Harvey B. Niell

The Postabsorptive Hydroxyproline in the Long-Term Evaluation of Patients With Breast Cancer

The postabsorptive urinary hydroxyproline excretion test (Spot‐HYPRO) was evaluated for its usefulness in reflecting the presence or absence of bone metastasis in 75 women with breast cancer. A comparison was made between the Spot‐HYPRO values and bone disease, as documented by bone scanning supported by skeletal x‐rays. Breast cancer patients with skeletal metastasis had 3–4‐fold elevations in Spot‐HYPRO above the control values (P < 0.001). Mild elevations were noted in breast cancer patients without skeletal metastasis (P < 0.025). Thirty patients received serial Spot‐HYPRO and bone scans for 6 to 48 months (average, 24 months). There was a 90% correlation between changes in Spot‐HYPRO and simultaneous changes on bone scan. Elevations in Spot‐HYPRO preceded changes found on bone scan by an average of 3 months. The authors conclude that the Spot‐HYPRO is a simple, convenient, and accurate method of documenting and following bone metastasis in patients with breast cancer.

Reversed-phase high-performance liquid chromatographic determination of mitomycin C in human serum.

A reversed-phase high-performance liquid chromatographic method is presented by which the cancer chemotherapeutic agent, mitomycin C, may be measured in human serum. A mobile phase of methanol:water (35:65) passed through a mu-Bondapak C-18 column at a rate of 1.0 ml/min produced a sharp, symmetrical band for mitomycin C. An improved serum extraction procedure, using a reversed-phase sample preparation cartridge, proved to be efficient and reproducible. Recovery over a concentration range of 10-100 ng/ml was 81.6% with a between-day coefficient of variation of 4.6% (n = 5). The within-day coefficient of variation at 50 ng/ml was 5.6% (n = 10). Ultraviolet detection at a wavelength of 365 nm was sensitive to serum concentrations of 10 ng/ml. Serum concentration-time course data from lung cancer patients receiving mitomycin C by rapid intravenous injection are presented.

Phase II study of prolonged oral etoposide in combination with intravenous cisplatin in advanced non-small cell lung cancer.

The objectives of the study were to evaluate the combination of cisplatin and prolonged oral etoposide for response rate, survival, and toxicity. The treatment regimen consisted of etoposide (50 mg/m2/day) p.o. for 21 consecutive days and cisplatin (100 mg/m2) i.v. on day 1 every 28 days for up to six courses. Patients with Stage IIIB or IV non-small cell lung cancer who had not received prior chemotherapy and had an ECOG performance status of 0-2 were eligible if they had normal bone marrow, liver and renal functions. Patients were followed weekly for toxicity including complete blood counts. The total number of patients entered in the study was 60, of whom 56 were male and four female, 40 white and 20 African Americans. Median age was 64 years (range, 39-77). Performance status 0, 1, and 2 was present in five, 39, and 16 patients, respectively. Fourteen patients had Stage IIIB and 46 Stage IV disease. A total of 142 treatment courses were administered (median 2, range 1-6). Three patients had a complete response and 19 patients had a partial response for an objective response rate of 37% (95% confidence interval, 31-43%). Median survival was 5 months (range, 1-39+). Neutropenia was the major toxicity with Grade 4 occurring in 25 patients after the first course. The following percent of patients experienced severe or life-threatening hematologic toxicity (Grade 3 and 4 combined) over all courses: leukopenia, 73%; neutropenia, 73%; anemia, 42%; and thrombocytopenia, 37%. Three patients died of neutropenic sepsis.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of mitomycin C in non-oat cell carcinoma of the lung

SummaryThe disposition kinetics of the cancer chemotherapeutic agent mitomycin C have been studied in six male patients receiving mitomycin C in combination with cisplatin and vinblastine for non-oat cell carcinoma of the lung. Following rapid IV administration of mitomycin C (10 mg/m2), serum concentration-time course data were biexponential, with biologic half-lives of 46.2 ± 12.1 min (mean ± SD). Pharmacokinetic analysis of data by the CSTRIP and NONLIN digital computer programs generated parameters which suggested extensive distribution (Varea=656.8±169.8 ml·kg−1, mean ±SD) and, as reported for other alkylating agents, rapid elimination (total body clearance=10.3 ± 3.2 ml · kg−1 · min−1, mean ± SD). Interpatient variations in pharmacokinetic parameters were relatively small, suggesting that close monitoring of mitomycin C therapy might be unnecessary in patients with normal renal and hepatic function.

Total and nondialyzable hydroxyproline excretion in stage D2 prostate cancer

Hydroxyproline is excreted in urine as a breakdown product of normal bone turnover: A dialyzable (D) fraction (90% of total) reflects active bone destruction and a nondialyzable (ND) fraction reflects bone growth/regrowth. In metastatic prostate cancer where blastic osseous metastases predominate, disease progression on bone scan correlated with elevation of both total hydroxyproline excretion (7.84 + 1.28, P <0.001) and the ND urinary level (0.94 ± 0.20, P <0.01). In patients with a serially stable/improving scan, urinary excretion of each fraction (2.18 + 0.27 and 0.27 ± 0.01) was similar to that of men with no evidence of disease. For Stage D2 prostate cancer, these two markers satisfactorily monitor osseous activity in the intervals between serial bone scintigraphy. Cancer 53:117‐121, 1984.

Growth characteristics of N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide (FANFT)-induced mouse bladder tumor lines in a human tumor stem cell assay.

Four N‐[4‐(5‐nitro‐2‐furyl)‐2‐thiazolyl]‐Formamide (FANFT)‐induced mouse bladder tumor (MBT) lines were tested for their ability to form colonies in a tumor stem cell assay. Anticancer drug testing was done using this assay to determine whether reproducible colony survival curves could be produced. All four cell lines produced colonies at 10–14 days, whether taken from culure or murine tumor. Cloning efficiencies ranged from 0.29% to 1.93% from culture and from 0.005% to 0.05% from the murine source. Growth characteristics were described. Cells from colonies were histologically similar to the original cells plated. A linear relationship existed between the number of cells plated and the number of colonies produced. In vitro drug studies were reproducible and correlated with in vivo data. Therefore, MBT lines can be used for in vitro drug testing in a tumor stem cell assay and may be useful in selecting active chemotherapeutic agents in the murine tumor model.

The Clonogenic Growth of Cells Derived From Bladder Barbotage in Patients With Transitional Cell Carcinoma of the Bladder: A Preliminary Report

Tumor cells obtained from bladder washings in 41 patients with transitional cell carcinoma of the bladder and 15 control subjects were analyzed for their ability to produce cluster and/or colony formation in a tumor stem cell assay. In vitro cell growth was correlated with the presence of tumor at the time of bladder washing, tumor grade and treatment status. Of 34 bladder washings from patients with biopsy-proved transitional cell carcinoma 88 per cent produced cluster and/or colony formation. Specimens from patients not currently receiving intravesical chemotherapy at the time of bladder barbotage produced colonies in 54 per cent of the cases, compared to 25 per cent from patients receiving therapeutic or maintenance therapy. Higher grade tumors produced more viable cells at bladder barbotage but clonal growth rates were independent of histologic grade. We conclude that bladder barbotage may serve as a source of cells for chemotherapeutic drug testing in patients with transitional cell carcinoma of the bladder. Bladder washings also may be useful as a source of tumor cells for monitoring the in vivo growth potential of bladder cancer in the tumor stem cell assay.

The postabsorptive urinary hydroxyproline (Spot‐HYPRO) in patients with multiple myeloma

The simple postabsorptive urine hydroxyproline (Spot‐HYPRO) with dialyzable and non‐dialyzable (ND) fractions was measured in 28 patients with multiple myeloma. Myeloma patients with bone disease had higher total Spot‐HYPRO and dialyzable fractions (P < 0.001) than myeloma patients without bone disease or controls. The ND fraction of the Spot‐HYPRO was elevated in myeloma patients with renal disease as compared with myeloma patients without renal disease and controls (P < 0.01). Follow‐up studies of ten myeloma patients demonstrated a close correlation between Spot‐HYPRO and the dialyzable fraction and the evolution of bone disease. The Spot‐HYPRO and its dialyzable fraction constitute a simple, inexpensive, and accurate test for the diagnosis and follow‐up of the skeletal disease in patients with multiple myeloma.

Anticancer drug activity in human bladder tumor cell lines

A panel of ten human bladder tumor cell lines were tested for drug sensitivity to ten standard or investigational anticancer drugs using a tumor colony assay. The activity of these anticancer agents in vitro was then compared with the clinical activity of these agents in bladder cancer. Drug activity was found in only five of the ten cell lines. In only 9 of 100 drug assays was the inhibition of colony growth lower than 30% of the controls. The activity of the more active anticancer drugs in bladder cancer (i.e., methotrexate and cisplatin) was not predicted using the tumor colony assay. Overall, the low level of activity of most anticancer drugs tested paralleled the clinical experience of drug resistance found in human bladder cancer.

Effect of concentration and time of drug exposure on clonal growth of murine bladder cancer

The use of a tumor colony assay was evaluated for its ability to predict anticancer drug response in an N[4-(5-nitro-2-furyl)-2-thiazolyl] formamide mouse bladder tumor model. One-hour and continuous drug exposure were compared to determine what effect altering drug concentration and time of exposure would have on the predictability of the tumor colony assay in the murine model. Ten anticancer drugs were tested in the murine model, and tumor cells removed from control mice were used for in vitro drug testing. One-hour and continuous drug exposure (using the one-hour drug level) were performed simultaneously and the in vitro and in vivo data compared. Using one-hour drug incubation in the tumor colony assay resulted in a true positive predictive rate of 54 per cent and a true negative predictive rate of 70 per cent. Continuous drug incubation overestimated drug sensitivity resulting in a drop in the predictability of the tumor colony assay. We conclude that using one-hour drug exposure the tumor colony assay is predictive of chemotherapeutic drug response in this murine bladder tumor model.