A phase I clinical and pharmacokinetic study of recombinant human tumor necrosis factor (rH-TNF) was conducted in a single dose schedule in 33 patients with advanced cancer. rH-TNF was given by i.v. infusion over 30 min with a starting dose of 1 x 10(5) units/m2. The dose was escalated up to 16 x 10(5) units/m2 according to the modified Fibonacci scheme. Toxic effects were similar but not identical to those reported with interferons and interleukin-2, and included fever, rigors, nausea and vomiting and anorexia in a non-dose-dependent manner, and hypotension, leukocytosis, thrombocytopenia and transient elevation of transaminases (SGOT and SGPT) in an approximately dose-dependent manner. DIC syndrome was observed in one patient who had received 16 x 10(5) units/m2. The dose-limiting toxicities were hypotension, thrombocytopenia and hepatotoxicity, and the maximum tolerated dose in a single i.v. infusion of rH-TNF appeared to be 12 x 10(5) units/m2 when thrombocytopenia and elevation of SGOT and SGPT were taken as the dose-limiting toxicities. However, if hypotension was included, the maximum safely tolerated dose appeared to be 5 x 10(5) units/m2.
Three human gastric cancer cell lines, NU-GC-2, NU-GC-3 and NU-GC-4 were established in vitro from the cancer tissues obtained from 3 patients during surgery. The pathological findings of the gastric tumors of these cases revealed poorly differentiated adenocarcinoma (and partial signet-ring cell carcinoma in the case of NU-GC-4). NU-GC-2 and NU-GC-4 were originally obtained from metastatic paragastric lymph nodes and NU-GC-3 was obtained from a metastatic tumor in the brachial muscle. The cells of NU-GC-2 and NU-GC-3 are polygonal in shape and grow as a monolayer sheet. NU-GC-4 cells, however, are mainly spherical in shape with a few free floating cells. Electron microscopy revealed epithelial characteristics in all 3 cell lines. The average doubling time of NU-GC-2 was 36.1 hours, that of NU-GC-3 was 38.2 hours and that of NU-GC-4 was 29.9 hours. The modal chromosome number of NU-GC-2 was 62, that of NU-GC-3 was 58 and those of NU-GC-4 grown in in vitro and in vivo were 52-54 and 53, respectively. In vitro and in vivo lines of NU-GC-4 were established from the same tumor. These two cell lines are quite similar in morphology, but slightly different in karyotype. The in vitro sensitivity to anticancer agents was highest in NU-GC-4 and lowest in NU-GC-2. Of the anticancer agents, mitomycin C and adriamycin were most effective on the cells of all 3 cell lines.
Tumor growth of Yoshida sarcoma implanted in the remnant liver was studied in rats subjected to a hepatectomy. After 70 percent hepatectomy, the liver progressively regenerated and the total liver weight was reverted to by 10 days after the operation. Concomitantly with liver regeneration, tumor growth in the remnant liver was stimulated significantly, compared with that in the sham-operated liver. Incorporation of tritiated thymidine into tumor cells in the remnant liver was strikingly high and progressive, while that in the sham-operated liver was low and retained. Mitomycin C given to the hepatectomized rats was more effective against the tumor in the remnant liver than in the sham-operated liver. We conclude from this study that cancer cell proliferation in the remnant liver can be accelerated by the process of liver regeneration.
In a sixty-three year old Japanese man with a history of long standing pulmonary tuberculosis, an unusual esophago-cutaneous fistula developed. The possibility of esophago-pleuro-cutaneous fistula was considered, because there was an old tuberculosis causing lung abscess of hilar lymph node adenopathy and which facilitated development of an extensive fistulous tract. The patient was effectively treated by palliative surgical procedure. This may be the first report of a benign esophago-pleuro-cutaneous fistula.
An in vitro drug sensitivity test was developed to estimate the lethal effects of drugs on cancer cells. Cancer cells were incubated in the presence of radioactive precursors and anticancer drugs. The drug effects were estimated from the changes in rates of incorporation of precursors into DNA, RNA, and protein. A microtiter plate and a multiple automatic cell harvester made feasible handling of a large number of samples. Incorporation of radioactive precursors was well correlated with drug-induced cell lethality. The results of this test were also correlated with in vivo regression of tumors of mice. This test appeared to be more reliable than other similar tests of cell lethality in vitro. For utilization in clinical studies, a test plate was simplified and 25 human cancers were tested. The in vitro results demonstrated a positive correlation with clinical results in 80% of the observations.
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