Lawrence Helson

Summary Continuous cell lines, SK-N-SH and SK-N-MC, were established in cell culture from human metastatic neuroblastoma tissue and maintained in vitro for 1 to 2 years. SK-N-SH comprises two morphologically distinctive cell types, a small spiny cell and a large epithelioid cell. SK-N-MC is composed of small fibroblast-like cells with scant cytoplasm. In monolayer culture both cell lines form disoriented growth patterns and reach high saturation densities. Population-doubling times were 44 and 32 hr for SK-N-SH and SK-N-MC, respectively. Inoculum levels of 10 7 cells of both lines produced tumors confirmed by histopathological examination, at frequencies of 30 to 40% in cheek pouches of conditioned Syrian hamsters. SK-N-SH cells are characterized by high dopamine-β-hydroxylase activity while SK-N-MC cells have no detectable activity. However, for SK-N-MC but not SK-N-SH, the presence of intracellular catecholamine was indicated by formaldehyde-induced fluorescence. The lines are near-diploid with several chromosomal markers; SK-N-MC cells contain double- minute chromosomes. Growth, biochemical, and cytogenetic properties confirmed that the lines comprise malignant cells of neurogenic origin.

A clinical trial was undertaken to improve the therapeutic index of cis-platinum diammine dichloride with a concomitantly administered mannitol induced diuresis. Sixty patients, heavily pretreated, were entered; fifty-one are evaluable. The technique of concomitant osmotic diuresis and CPDD administration is described in detail. Doses ranged from 3 mg/kg to 5 mg/kg. At 5 mg/kg, dose-limiting renal, marrow and ototoxicity were seen, and resulted in one drug death. Marrow toxicity was moderate. Renal toxicity was limited to transient elevations in serum creatinine levels, except in some patients who had renal impairment prior to CPDD treatment. These patients had moderate renal toxicity. Serial treatments as frequently as once every 3 weeks were used to maintain responses. Serial high dose CPDD produced only mild renal dysfunction. Ototoxicity, usually subclinical, was quantitated audiometrically, and found to be dose related, but not clinically prohibitive at 4 mg/kg or less. The overall response rate (PR/MR) was 42%. Clinically significant responses in epidermoid carcinoma of the head and neck, adenocarcinoma of the ovary, and germ cell tumors of the testis were seen. All six responding patients with germ cell tumor of the testis, had been resistant to low dose (1mg/kg) CPDD. Two responding patients with ovarian adenocarcinoma had been resistant to alkylating agents.

One hundred and sixty-five cases of malignant schwannoma were reviewed. Sixty-five (40%) of the patients had evidence of disseminated neurofibromatosis. Patients with neurofibromatosis were younger, had malignant schwannomas that were centrally rather than peripherally located, and had a shorter five-year survival (23%) than patients with solitary malignant schwannomas (47%). Histologically, tumors developing in patients with neurofibromatosis had a collagenous appearance, while tumors in patients without neurofibromatosis were undifferentiated and highly cellular. The clinical course of both groups of patients tended to be that of multiple local recurrences, although local recurrence had a more ominous prognosis in patients with neurofibromatosis. Chemotherapy responses in all these patients were extremely poor; however, the results of adjuvant therapy after surgery appeared encouraging. Fourteen patients (8.5%) had a malignant schwannoma in an area of prior radiation therapy and died of disease a median of 14 months after diagnosis. Malignant schwannoma should be considered in the differential diagnosis of tumors developing in areas previously treated with radiation.

A phase II trial of a single 5-day course of deferoxamine in 9 patients with neuroblastomas was completed. Within 2 days of completion of treatment responses were observed in 7 of 9 patients and there was no drug toxicity. These responses were a decrease in bone marrow infiltration and, in one patient, a measurable reduction in her tumor mass. We conclude that deferoxamine given as an 8-h i.v. infusion daily for 5 days at 150 mg/kg/day has antitumor activity.