Recombinant human tumor necrosis factor administered as a 24-hour intravenous infusion. A phase I and pharmacologic study.

Recombinant human tumor necrosis factor (rH-TNF) is a cytokine with direct antitumor properties. In a phase I trial we continuously infused rH-TNF for 24 hours. We gave a total of 115 courses of therapy to 50 patients. Doses ranged from 4.5 to 645 micrograms of rH-TNF/m2. Systemic toxicity, including fever, chills, fatigue, and hypotension, increased with the dose of rH-TNF administered. Doses greater than 454 micrograms/m2 frequently caused severe lethargy and fatigue, which precluded hospital discharge of the patient at the completion of therapy. The dose-limiting toxicity was hypotension, and five patients treated at the two highest dose levels required dopamine treatment. Other organ-specific toxicity was modest and spontaneously resolved after 48 hours. The 24-hour infusions of rH-TNF were associated with significant decreases in serum cholesterol and high-density lipoprotein levels. Pharmacokinetic studies using an enzyme-linked immunosorbent assay demonstrated peak plasma rH-TNF levels of 90-900 pg/mL. Despite continuous infusion of rH-TNF, no steady-state level was achieved. The recommended phase II dose for rH-TNF as a 24-hour continuous infusion is 545 micrograms/m2.

Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism.

Recombinant human tumor necrosis factor (rH-TNF) is a cytotoxic monokine with pleiotropic effects. A phase I trial of rH-TNF was initiated using a five-day continuous intravenous (IV) infusion repeated every 28 days. Thirty-eight courses of therapy were administered to 19 patients. The starting dose was 5 X 10(4) U/m2/d, with escalations to 1.0 X 10(5), 2.0 X 10(5), 2.4 X 10(5), and 3.0 X 10(5) U/m2/d. Systemic side effects, including fever, chills, hypotension, fatigue, anorexia, and headaches, were mild and self-limiting. At the maximum tolerated dose of 3.0 X 10(5) U/m2/d, dose-limiting hematologic toxicity was manifested by transient thrombocytopenia and leukopenia. Elevated bilirubin levels were also seen at the higher dose levels. Lipoprotein analysis demonstrated that the five-day treatment with rH-TNF was associated with decreases in high-density lipoproteins, as well as increases in triglycerides and very-low-density lipoproteins. Pharmacokinetic studies using an enzyme-linked immunosorbent assay (ELISA) test indicated plasma rH-TNF levels less than 0.2 U/mL. The recommended phase II dose of rH-TNF administered as a five-day continuous infusion is 2.4 X 10(5) U/m2/d.

A phase I trial of recombinant human tumor necrosis factor and interferon-gamma: effects of combination cytokine administration in vivo.

The combination of tumor necrosis factor (TNF) and interferon-gamma has synergistic bioactivity in numerous preclinical model systems. We have tested this potential synergism in vivo by administration of both cytokines to patients with advanced cancer using overlapping 24-hour continuous intravenous (IV) infusions in a phase I trial. Thirty-six patients were treated with a fixed dose of interferon-gamma (200 micrograms/m2/d) with interpatient dose escalation of TNF (from 5 to 205 micrograms/m2/d). The dose-limiting toxicity at the maximal-tolerated dose (MTD) of TNF (205 micrograms/m2) with interferon-gamma was hypotension. Other toxicities noted included an influenza-like syndrome, transient decreases in circulating leukocyte and platelet counts, subclinical evidence of disseminated intravascular coagulation, and the sporadic occurrence of acute pulmonary toxicity. The recommended phase II dose for this combination schedule is TNF, 136 micrograms/m2, with interferon-gamma, 200 micrograms/m2. The addition of interferon-gamma to TNF resulted in a greater than three-fold increase in toxicity compared with TNF administered as a single agent, supporting the hypothesis that the combination of these cytokines may induce synergistic effects in vivo.

A phase I study of intermittent continuous infusion high dose cytosine arabinoside for acute leukemia.

We previously administered ara-C at a dose rate of 250 mg/m2/hr for 36-72 hr to patients with leukemia. Gastrointestinal toxicity was dose-limiting. This regimen was modified to an every other day schedule, administering 24-hr periods of high dose continuous infusion ara-C, each followed by a 24-hr rest period. Sixteen patients with relapsed/refractory acute myeloid leukemia (AML) (N = 4), secondary AML (N = 2), relapsed/refractory acute lymphoblastic leukemia (N = 7), or CML in blast crisis (N = 3) received this regimen of three 24-hr infusions with two intercurrent 24-hr rest periods. Grade 3 gastrointestinal toxicity was encountered in 57% of the courses, and hypoplasia was achieved in all patients. Three of the patients died while hypoplastic, two with septicemia and another with intracranial hemorrhage. There were five responding patients (2 CRs, 3 PRs). Median steady-state plasma ara-C levels were 24 microM, 22 microM, and 20 microM during the first, second, and third 24-hr infusions, respectively. Ara-C levels ranged from 4-118 microM during the infusions and were always below 4.5 microM during the rest periods. A significant level of ara-C incorporation into DNA was detected in each of the five patients studied, thus demonstrating that (ara-C)DNA formation is detectable in blasts from patients receiving high dose continuous infusion ara-C therapy. These findings suggest that alternate day continuous infusion ara-C may be useful in the treatment of acute leukemia and CML in blast crisis.

A neurocytoma and an associated lenticulostriate artery aneurysm presenting with intraventricular hemorrhage: case report.

OBJECTIVE AND IMPORTANCE: Hemorrhage associated with central neurocytoma has been described previously, but never in association with an aneurysm originating from a feeding artery. We present the first reported case of a central neurocytoma in a patient with intraventricular hemorrhage caused by rupture of an aneurysm on a lenticulostriate artery that supplied the tumor. CLINICAL PRESENTATION: A 35-year-old man who presented with an intraventricular hemorrhage underwent magnetic resonance imaging and cerebral angiography that disclosed a right lateral intraventricular mass and a 7-mm fusiform aneurysm from a lateral lenticulostriate branch of the right middle cerebral artery. INTERVENTION: The patient underwent a contralateral transcallosal exploration and resection of the tumor, with excision of the adjacent lenticulostriate artery aneurysm. Pathological review demonstrated that the tumor was a neurocytoma. The aneurysm was discrete from the tumor but occurred on a vessel that supplied the tumor. CONCLUSION: Previous reports have demonstrated that intraventricular neurocytoma may present with tumor hemorrhage. In this case, an aneurysm separate and distinct from the tumor was the bleeding culprit, and the aneurysm was on an artery that fed into the tumor. Any such aneurysm must be identified and treated appropriately for therapy to be complete.

Recombinant human gamma interferon administered by continuous intravenous infusion in acute myelogenous leukemia and myelodysplastic syndromes.

Nine patients (median age, 58; range: 37-74) with relapsed de novo acute myeloid leukemia (AML) (3), AML after prior myelodysplastic syndrome (MDS) (4), or MDS (2) were treated with 2-20 x 10(6) U/m2/day (1-10 mg/m2/day) of recombinant human interferon gamma (rIFN gamma; Biogen) on a 14-day continuous intravenous infusion schedule. The two patients who received the initial dose of 20 x 10(6) U/m2/day (1.0 mg/m2/day) could only tolerate 6 days of therapy because of severe hepatotoxicity. Two patients who received the revised starting dose of 10 x 10(6) U/m2/day also could not complete a full course of rIFN gamma due to renal failure in one case and pulmonary deterioration in the other. A reversible dose-related rise in SGOT was seen in six patients. All patients developed a severe flu-like syndrome characterized by myalgias and fevers. These toxicities were not associated with detectable serum levels of tumor necrosis factor (TNF). Although blasts from three of five assessable patients displayed increased expression of the Ia (HLA-DR) antigen, there were no hematological responses. Steady-state rIFN gamma plasma levels in patients who tolerated a complete infusion were < 40 U/ml, a concentration below that required to induce differentiation of myeloid leukemic cell lines in vitro. We conclude that continuous infusions of rIFN gamma at doses as low as 2 x 10(6) U/m2/day are poorly tolerated in patients with AML and MDS; the maximum tolerated dose is approximately 2 x 10(6) U/m2/day.

Sleep time following anesthesia in mouse lines selected for resistance or susceptibility to fescue toxicosis.

In previous work, a mouse line selected for resistance (R) to fescue toxicosis had higher activities of two hepatic Phase II detoxification enzymes than a mouse line selected for fescue toxicosis susceptibility (S). The primary objective of the present study was to determine whether those same lines also differed in hepatic Phase I enzyme activity, estimated from sleep time (ST) following sodium pentobarbital anesthesia. Additional objectives were to determine whether ST differences between lines were modulated by endophyte-infected fescue in the diet (with or without an enzyme inducer) and whether ST of individual mice was correlated with the effect of a toxin-containing diet on the postweaning growth of those mice. In Exp. I, 24 males from each line were randomly assigned to each of five diets: control (commercial rodent food meal); E+ (50% endophyte-infected fescue seed, 50% control); E+P (the E+ diet supplemented with 1,000 ppm phenobarbital); E- (50% endophyte-free fescue seed, 50% control); and E-P (the E- diet supplemented with 1,000 ppm phenobarbital). After 4 wk on these diets, ST was measured on all the mice. A second ST was recorded on each mouse by randomly sampling one-fourth of the population after 1, 2, 3, or 4 wk on a pelleted rodent food diet. Regardless of diet, R mice had shorter first and second ST than S mice (P < 0.01), suggesting higher hepatic Phase I microsomal enzyme activity. Mice on both phenobarbital-supplemented diets had shorter first ST than mice whose diets did not include that microsomal enzyme inducer (P < 0.01). In Exp. II, ST was measured on male and female R and S mice (n = 280) after they had been fed the E- diet for 2 wk, then the E+ diet for 2 wk, and then a pelleted rodent food diet for 2 wk. Growth response to the E+ diet was the percentage of reduction in gain on the E+ diet compared to gain on the E- diet the previous 2 wk. As in Exp. I, S mice slept longer than R mice (P < 0.01). The residual correlation between ST and gain reduction associated with the E+ diet equaled 0.04. Thus, an animal's apparent Phase I enzyme activity did not predict its growth rate depression on the toxin-containing diet. Based on these and previous studies, divergent selection for toxicosis response in mice was successful partially by causing divergence in activities of hepatic Phase I and II detoxification enzymes.

Regulation of prostaglandin endoperoxide H synthase-2 expression by 2,3,7,8,-tetrachlorodibenzo-p-dioxin.

We have examined the molecular mechanisms for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-stimulated prostaglandin synthesis in Mardin Darvey canine kidney cells (MDCK). TCDD stimulates prostaglandin synthesis in these cells, at least in part, by elevating prostaglandin endoperoxide H2 synthase-2 (PGHS-2) levels. TCDD-stimulated transcription of the PGHS-2 gene was maximal (6-fold) within 2 h and resulted in a 100-fold increase in PGHS-2 mRNA and a 25-fold increase in PGHS-2 protein levels by 4 h. Transient transfection experiments using luciferase-reporter plasmids demonstrated that control element(s) responsible for TCDD activation of the murine PGHS-2 promoter in MDCK cells are located in the first 965 nucleotides upstream from the PGHS-2 transcriptional initiation site. A canonical xenobiotic response element, similar to those that control transcription of other well-known TCDD-sensitive genes, is present at position -157, but does not appear to be sufficient for halogenated aromatic hydrocarbon (HAH) activation of the PGHS-2 promoter. TCDD failed to stimulate transcription from the PGHS-2 promoter when reporter plasmids were transfected into Hepa 1c1c7 cells, a line which contains the functional aryl hydrocarbon receptor. It seems likely that inappropriate expression of PGHS-2 may contribute to the toxic effects of TCDD and other HAHs. In particular, PGHS-2 expression may affect those toxic reactions that involve inappropriate cellular growth, such as dermal hyperplasia and tumor formation. It is also likely that elevated synthesis of prostaglandins, which are potent regulators of immune function, could play a role in the immunotoxicity associated with HAH exposure.