Urinary excretion of ifosfamide, 4-hydroxyifosfamide, 3- and 2-dechloroethylifosfamide, mesna, and dimesna in patients on fractionated intravenous ifosfamide and concomitant mesna therapy.

The oxazaphosphorine antineoplastic ifosfamide (IF) is metabolized by two different initial pathways: ring oxidation ("activation"), forming 4-OH-IF ("activated IF"), and side-chain oxidation with liberation of chloroacetaldehyde (CAA), forming the inactive metabolites 3-dechloroethylifosfamide or 2-dechloroethylifosfamide (3-DCE-IF, 2-DCE-IF). 4-OH-IF and 4-OH-IF-derived acrolein are thought to be responsible for IF-induced urotoxicity (hemorrhagic cystitis), whereas CAA may be involved in IF-associated nephrotoxicity (renal tubular damage). The thiol compound 2-mercaptoethane sulfonate sodium (mesna) has proved to inactivate sufficiently the urotoxic metabolites of oxazaphosphorine cytostatics and is therefore routinely given to patients receiving IF chemotherapy. The cumulative urinary excretion of IF, 4-OH-IF, 3-DCE-IF, 2-DCE-IF, mesna, and its disulfide dimesna was studied in 11 patients with bronchogenic carcinoma receiving IF on a 5-day divided-dose schedule (1.5 g/m2 daily) with concomitant application of mesna (0.3 g/m2 at 0,4, and 8 h after IF infusion). On day 1 the mean cumulative 24-h urinary recoveries (percentage of the IF dose) recorded for IF, 4-OH-IF, 3-DCE-IF, and 2-DCE-IF were 13.9%, 0.52%, 4.8%, and 1.5%, respectively. On day 5 the corresponding values were 12.2%, 0.74%, 9.9%, and 3.6%, respectively. This time-dependent increase in urinary excretion of IF metabolites, which is caused by rapid autoinduction of hepatic oxidative metabolism, may result in a higher probability for the development of urotoxic and nephrotoxic side effects during prolonged IF application. The mean 24-h urinary recoveries (percentage of the daily mesna dose) recorded for mesna/dimesna on day 1 (day 5) were 23.8%/45.2% (21.2%/39.8%), respectively. The mean molar excess of urinary reduced ("free") mesna over 4-OH-IF ranged from 11 to 72 on day 1 and from 6 to 40 on day 5. This indicates that although urinary excretion of 4-OH-IF rises with repeated IF application, mesna in standard doses should sufficiently inactivate the urotoxic IF metabolites.

Altered composition of urinary heparan sulfate in patients with COPD.

In patients with emphysema the integrity of the extracellular matrix (connective tissue skeleton) is compromised. In this study we analyzed glycosaminoglycans, which are main constituents of this matrix, in urines from patients with chronic obstructive pulmonary disease (COPD)/emphysema. Glycosaminoglycans (GAGs) were purified by anion exchange chromatography and quantified using the 1,9-dimethylmethylene blue assay. Heparan sulfate (HS) was assayed using three different chemical methods: digestion with heparitinase or with nitrous acid and by use of an adapted 1,9-dimethylmethylene blue assay. A specific epitope on the HS molecule, defined by the monoclonal antibody JM403, was determined using an inhibition enzyme immunoassay. In patients with COPD total urinary glycosaminoglycan and HS content were not altered. The JM403 epitope of HS, however, was greatly decreased in patients (0.6 versus 4.1 units/mg creatinine for control subjects, p < 0.0001). A similar pattern was observed when patients with bronchial carcinoma with and without emphysema were compared (0.4 versus 2.4 units/mg creatinine respectively, p < 0.0005). Patients with sarcoidosis did not show a decreased epitope content. These results indicate a structural change or an altered processing of the HS molecule in patients with emphysema. Taking into consideration the importance of HS for the stability of the alveolar extracellular matrix, this change may be associated with the pathogenesis of emphysema.

Urinary gonadotropin fragment measurements in patients with lung and esophageal disease.

Urinary gonadotropin fragment (UGF), a small glycoprotein and an intracellular processing product of human chorionic gonadotropin, has been demonstrated in trophoblast tissue and in nontrophoblastic cancers. Levels of UGF were assayed in 107 patients with malignant and benign pulmonary and esophageal lesions to determine if elevated levels were associated with the presence or progression of malignancy. There were 64 patients with primary bronchogenic carcinoma, 9 with metastatic pulmonary malignancies, 7 with lymphoma, 2 with mesothelioma, 9 with esophageal carcinoma, 1 patient each with metastatic cancer to chest wall and carcinoid, and 14 patients with benign pulmonary and esophageal lesions. Sensitivity was only 24% for urine samples from patients with demonstrable cancer. False-positive rates were 6% and 12% for urine samples from patients with benign lesions and those without evidence of residual cancer following treatment, respectively. Although elevated levels of UGF are present in some patients with pulmonary and esophageal cancer it is neither sensitive nor specific enough for use as a tumor marker.

Polarographic assay of submicrogram quantities of cis-dichlorodiamineplatinum (II) in biological samples.

Differential pulse polarographic assay of the antineoplastic agent cis-dichlorodiamineplatinum II and its analogues was performed after acid oxidative hydrolysis (HClO4, HNO3, HCl) of biological samples (plasma, tissue homogenates, urine) and reaction with ethylenediamine. Platinum levels and kinetics were determined in blood and urine of patients with non-oat-cell lung carcinoma. Detection limit of the polarographic assay was 0.5 ng platinum; analytical error was +/- 3%. Levels of free cis-dichlorodiamineplatinum (II) in plasma fell in samples stored at -20 degrees C; the half-life of free drug was 38 h.

Urine calcitonin levels in patients with bronchogenic carcinoma.

We demonstrated previously that high serum calcitonin values in bronchogenic carcinoma are useful clinically as a parameter of progress of the disease and response to therapy. After developing a procedure for the measurement of calcitonin in urine, we studied serum and urine levels in 41 patients with lung cancer, using both a carboxyl terminus and a midportion recognizing antiserum. In general, midportion antiserum was more useful. Urine calcitonin measurements alone were superior to serum in terms of numbers of patients having increased values with one or both antisera (76% vs 46%). When both antisera were used to assay both serum and urine, 90% of patients had abnormal values. Once a tissue diagnosis has been established, the radioimmunoassay of urinary calcitonin offers a new dimension to the utility of this hormone as a marker for bronchogenic carcinoma.

Bronchogenic squamous cell carcinoma metastatic to kidney. Detection by urine sediment cytology.

A fifty-seven-year-old man with bronchogenic squamous cell carcinoma is described. There was clinical suspicion of metastatic involvement of the kidneys. Urine sediment cytology revealed neoplastic squamous cells consistent with metastatic squamous cell carcinoma. Subsequent autopsy confirmed the renal involvement. In the right kidney the tumor had invaded and breached the renal pelvic wall. It is suggested that urine sediment cytology should be considered a useful diagnostic procedure in this clinicopathologic setting.