.2 Other glucose transporter proteins may also play a role in intracellular translocation of this compound. This targeting mechanism, together with the accelerated metabolic rate and increased glucose consumption of tumor cells, suggests potentially enhanced tumor selectivity for glufosfamide and introduces a novel concept for drug targeting. Another interesting characteristic of glufosfamide is the lack of release of the urothelium irritant acrolein because of the absence of the oxazophosphorine ring in its structure. Oxazophosphorines are metabolized in the liver by cytochrome P450 to open-ring aldose forms that decompose to acrolein and the alkylating metabolites.3 Glufosfamide does not require metabolic activation in the liver. It is transported intact into cells, where the active moiety isophosphoramide mustard is thought to be released by either spontaneous hydrolysis or hydrolysis catalyzed by intracellular glucosidases.4 Preclinical pharmacokinetic studies of glufosfamide demonstrated rapid renal clearance, high tissue distribution, and low protein binding.5 Toxicity studies in rodents showed that glufosfamide was more toxic when given orally, apparently because of a pronounced first-pass effect and increased production of toxic metabolites. The lethal dose for 10% of mice was 533 mg/kg for single oral dosing and 1,795 mg/kg for a single intravenous (IV) infusion. The IV-infusion lethal dose for 50% of rats and mice was 1.7 and 3.8 times higher, respectively, compared with oral administration. Nevertheless, the acute and subacute toxicity profiles were similar for both routes of administration. The major toxicity targets identified histologically were the bone marrow, the kidney, the skin, and the genital tract, and the observed alterations were minor and reversible.6 The New Drug Development and Coordinating Committee of the European Organization for Research and Treatment of Cancer selected glufosfamide for clinical evaluation because of its interesting pharmacologic properties and its possible selectivity for tumors that express the glucose transporters. This phase I trial of a biphasic, rapid/slow 6-hour infusion of glufosfamide was initiated in June 1997. The schedule was based on a simulation model that was developed by using pharmacokinetic data from an ongoing phase I trial of a 1-hour IV glufosfamide infusion. It aimed to rapidly achieve steady-state concentrations and expose tumor cells to the study drug over a moderately prolonged time, with the intent to optimize selective uptake by the glucose transport system.
Study Design and Objectives This was an open-label, uncontrolled, dose-finding and pharmacokinetic phase I trial with between-patient dose escalation. Two European Organization for Research and Treatment of Cancer Early Clinical Studies Group centers collaborated in this study: the Department of Medical Oncology, University of Ioannina, School of Medicine, Ioannina, Greece, and the Cancer Research Campaign Centre for Cancer Therapeutics, The Institute of Cancer Research, Belmont, Sutton, United Kingdom. Study monitoring was done by the New Drug Development Office (NDDO) Oncology, Amsterdam, the Netherlands. Primary objectives were as follows: (a) to determine the maximum-tolerated dose (MTD) and characterize the toxic effects of glufosfamide in humans when administered as a 6-hour infusion, with one quarter of the total dose given as a rapid half-hour infusion followed by the remaining three quarters of the total dose given as a 51/2-hour infusion; (b) to propose a safe dose for phase II evaluation; and (c) to study the pharmacokinetics at the different dose levels. A secondary objective was to collect evidence of antitumor activity with this agent and schedule.
Chemistry and Formulation
Administration and Dose Escalation An extended two-step, 6-hour IV infusion was used in this study: one quarter of the dose was administered in 30 minutes, and the remaining three quarters were given over the next 51/2 hours. The starting dose level was 800 mg/m2, based on data from another, parallel-running phase I study of short infusion (principal investigator: coauthor A.H). Prophylactic antiemetic treatment was allowed for subsequent courses only if nausea and vomiting occurred during the first course.
A minimum of three assessable patients (receiving at least one course of treatment) were entered at nontoxic dose levels. In case of
Patients
Safety and Efficacy Assessment Although efficacy evaluation was not an end point in this phase I study, tumors were assessed for response every two cycles using World Health Organization criteria. Patients were assessable for antitumor activity if disease measurements were recorded for at least 6 weeks after the first dose of therapy. A complete response was defined as the disappearance of all known disease, and partial response was defined as an at least 50% decrease of the sum of the products of the largest perpendicular diameters of all measurable bidimensional lesions or the sum of largest diameters of all unidimensional lesions. Objective responses had to be confirmed with a second assessment not less than 4 weeks apart.
Pharmacokinetics Bioanalysis. The analytic work was performed in the Department of Biologic Research Biochemistry, ASTA Medica, and at Analytico Research B.V. (formerly BCO; Breda, the Netherlands). Two methods, A/1 and A/2 (data on file, Knebel and Winkler, 1999), were used at ASTA Medica, and method B/2 was used at Analytico (data on file, Bender, 1998). Plasma was assayed with methods A/1, A/2, and B/2; urine was assayed with method B/2 only. Samples were pretreated by ultrafiltration (A/1 and A/2) or by solvent protein precipitation (B/2), followed by liquid chromatography (LC) and tandem mass spectrometry (MS/MS) detection with a TurboIon Spray Interface (Applied Biosystems, Foster City, CA). D-24144 (=[13C]D-19575) was used as internal standard. The high-performance LC–MS/MS system was a Finnigan TSQ 7000 (ThermoQuest Corp, San Jose, CA) or an API 3/300 (PE Sciex, Concord, Ontario, Canada). Frozen plasma and urine samples were thawed at ambient temperature, "vortex"-mixed, and centrifuged for 10 minutes. Plasma/urine samples with expected concentrations above the calibration range were diluted with a 0.009% aqueous sodium acetate solution. For calibration, blank plasma and blank urine samples were spiked daily with glufosfamide at concentrations of 0.05, 0.07, 0.1, 0.3, 0.7, 1, 3, 5, 7, and 10 µg/mL for plasma and 0.2, 0.5, 1, 2, 5, 10, 25, 50, 75, and 100 µg/mL for urine. The chromatograms were evaluated with the internal standard method using peak-area ratios for calculation purposes. Calibration curves were evaluated with linear regression weighted by 1/x, 1/x2, 1/x1.5, or 1/y2, depending on the LC-MS/MS system used and the respective software (data on file, Knebel and Winkler, 1999). All calculations were done using the Quan Guide (Thermo Quest Corporation, San Jose, CA) or MacQuan (PE Sciex) calculation program. Quality control samples at three concentrations (0.15, 1, and 9 µg/mL for plasma and 0.6, 10, and 90 µg/mL for urine) or four concentrations (0.05, 0.5, 0.7, and 5 µg/mL for plasma) were analyzed along with every analytic series (batch). If more than two of six quality control samples or all quality control samples at one concentration level differed by more than ± 15% (plasma) and ± 20% (urine) from the theoretical value within a batch, results were rejected and the test samples reanalyzed. Pharmacokinetic analysis. All pharmacokinetic evaluations were based on the real blood sampling times as documented on the respective case report forms (CRFs). Noncompartmental pharmacokinetic calculations were performed with validated Excel-based software (FUNCALC; ASTA Medica, 1997). Arithmetic mean, coefficient of variation, median, lower quartile (25% quartile), upper quartile (75% quartile), minimum, and maximum, as well as geometric mean with corresponding coefficient of variationln and 95% confidence intervalln, were calculated for elimination half-life, volume of distribution at steady state, volume of distribution during terminal phase, total plasma clearance, renal clearance, and urinary excretion over all dose groups (normalization was to 1.73 m2 body surface). For the pharmacokinetic parameters area under the time–versus-concentration curve (AUC) and average concentration during infusion from time point 0 hours to 6 hours (Cav,0-6), the arithmetic mean was calculated for each dose group. For calculation of arithmetic mean, values below the limit of quantification were set to zero. Dose linearity of the average concentration from 0 to 6 hours and AUC was investigated for the 800- to 6,000-mg dose range. Calculations were performed with the individual values of each dose group. Renal clearance was calculated as the ratio of amount excreted in urine to total plasma AUC. As an approximation, the cumulative amount of glufosfamide excreted in urine over a 48-hour period was used for the numerator. Ethical considerations. Independent ethical committees at the two centers involved approved the study protocol and the patient informed consent form. Informed written consent was obtained from each patient before enrollment. The trial was conducted in accordance with the laws and guidelines current at the time: the national drug laws, the principles of the Declaration of Helsinki, and the European Note for Guidance for Good Clinical Practice. The protocol informed consent, CRFs, study conduct, and study reports were subject to an internal review. Monitoring. The study was monitored by NDDO Oncology. Investigators entered the information required by the protocol onto CRFs developed by NDDO Oncology for the study. The CRFs were then forwarded to the data management unit of NDDO Oncology. All data from the CRFs were entered into REMOTE ACES database, version 1.0. An independent visual data check was done in order to ensure the quality of data entry. Monitors visited the investigators regularly to verify the CRFs for correctness and completeness, obtaining corrections at the centers where necessary. The following items were regularly checked against source data: all patient eligibility criteria, baseline physical examination results, prior treatment, drug administration, adverse events, laboratory outcomes, efficacy data, and off-study data. Data quality assurance was done by complete data check. On completion of the clean-up procedures, the database was locked.
Table 1 summarizes the patients’ characteristics. Twenty-one patients (10 women and 11 men; median age, 56 years) with a variety of refractory or pretreated solid tumors were enrolled onto this study. Two patients were chemotherapy-naïve; the others had received prior chemotherapy. Five dose levels (800, 1,600, 3,200, 6,000, and 4,500 mg/m2) were explored. Three patients were entered at dose levels I, II, and III, and six patients were entered at dose levels IV and V (Table 2).
All patients received at least one course of treatment with glufosfamide, and a total of 62 courses were administered. The median number of courses given per patient was two (range, one to eight). Courses were repeated every 3 weeks, and only in four cases was treatment delayed for logistic reasons. One patient with a serum bilirubin concentration of 2.2 mg/dL on the day of the first course was considered eligible because at registration, 3 days before treatment, she had a normal bilirubin level. Two patients discontinued the trial because of adverse events.
Safety
At the time of study initiation, no CTC grade was available for inorganic phosphorus and metabolic acidosis. These abnormalities were graded by severity, according to the investigator’s opinion. For a clearer picture of the intensity of these events, the nadirs of the inorganic phosphorus and plasma pH were reassessed according to the revised National Cancer Institute CTC, version 2.0 (Table 4).
The adverse events that occurred at the lower dose levels and hematologic toxicity as summarized in Table 5 were generally mild. A short-lived grade 4 neutropenia was seen in two and a grade 4 leukopenia was seen in one out of six patients treated at 6,000 mg/m2, but these toxicities were not complicated by infections. Other reported toxicities were mild nausea, vomiting, fatigue, proteinuria, glucosuria, alopecia, and taste disturbances (dysgeusia).
Dose-Limiting Toxicity: Case Illustration Patient no. 11. Patient no. 11, a 70-year-old woman with breast cancer metastatic to the liver, was treated with glufosfamide 6,000 mg/m2 as a third-line chemotherapy. During course 2, she developed grade 3 hypokalemia, moderate hypophosphatemia, a grade 1 increase in creatinine, and metabolic acidosis (grade 3 according to National Cancer Institute CTC version 2.0). Hypophosphatemia and hypokalemia became evident on day 8 after the second dose of the drug and worsened 1 week later. The patient was admitted to the hospital with the diagnosis of renal tubular acidosis and was treated with IV supplementation of potassium bicarbonate and phosphate. The study drug was considered to be the most likely cause of this toxic event. Furthermore, the patient developed grade 3 leukopenia and grade 2 neutropenia. The increase in serum creatinine and the metabolic acidosis resolved on days 11 and 12, respectively. Hypokalemia resolved on day 25. Hypophosphatemia improved but never resolved completely. The patient was taken off treatment and died 2 months later of malignant disease. Patient no. 14. Patient no. 14, a 61-year-old man with pretreated advanced colon cancer, was enrolled at the 6,000-mg/m2 dose level. He received a total of three courses of glufosfamide and had significant palliation of his symptoms, a decrease in his tumor markers, and significant shrinkage of the tumor mass that did not qualify as an objective response. A week after his third course of treatment with glufosfamide (on day 8), he was admitted to the Department of Nephrology with grade 3 metabolic acidosis, grade 3 hypokalemia, a grade 2 increase in serum creatinine, grade 1 hypophosphatemia, and grade 1 proteinuria. The study drug was considered to be the cause of this toxic event. The patient was placed on IV potassium and phosphate supplementation. While hospitalized he also developed febrile neutropenia that was successfully treated with antibiotics. The neutropenia resolved after 2 days, and the fever lasted only 6 hours. The hypokalemia and increased serum creatinine lasted for 2 weeks and resolved on day 22. The proteinuria and hypophosphatemia were resolved 2 months later. The patient died 8 months later of tumor progression.
Efficacy
Pharmacokinetics Bioanalytics performed reliably, with coefficients of determination (r2) of the calibration lines ranging from 0.993 to 0.999 for all three analytic methods used. The individual plasma concentration–time courses of glufosfamide from 18 patients in five different dose groups (800, 1,600, 3,200, 4,500, and 6,000 mg/m2) were combined. The mean concentration-time profiles are shown in Fig 4.
The relationship between dose and AUC was linear over the dose range studied (Fig 5). The dose-independent pharmacokinetic parameters are summarized in Table 6. The median terminal plasma half-life was 2.3 hours, and the amount excreted intact in the urine amounted to 34.2%. Pharmacokinetic data for the two patients who developed renal toxicity did not differ essentially from the pharmacokinetic data of the others who were treated at the same dose level, although the AUCs obtained by these patients were clearly on the high side. (Table 7).
Enhanced antitumor selectivity constitutes a priority in the development of new anticancer agents. Chemical modification of established antitumor drugs may be one way to optimize their pharmacology and possibly improve anticancer selectivity. Glufosfamide is a new alkylating cytotoxic agent developed from ifosfamide that has the potential to target tumor cells by functioning as a substrate for the plasma membrane glucose transport system. Rapidly proliferating and energy-consuming cancer cells are known to overexpress certain glucose transport proteins.7,8 Initial work done by Pohl et al1 suggested an active transmembrane transport mechanism for glufosfamide, and recently, Veyhl et al2 identified a low-affinity sodium/glucose cotransporter that translocates this compound actively across the plasma membrane. This is the SAAT1 molecule, a member of the Na+/glucose gene family of cotransporters that was initially isolated from a pig renal cell line but was also found expressed in various human carcinomas and tumor cell lines.2,9,10 According to Veyhl et al, uptake of glufosfamide by SAAT1 was phlorizin-inhibitable, stereospecific, and substrate-dependent with a higher affinity and a smaller maximal velocity in comparison to D-glucose. In the same work, the high-affinity SGLT1 transporter was not found to participate in the mechanism of cellular uptake of glufosfamide; the facilitative glucose transporters were not investigated. Two major observations came out of this study: glufosfamide administered by 6-hour infusion in humans can cause dose-limiting renal tubular toxicity and can produce interesting antitumor activity in refractory tumors. Oxazophosphorine cytotoxic drugs are DNA-alkylating agents that need cytochrome P450 activation in the liver to become therapeutically active. Ifosfamide, a widely used oxazophosphorine, is a potentially nephrotoxic and urotoxic drug. Renal tubules and the bladder constitute primary targets for potentially toxic ifosfamide metabolites undergoing renal excretion, such as chloracetaldehyde, a major metabolite of side-chain oxidation, and acrolein, a metabolite of the oxazophosphorine ring.11,12 In glufosfamide, the therapeutically active isophosphoramide mustard is coupled to D-glucose via a beta-glycosidic linkage, constituting a hydrophilic conjugate with the potential to release the active drug intracellularly by hydrolysis. Therefore, on theoretical grounds, this drug does not require metabolic activation, and in animal studies it was only found to form metabolites to a limited extent when given intravenously.5 In our study, hemorrhagic cystitis was not recorded and myelotoxicity was mild at clinically effective dose levels. Nevertheless, renal tubular toxicity was the dose-limiting event for glufosfamide given on this schedule. The observed nephrotoxicity resembled more or less the extensively studied but incompletely understood renal toxicity of ifosfamide, for which proximal tubular damage has been characterized as a primary toxic event.12,13 One can only hypothesize that tubular damage by both drugs might be related to a common metabolite or to the highly reactive isophosphoramide mustard itself. The first hypothesis is supported by the low urine excretion of intact drug in this study, which suggests a substantial metabolism of glufosfamide in humans. Regarding a possible direct involvement of isophosphoramide mustard in tubular damage, this may have been facilitated through active uptake of glufosfamide by the sodium/glucose cotransporters that are activated at the cell membranes of the proximal tubule for reabsorption of filtered glucose.14,15 In this study, our aim was to expose tumor cells over a prolonged time to this rapidly eliminated agent to better exploit the mechanism of the cellular uptake of glufosfamide, given that transportation through the glucose transporters shows saturable substrate dependence.2 Thus, a biphasic, fast/slow infusion was selected in order to achieve steady-state plasma levels of the drug rapidly and sustain them over a relatively prolonged period. Pharmacokinetic analysis showed that the pharmacokinetic simulation was successful. Obtained data confirmed the accuracy of the computer simulation in that the two-step infusion schedule produced the desired profile of rapidly achieved and sustained plasma concentrations for more than 6 hours. Renal excretion of the intact drug was moderate, although data from rodents showed primarily renal excretion of unchanged drug when administered as a single agent.5 In our study, renal excretion was half of that observed in rats after single bolus administration, indicating a possible difference in metabolism between species or influence of duration of administration on metabolic rate. Although by design this study was not directed to allow estimation of efficacy, there was strong evidence of antitumor activity in refractory solid tumors. Accelerated rates of glucose transport and increased glucolysis are characteristic features of malignant transformed cells, mediated by overexpression of glucose transporters.16,17 Of the two major families of transmembrane glucose transporters,18 ie, the facilitative glucose transporters (GLUT1-5) and the sodium-dependent glucose transporters (SGLT1-2), cancer research has focused mostly on the facilitative glucose transporters.19 Three types of the family of facilitative glucose transporters (GLUT1, GLUT2, and GLUT3) have been found to be elevated in most cancer tissues studied.8 Pancreatic carcinoma was theoretically a particularly attractive candidate for glufosfamide therapy because of intense GLUT1 expression,20 and this was evidenced by an impressive, longstanding complete response in an advanced pancreas carcinoma case that occurred at a subtoxic dosage. Indications of antitumor activity were also seen in two metastatic colon cancers and one breast carcinoma, all heavily pretreated. These tumor types have also been shown to overexpress transmembrane glucose transporters.21-23 In conclusion, the principal and dose-limiting toxicity of glufosfamide given as a biphasic, rapid/slow, 6-hour infusion every 3 weeks was reversible renal tubular acidosis. The MTD with this schedule was 6,000 mg/m2, and the recommended phase II dose was 4,500 mg/m2. Myelotoxicity was seen but was generally mild. Glufosfamide caused renal toxicity, consisting of metabolic acidosis, a transient increase in serum creatinine, hypophosphatemia, hypokalemia, hyperphosphaturia, glucosuria, and an increase in urine beta-2-microglobulin, and this was dose-dependent. The remarkable antitumor activity seen in chemotherapy-resistant carcinomas in this trial warrants further clinical exploration of glufosfamide, despite the renal toxicity. Phase II studies should be conducted under close monitoring of renal function. Checks on serum potassium, creatinine, and, if indicated, blood pH, 8 to 15 days after treatment are strongly advised in patients receiving glufosfamide for early detection of evolving renal tubular damage.
Sponsored by ASTA Medica AG, Frankfurt, Germany. Trial results were presented at the Tenth National Cancer Institute–European Organization for Research and Treatment of Cancer Symposium on new drugs in cancer therapy, Amsterdam, the Netherlands, June 16-18, 1998, and at the Twenty-Third Congress of the European Society for Medical Oncology, Athens, Greece, November 6-10, 1998 (Ann Oncol 9:128, 1998 [suppl 4]).
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Veyhl M, Wagner K, Volk C, et al: Transport of the new chemotherapeutic agent beta-D- glucosylisophosphoramide mustard (D-19575) into tumor cells is mediated by the Na+-D-glucose cotransporter SAAT1. Proc Natl Acad Sci U S A 95: 2914-2919, 1998
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Brock N: Oxazaphosphorine cytostatics: Past-present-future—Seventh Cain Memorial Award lecture. Cancer Res 49: 1-7, 1989
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Gopalan V, Pastuszyn A, Galey WRJ, et al: Exolytic hydrolysis of toxic plant glucosides by guinea pig liver cytosolic beta-glucosidase. J Biol Chem 267: 14027-14032, 1992 5. Stuben J, Port R, Bertram B, et al: Pharmacokinetics and whole-body distribution of the new chemotherapeutic agent beta-D-glucosylisophosphoramide mustard and its effects on the incorporation of [methyl-3H]-thymidine in various tissues of the rat. Cancer Chemother Pharmacol 38: 355-365, 1996[Medline] 6. Glufosfamide [investigator’s brochure]. Frankfurt, Germany, ASTA Medica, 1999
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Younes M, Lechago LV, Somoano JR, et al: Wide expression of the human erythrocyte glucose transporter Glut1 in human cancers. Cancer Res 56: 1164-1167, 1996 8. Yamamoto T, Seino Y, Fukumoto H, et al: Over-expression of facilitative glucose transporter genes in human cancer. Biochem Biophys Res Commun 170: 223-230, 1990[Medline]
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Kong CT, Yet SF, Lever JE: Cloning and expression of a mammalian Na+/amino acid cotransporter with sequence similarity to Na+/glucose cotransporters. J Biol Chem 268: 1509-1512, 1993
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Mackenzie B, Panayotova-Heiermann M, Loo DD, et al: SAAT1 is a low affinity Na+/glucose cotransporter and not an amino acid transporter: A reinterpretation. J Biol Chem 269: 22488-22491, 1994
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Bruggemann SK, Kisro J, Wagner T: Ifosfamide cytotoxicity on human tumor and renal cells: Role of chloroacetaldehyde in comparison to 4-hydroxyifosfamide. Cancer Res 57: 2676-2680, 1997 12. Skinner R, Sharkey IM, Pearson AD, et al: Ifosfamide, mesna, and nephrotoxicity in children. J Clin Oncol 11: 173-190, 1993[Abstract] 13. Patterson WP, Khojasteh A: Ifosfamide-induced renal tubular defects. Cancer 63: 649-651, 1989[Medline]
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Turner RJ, Silverman M: Sugar uptake into brush border vesicles from normal human kidney. Proc Natl Acad Sci U S A 74: 2825-2829, 1977 15. Kanai Y, Lee WS, You G, et al: The human kidney low affinity Na+/glucose cotransporter SGLT2: Delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest 93: 397-404, 1994
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Rempel A, Mathupala SP, Griffin CA, et al: Glucose catabolism in cancer cells: Amplification of the gene encoding type II hexokinase. Cancer Res 56: 2468-2471, 1996 17. Lundholm K, Edstrom S, Karlberg I, et al: Glucose turnover, gluconeogenesis from glycerol, and estimation of net glucose cycling in cancer patients. Cancer 50: 1142-1150, 1982[Medline] 18. Elsas LJ, Longo N: Glucose transporters. Annu Rev Med 43: 377-393, 1992[Medline]
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Reske SN, Grillenberger KG, Glatting G, et al: Overexpression of glucose transporter 1 and increased FDG uptake in pancreatic carcinoma. J Nucl Med 38: 1344-1348, 1997 21. Brown RS, Wahl RL: Overexpression of Glut-1 glucose transporter in human breast cancer: An immunohistochemical study. Cancer 72: 2979-2985, 1993[Medline] 22. Grover-McKay M, Walsh SA, Seftor EA, et al: Role for glucose transporter 1 protein in human breast cancer. Pathol Oncol Res 4: 115-120, 1998[Medline] 23. Haber RS, Rathan A, Weiser KR, et al: GLUT1 glucose transporter expression in colorectal carcinoma: A marker for poor prognosis. Cancer 83: 34-40, 1998[Medline] Submitted March 13, 2000; accepted June 9, 2000.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
grade 2 nonhematologic toxicity, except alopecia or inadequately treated nausea and vomiting (no prophylactic antiemetic medication was allowed during the first course, per protocol), or 
2 on the World Health Organization scale; (c) life expectancy 
