A stable isotope method for the simultaneous measurement of matrix synthesis and cell proliferation in articular cartilage in vivo.

OBJECTIVE: Measurements of cell proliferation and matrix synthesis in cartilage explants have identified regulatory factors [e.g., interleukin-1 (IL-1)] that contribute to osteoarthritis and anabolic mediators [e.g., bone morphogenic protein-7 (BMP-7)] that may have therapeutic potential. The objective of this study was to develop a robust method for measuring cell proliferation and glycosaminoglycan synthesis in articular cartilage that could be applied in vivo. METHODS: A stable isotope-mass spectrometry approach was validated by measuring the metabolic effects of IL-1 and BMP-7 in cultures of mature and immature bovine cartilage explants. The method was also applied in vivo to quantify physiologic turnover rates of matrix and cells in the articular cartilage of normal rats. Heavy water was administered to explants in the culture medium and to rats via drinking water, and cartilage was analyzed for labeling of chondroitin sulfate (CS), hyaluronic acid (HA) and DNA. RESULTS: As expected, IL-1 inhibited the synthesis of DNA and CS in cartilage explants. However, IL-1 inhibited HA synthesis only in immature cartilage. Furthermore, BMP-7 was generally stimulatory, but immature cartilage was significantly more responsive than mature cartilage, particularly in terms of HA and DNA synthesis. In vivo, labeling of CS and DNA in normal rats for up to a year indicated half-lives of 22 and 862 days, respectively, in the joint. CONCLUSIONS: We describe a method by which deuterium from heavy water is traced into multiple metabolites from a single cartilage specimen to profile its metabolic activity. This method was demonstrated in tissue culture and rodents but may have significant clinical applications.

Phase II trial of 10-deaza-aminopterin in patients with advanced colorectal cancer.

Twenty-two patients with advanced colorectal cancer were treated with 10-deaza-aminopterin given intravenously twice weekly for four doses beginning at 15 mg/m2. Twelve patients had no prior chemotherapy. Dose-limiting toxicity was mucositis. Tumor regression was not seen in any patient.

Phase II trial of menogarol in the treatment of advanced adenocarcinoma of the pancreas.

Fifteen patients with advanced adenocarcinoma of the pancreas were treated with menogarol 150-225 mg/m2 i.v. every 3 weeks. All patients had bidimensionally measurable disease. This regimen and dosage schedule are well tolerated, with minimal toxicity that included myelosupression; median white blood cell (WBC) count nadir of 2,700 cells/mm3 (range 1,400-7,100 cells/mm3) and median platelet nadir of 162,000 cells/mm3 (range 53,000-390,000 cells/mm3). Anorexia occurred in one patient, nausea or vomiting in six, phlebitis in one, and alopecia in six patients. No patients responded. At this dosage and schedule, there is no role for menogarol in the treatment of advanced pancreatic adenocarcinoma.

Etoposide (VP-16) in the treatment of advanced adenocarcinoma of the pancreas.

Twenty-six patients with advanced adenocarcinoma of the pancreas were treated with etoposide (VP-16), 100-180 mg/m2 i.v., days 1, 2, and 3, monthly. Twenty-five had bidimensionally measurable disease and one had evaluable disease only. This regimen and dosage schedule were well tolerated, with minimal toxicity including myelosuppression; a median WBC count nadir of 3,600 cells/mm3 (range 200-2,400); and a median platelet nadir of 215,000 cells/mm3 (range 15,000-405,000). However, no patients responded and only two had stable disease for 3.5 and 4 months, respectively. At this dosage and schedule, there is no role for VP-16 in the treatment of advanced pancreatic adenocarcinoma.

MIFA III (mitomycin-C, 5-fluorouracil, and adriamycin) chemotherapy for advanced adenocarcinoma of the pancreas.

Twenty-nine patients with advanced adenocarcinoma of the pancreas were treated with a combination of mitomycin-C, 5-fluorouracil, and adriamycin (MIFA III). Four of these patients achieved a partial response, and two achieved a minor response. An additional seven patients had evidence of disease stabilization. The median survival period from initiation of therapy for responders was 13.5 months as compared to 7.6 months for those with stable disease and 3.2 months for nonresponders (p = 0.001). Myelosuppression was the primary toxicity. Prolongation of survival was demonstrated in responding patients who had failed prior chemotherapy. The MIFA III regimen is active, well tolerated, and warrants further investigation in previously untreated patients.

Trabecular (Merkel cell) carcinoma of the skin. Treatment of primary, recurrent, and metastatic disease.

Four new patients with trabecular (Merkel cell) carcinoma of the skin are described, and an additional 76 patients from the literature are reviewed. The mean age of the combined group of patients was 68; 84% were 60 years or older. Primary tumors appeared most frequently on the head and neck (44%), leg (28%), arm (16%), or buttock (9%). No primary tumor appeared on the trunk. The rate of local recurrence was 36%, regional metastatic disease, 53%; distant metastases, 28%; and death due to metastatic tumor (minimally), 25%. It appears that trabecular carcinoma of the skin is more aggressive and lethal than previously thought. The authors recommend that patients with this tumor undergo wide resection of the primary site and, in healthy patients, prophylactic regional node dissection. Both radiation therapy and chemotherapy are effective in palliating unresectable disease.

Phase II trial of cisplatin (CPDD) in previously treated patients with advanced soft tissue sarcoma.

Thirty-six previously treated adult patients with advanced soft tissue sarcomas received CPDD 120 mg/m2 with mannitol diuresis. There were only two (6%) partial responses and five (15%) minor responses in 34 evaluable patients. Toxicity included nausea and vomiting, myelosuppression, mild ototoxicity and mild to moderate, transient nephrotoxicity. CPDD has minimal antitumor activity in previously treated patients with soft tissue sarcomas.

Cisplatin. A phase II evaluation in previously untreated patients with soft tissue sarcomas.

A Phase II trial of moderately high-dose cisplatin (120 mg/m2 with mannitol diuresis) was conducted in 26 previously untreated patients with soft tissue sarcomas. One partial response (major response rate, 4%) and two minor responses were seen. Severe nausea and vomiting and transient increases in the serum creatinine level were the most common side effects of treatment. Cisplatin has minimal activity as a single agent in patients with soft tissue sarcoma.