Phase I clinical trial of recombinant human tumor necrosis factor.

A phase I and pharmacokinetic study of recombinant tumor necrosis factor (rH-TNF Asahi) was carried out in 29 patients, who received a total of 72 courses with doses ranging from 1 to 48 X 10(4) units/m2. Drug was given as 1-h i.v. infusions. Acute toxicities, taking the form of fever, chills, tachycardia, hypertension, peripheral cyanosis, nausea and vomiting, headache, chest tightness, low back pain, diarrhea and shortness of breath were seen, but were not dose-limiting or dose-related. Some early rise in SGOT, without any change in serum bilirubin, was noted at the highest doses. Eosinophilia, monocytosis, mild hypocalcemia and an increase in fibrin degradation products were seen in a few patients. The dose-limiting toxicity was hypotension, which occurred after the end of the drug infusion and was seen in all 5 patients treated at the highest dose. There was no mortality or long-term morbidity. There were no responses. Pharmacokinetic studies indicated a rapid plasma clearance and a short plasma half-life, generally less than 0.5 h.

Phase I clinical trial of ethyl 6-deoxy-3,5-di-O-methyl 6-(3 methyl-3-nitrosoureido)-alpha-D-glucofuranoside (CGP 6809).

A phase I study of single i.v. doses of a new sugar containing nitrosourea 6-deoxy-3,5 di-O-methyl 6-(3 methyl-3-nitrosoureido)-alpha-D-glucofuranoside (CGP 6809, EDMN) has been carried out in 47 patients with advanced solid tumors. Nine dose levels between 200 and 4500 mg/m2 were examined. Nausea and vomiting were seen in most patients but were controlled with antiemetics. Myelosuppression was minimal. The dose-limiting toxicity was hepatotoxicity, occurring early (peak at days 2-4) and resolving rapidly. No cumulative toxicity was seen with an every 6 weeks schedule. Other toxicities were abdominal pain, diarrhea, arm pain, restlessness, and headache. Pharmacokinetic studies in 20 patients using an HPLC assay and in 5 patients using [14C]EDMN showed a short half-life, rapid plasma clearance, rapid metabolism, and minimal excretion of unchanged drug. There was one partial response in a patient with colon carcinoma. The recommended dose for phase II studies in 3750 mg/m2 every 6 weeks.

Increased cytosol glucocorticoid receptor content of leiomyosarcoma.

Glucocorticoid receptor content was determined in cytosol preparations of soft tissue tumors from 42 patients. Leiomyosarcoma had significantly elevated receptors in comparison to malignant melanoma, liposarcoma, malignant fibrous histiocytoma, and invasive desmoid.

Action of demecolcine (colcemid) in the murine sarcoma 180 tumor.

Iv infusions of demecolcine (Colcemid) were established in mice bearing the Sarcoma 180 tumor. During demecolcine infusion at a rate of 6 microgram/hr, the tumor labeling index following 3H-thymidine administration and the mean grain count per labeled cell did not differ significantly from control values. Cells in anaphase and telophase disappeared from the tumor sections, and the net number of cells in the earlier stages of mitosis increased for 20 hrs. The rate of mitotic accumulation during the initial 8 hrs of demecolcine infusion was about one third of what would be expected from the known cell cycle values for this tumor. This reduced rate of accumulation does not appear to result from death of mitotic cells, escape of cells from metaphase blockade, or S-phase arrest secondary to inhibition of DNA synthesis; it is suggested that the reduced accumulation rate is secondary to demecolcine damage to interphase cells. Tumor cells that have been gathered by 4-hr demecolcine infusions may be released in synchronous fashion following the end of the infusion. A small proportion of these cells will recycle synchronously during the following mitotic period.

In vivo cell cycle synchronization of the murine sarcoma 180 tumor following alternating periods of hydroxyurea blockade and release.

The durations of the cell cycle intervals of the murine Sarcoma 180 tumor were determined by computer analysis of the fraction-labeled mitosis curve following tritiated thymidine administration. This tumor has a usual total cell cycle duration of 19.6 hr, a DNA synthetic time of 8.3 hr, and a growth fraction of 1. Approximately 38% of cells are in S phase at one time. Hydroxyurea (HU) infusions (i.v.) at 1.17 mg/hr into tumor-bearing mice rapidly inhibit tumor DNA synthesis. Following a 5-hr HU infusion, 58% of all tumor cells are in S phase, and maximal tumor mitotic rates after release of the HU blockade are double control rates. HU was infused for 5 hr, followed by 7 hr of Ringer's solution, and then another 5 hr of HU. Following this 2-cycle blockade, 70% of tumor cells are in S phase, predominantly in early S phase and at the G1-S junction. After release, peak mitotic rates are 2.5 times control. The duration of the intermitotic time of the tumor following HU infusion is less than the total cell cycle time of control tumor. Cycles of HU infusion and release, timed according to the predetermined duration of the cell cycle intervals, will synchronize significant increments of S phase or mitotic cells of the Sarcoma 180 tumor during predictable periods of time.

Association of renal injury with combined cephalothin-gentamicin therapy among patients severely ill with malignant disease.

There is a high incidence of primary renal tubule damage among patients with malignant disease who die following recent treatment with combinations of cephalothin and gentamicin. Administration of this combination of antibiotics appears to make the patient appreciably more susceptible to severe renal injury if an additional, often minor, insult to the renal tubules is superimposed. In the present study, significant blood loss or bacterial infection not promptly controlled by the antibiotic combination were two factors that provided this additional insult to many patients; the renal injury in these patients could not be attributed to bleeding or infection alone. The combination of cephalothin plus gentamicin carries the potential of causing renal tubule injury and places the patient severely ill with malignant disease at risk for renal failure from many clinical complications which are commonly associated with their primary illness.