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Effects of human natural interferon alpha (nIFN) alone, human natural tumor necrosis factor alpha (nTNF) alone and their combination (OH-1) were tested on three human mesothelioma lines implanted in nude mice. Tumors were transplanted subcutaneously by trocar on treatment day -12. nIFN was given intraperitoneally (i.p.) at a dose of 2 x 10(7) or 2 x 10(8) IU kg-1 day-1, 5 days a week for 3 weeks. nTNF was given i.p. at a dose of 2 x 10(7) or 2 x 10(8) U kg-1 day-1 in the same schedule as that of nIFN. Tumor diameters were serially measured and tumor volumes were calculated. Antitumor effects were assessed by two methods: comparison of final tumor volumes in treated and control groups (T/C), and changes in median average total tumor volume. The treatment produced no clinically discernible toxicities. nIFN had strong inhibitory activity against all three human mesothelioma lines. nTNF alone had modest activity only at the high dose used. The combination of the two produced activity essentially similar to that produced by nIFN alone. High-dose nIFN may have a role as an active agent in the treatment of patients with mesothelioma.

A patient with malignant mesothelioma experienced tumor recurrence 3 months after pleuropneumonectomy. Samples of the tumor were transplanted into nude mice to assess chemosensitivity. There was close concordance between the results in xenografts and the clinical outcome in this patient. Both mitomycin and to a lesser extent cisplatin were effective as single agents against the nude mouse xenografts, and the combination of these two drugs produced a complete response both in the patient and in the xenografts. The patient survived 18 months from onset of chemotherapy and 24 months from diagnosis. The duration of clinical complete response to chemotherapy was 14 months, despite the fact that mitomycin, the most effective agent against the xenografts, was discontinued after only two cycles because the patient developed pulmonary toxicity. This direct patient-xenograft correlation further validates the usefulness of the nude mouse model in the search for effective therapies for malignant mesothelioma, a tumor characterized by frequent refractoriness to most available agents.

The combination of mitomycin-C and etopzoside showed synergistic cell kill effects in vitro against HEp-2 laryngeal squatnous carcinoma cells both in monolayer and in multicellular tumor spheroid systems. This cornbination was also synergistic in inhibiting HEp-2 tumors growing in nude mice. One course of this combination produced no complete regression of this tumor. When these two agents were combined with recombinant human granulocyte colony-stimulating factor (G-CSF) mutein, the doses of the drugs could be escalated approximately 1.5-fold higher than the doses that were tolerated without G-CSF support. With this modest close intensication, apparent cure MWS observed. High-dose mitomycin-C plus etoposide with G-CSF support may be useful, for the treatment of patients with inoperable squamous cell carcinoma of the head and neck.

Serum concentrations of unhydrolyzed hyaluronic acid (HA) in nude mice bearing human malignant mesothelioma xenografts were determined by size-exclusion chromatography. HA rose to 8-16 micrograms/mL (controls: less than 1 micrograms/mL) by the fourth to fifth day after tumor (epithelial) transplantation, 3 to 5 days before palpability. Decreases in HA during late tumor growth are probably attributed to tumor necrosis, based on the observation that HA was 2.5 times less in necrotic than in viable tumor tissues. This serum biomarker, recognizable before physical detectability of xenografted tumors, should have applicability to monitoring experimental chemotherapy in mice and to early diagnosis and monitoring of human malignant mesothelioma.