Phase I and pharmacokinetic study of etoposide phosphate by protracted venous infusion in patients with advanced cancer.

PURPOSE: Etoposide has schedule-dependent cytotoxic activity, and clinical resistance may be overcome with prolonged low-dose therapy. Oral bioavailability is variable, and protracted intravenous administration is limited by water insolubility, which requires large infusion volumes. Etoposide phosphate (EP) is a water-soluble prodrug that is rapidly converted in vivo to etoposide, and may be administered in concentrated solution. A phase I study was conducted to determine the toxicity, pharmacokinetics, and pharmacodynamics of EP administered as a protracted venous infusion in the ambulatory setting. METHODS: Twenty-three patients with advanced cancer were treated with a continuous infusion of EP using ambulatory pumps for 6 weeks followed by a 2-week rest. Cohorts were treated with EP at 10, 20, 25, and 30 mg/m2/d. Steady-state plasma etoposide levels (Css) and stability of EP in infusion pumps were measured using high performance liquid chromatography (HPLC). RESULTS: Myelosuppression, mucositis, and fatigue were dose-limiting. The maximum-tolerated dose (MTD) of EP was 20 mg/m2/d. The mean Css (+/- SD) of etoposide were 0.67 +/- 0.25, 1.14 +/- 0.24, 1.38 +/- 0.64, and 2.19 +/- 0.52 microg/mL at daily EP doses of 10, 20, 25, and 30 mg/m2, respectively. Neutropenia correlated with Css (r = 0.65, P = .008). EP was stable in infusion pumps for at least 7 days. Partial responses were observed in patients with hepatoma and non-small-cell lung cancer (one each). CONCLUSION: EP may be conveniently and safely administered as a low-volume protracted venous infusion in the ambulatory setting. Cytotoxic plasma concentrations of etoposide are obtained at the MTD. The pharmacodynamic relationships observed suggest the possibility of pharmacologically based dosing of EP.

Phase I study of high-dose etoposide phosphate in man.

Etoposide is a widely used cytotoxic agent with a broad spectrum of activity in human malignancies. This agent has been incorporated into many transplant regimens although toxicity occurs because of its poor water solubility and toxic excipients. Etoposide phosphate, a water soluble prodrug of etoposide, has been studied at conventional dosages in man and shown to have advantages over the parent compound. We have extended our previous experience with this new agent to evaluate the levels needed in transplantation protocols. This phase I study of intravenous high-dose etoposide phosphate over 2 h on days 1 and 2 was designed to determine whether or not dose linearity between the amount of etoposide phosphate administered to patients and generation of etoposide in vivo as seen with conventional dosages of this agent would be present at transplant-dose levels. In addition, the toxicities of these dose levels with the short infusion schedule were defined. A conservative dose escalation scheme was chosen based upon prior knowledge of etoposide. Thirty-one patients (19 male, 12 female) with CALGB performance status 0-1 with a variety of solid tumors entered this study. The patients were treated with dose levels of etoposide phosphate given as the etoposide-equivalent doses of 250, 500, 750, 1000, 1200, 1400, and 1600 mg/m2/day in 250-400 ml of normal saline given as an intravenous infusion over 2 h on days 1 and 2 every 28 days. After the maximal tolerated dose level was determined on this schedule, additional patients received etoposide phosphate as a 4 h infusion on both days in an attempt to reduce toxicities. G-CSF (5 micrograms/kg/day) was administered subcutaneously to all patients from day 3 until the WBC > or = 10000/microliters. Nonhematologic toxicity was considered to be dose limiting. Serial plasma samples for pharmacokinetics were obtained from patients on day 1 of cycle 1. For the 2 h infusion, the maximum tolerated dose of etoposide phosphate was 1000 mg/m2/day x 2 with dose limiting mucositis. In the small number of patients studied, the maximum tolerated dose was reached for the 4 h infusion at 1400 mg/m2/day of drug, again due to mucositis. Other toxicities, despite the rapid infusion schedule, were modest with transient mild headache being most common. At the highest doses etoposide phosphate was efficiently and rapidly dephosphorylated to etoposide. Etoposide generated by dephosphorylation of etoposide phosphate had plasma disposition curves characteristic of etoposide administered parenterally. One partial response occurred in a patient with small cell lung cancer. Etoposide phosphate can be rapidly infused in modest fluid volumes at dosages required for transplantation protocols with minimal acute side-effects. On a 2 h schedule, mucositis becomes the dose limiting nonhematologic toxicity. Mucositis seems to correlate with peak dose levels of the drug rather than total drug administered. On a 4 h infusion schedule given sequentially for 2 days, the maximum tolerated dosage could be increased 40% compared to the 2 h schedule. The relative ease of administration and the rapid conversion of this prodrug into etoposide should make it useful in high-dose therapy settings.

Pharmacokinetic evaluation of high-dose etoposide phosphate after a 2-hour infusion in patients with solid tumors.

Etoposide phosphate, a water soluble prodrug of etoposide, was evaluated at levels potentially useful in transplantation settings in patients with malignancies. For pharmacokinetic studies of etoposide phosphate in this phase I study, 21 patients with solid tumors were treated with etoposide phosphate given as etoposide equivalents of 250, 500, 750, 1000 and 1200 mg/m2 infused over 2 h on days 1 and 2, and G-CSF 5 micrograms/kg per day starting on day 3 until WBC was > or = 10,000/microliters. Qualitative, quantitative, and pharmacokinetic analysis was performed as reported previously. Rapid conversion of etoposide phosphate into etoposide by dephosphorylation occurred at all dosage levels without indication of saturation of phosphatases. Plasma levels (C(pmax)) and area under the curve (AUC) of etoposide phosphate and etoposide demonstrated linear dose effects. For etoposide, plasma disposition demonstrated biphasic clearance, with mean T1/2 alpha of 2.09 +/- 0.61 h, and T1/2 beta of 5.83 +/- 1.71 h. An AUC as high as 1768.50 micrograms.h/ml was observed at a dose of 1200 mg/m2. The total body clearance (TBC) showed an overall mean of 15.72 +/- 4.25 ml/min per m2, and mean volume of distribution (VDss) of 5.64 +/- 1.06 l/m2. The mean residual time (MRT) for etoposide was 6.24 +/- 1.61 h. In urine, etoposide but not etoposide phosphate, was identified with large quantitative variations (1.83% to 33.45% of injected etoposide equivalents). These results indicate that etoposide phosphate is converted into etoposide with the linear dose-related C(pmax) and AUCs necessary for use of this agent at the high dosage levels needed in transplantation protocols. A comparison of pharmacokinetic parameters of high-dose etoposide with the values observed in our study with etoposide phosphate revealed comparable values for the clinically important C(pmax) and AUCs, clearance, terminal T1/2 and MRT. In contrast to the use of etoposide, etoposide phosphate can be delivered in aqueous vehicles and therefore may offer the advantage of ease of administration.

Phase II study of elsamitrucin (BMY-28090) for the treatment of patients with refractory/relapsed non-Hodgkin's lymphoma.

PURPOSE: To determine the response rate of patients with refractory/relapsed non-Hodgkin's lymphoma to treatment with elsamitrucin and to further characterize the toxic effects of elsamitrucin in this group of patients. PATIENTS AND METHODS: Eligibility required pathologically verified relapsed or refractory non-Hodgkin's lymphoma with no more than two prior chemotherapy regimens for patients with tumors classified by the International Working Formulation (IWF) as A-C and no more than one prior chemotherapy for those with IWF grades D-G. Patients were entered with either normal or impaired bone marrow function, but normal liver function tests were required unless clearly related to lymphomatous involvement of the liver. Elsamitrucin 25 mg/m2 was administered intravenously over 5-10 minutes weekly. RESULTS: Thirty-one patients entered the study and were treated for a median of six weeks (range 1-42). All patients were evaluable for toxicity and 30 for response. Mild nausea and/or vomiting and asthenia were the most frequently reported adverse events. Four (13%, 95% Cl 4.4-31.6%) partial responses were seen along with two (7%) minor responses while 9 (30%) patients had stable disease. CONCLUSION: Elsamitrucin showed modest activity in patients with relapsed or refractory non-Hodgkin's lymphoma. Toxicity was relatively mild, consisted mainly of asthenia, nausea and vomiting and did not include myelosuppression. The activity of elsamitrucin in this group of patients and its lack of myelosuppression suggest utility in this disease especially when combined with other proven agents.

Phase II randomized study of cisplatin plus etoposide phosphate or etoposide in the treatment of small-cell lung cancer.

PURPOSE: This randomized phase II study evaluated the efficacy and toxicity of etoposide phosphate when used in combination with cisplatin in the treatment of small-cell lung cancer. PATIENTS AND METHODS: Patients with previously untreated small-cell lung cancer were randomized to receive cisplatin in combination with either etoposide or etoposide phosphate. Molar-equivalent doses of etoposide and etoposide phosphate were used. Response rate, time to progression, survival, and toxicity were compared. RESULTS: Major response rates with etoposide phosphate and etoposide were 61% (95% confidence interval, 55% to 67%) and 58% (95% confidence interval, 52% to 64%), respectively (P = .85). No significant differences in median time to progression or survival were observed in patients who received etoposide phosphate versus etoposide. Grade 3 and 4 leukopenia occurred in 63% of patients who received etoposide phosphate compared with 77% who received etoposide (P = .16). CONCLUSION: The combination of etoposide phosphate and cisplatin is effective in the treatment of small-cell lung cancer, and can be administered with acceptable toxicity. Although this study was not designed to be a formal comparative trial, the efficacy and toxicity observed with this regimen were found to be similar to a standard etoposide/cisplatin regimen, using molar-equivalent etoposide doses. Because of its greater ease of administration, etoposide phosphate is preferable to etoposide for routine clinical use.

A phase I study of etoposide phosphate administered as a daily 30-minute infusion for 5 days.

PURPOSE: To determine the maximum tolerated dose, toxicities, kinetics, and disposition of etoposide phosphate when administered as a daily 30-minute infusion for 5 days. PATIENTS AND METHODS: Twenty-eight patients were enrolled in this phase I dose-escalation trial. Cohorts of patients received etoposide phosphate in etoposide equivalent doses of 50, 75, 100 and 125 mg/m2 intravenously for 30 minutes each day for 5 days. Pharmacokinetic sampling of both blood and urine was performed and concentrations of etoposide and etoposide phosphate were determined on day 1 of study for each patient and on day 4 of study for three patients receiving the 100 mg/m2 dose. RESULTS: The dose-limiting toxicity was reversible myelosuppression as evidenced by leukopenia and neutropenia. Toxicities seen were comparable to those expected from etoposide administration. With this schedule, the 100 mg/m2 dose was the maximum tolerated dose. Nonhematologic toxicities were generally mild. Two patients had major responses and three others had minor responses. Pharmacokinetic analyses revealed rapid (< 15 minutes) extensive conversion of etoposide phosphate to etoposide. Peak plasma etoposide concentrations and etoposide areas under the curve were proportional to the dose of etoposide phosphate administered. Etoposide kinetics were similar to those expected after a comparable dose of etoposide. CONCLUSIONS: Etoposide phosphate is a water-soluble pro-drug of etoposide that is rapidly converted to etoposide in vivo with a toxicity profile similar to etoposide. Etoposide generated from etoposide phosphate exhibits linear kinetics over a dose range of 50 to 125 mg/m2. When administered as a daily 30-minute infusion for 5 days, the dose-limiting toxicity is myelosuppression and 100 mg/m2 daily is the maximum tolerated dose.

Phase I study of etoposide phosphate (etopophos) as a 30-minute infusion on days 1, 3, and 5.

Etoposide phophate is a phosphate ester prodrug of etoposide designed to improve the pharmaceutical characteristics of the parent compound. A Phase I dose-escalating study of etoposide phosphate was conducted concurrently at two institutions to determine its toxicity, pharmacokinetics, and maximum tolerated dose. Etoposide phosphate was administered i.v. for 30 min on days 1, 3, and 5 every 21 days or on recovery from toxicity. Cohorts of at least three patients received etoposide phosphate at dose levels from 50 mg/m2 to 150 mg/m2 expressed as molar equivalents of etoposide. Blood and urine samples were obtained from all patients during the first cycle of treatment and the concentrations of etoposide phosphate and etoposide were measured. Thirty-nine patients with documented cancers received a total of 75 cycles of etoposide phosphate. The dose-limiting toxicity was myelosuppression which occurred at the 150-mg/m2 etoposide equivalent dose. Etoposide phosphate was rapidly and extensively converted to etoposide. No measurable etoposide phosphate was detectable in the plasma by 15-60 min after the end of the infusion. The mean half-life of etoposide at the different dose levels ranged from 5.5 to 9.3 h. The pharmacokinetics of etoposide, generated from etoposide phosphate, was linear over the dose range studied and was comparable to results reported in the literature for i.v. etoposide. In summary, i.v. etoposide phosphate is rapidly and extensively converted to etoposide. The maximum tolerated dose of etoposide phosphate when given on days 1, 3, and 5 is 150 mg/m2/day. The dose-limiting toxicity is myelosuppression. The maximum tolerated dose and adverse event profile are consistent with those of etoposide.

Clinical and pharmacokinetic overview of parenteral etoposide phosphate.

Etoposide phosphate (Etopophos, BMY-40481) is a water-soluble derivative of the widely used podophyllotoxin etoposide (VP-16). The phosphate ester renders the compound water-soluble, eliminating the need for formulation in polysorbate (Tween) 80, ethanol, and polyethylene glycol. As a result the compound can be given at high concentrations and as a bolus. In animals and in vitro, etoposide phosphate (EP) is rapidly and completely converted to VP-16. Clinical development of the i.v. formulation has focused on the identification of the maximum tolerated dose (MTD) and pharmacokinetic characteristics of the drug using a 5 daily dose schedule and a days 1, 3, and 5 schedule, with the drug being given over 30 or 5 (bolus) min. Myelosuppression was dose-limiting. Data from these trials show the rapid and complete conversion of EP to VP-16, a pharmacokinetic/pharmacodynamic relationship for myelosuppression and exposure to VP-16, and an MTD of 100 and 150 mg/m2 (molar equivalent to VP-16) when EP is given daily for 5 days and on days 1, 3, and 5, respectively. A formal randomized trial has been conducted to show the pharmacokinetic comparability of EP and VP-16. In this trial, exposure to VP-16 was the same after the parenteral administration of equimolar doses of EP or VP-16. The feasibility of bolus dosing and treatment at high concentrations has been demonstrated, with no effects on the cardiovascular system being noted. Parenteral EP is pharmacokinetically and biologically equivalent to VP-16 and has the advantages of the elimination of potentially toxic excipients; more convenient administration; and ability to be given as a bolus, at high concentrations, and as a continuous infusion.

Effects of therapy with didanosine on hematologic parameters in patients with advanced human immunodeficiency virus disease.

Myelosuppression is associated with human immunodeficiency virus (HIV) infection and may also be produced by agents used for the treatment of the disease or the treatment of its complications. Didanosine (ddl; 2',3'-dideoxyinosine) is a newer purine nucleoside that has recently become available for therapy for HIV infection. The effects of didanosine on peripheral blood counts have been retrospectively evaluated in the first 170 patients treated with this new agent in four phase I trials. Patients treated with didanosine showed statistically significant improvements in hemoglobin levels, white cell counts, and granulocyte and platelet numbers as compared with baseline values. These changes were seen with or without prior therapy with zidovudine, were somewhat more pronounced at higher doses of didanosine, and persisted for up to 1 year. Reported adverse events included peripheral neuropathy, diarrhea, and most notably, pancreatitis. It is concluded that, while some toxic side effects occur, didanosine therapy in HIV infection is associated with an amelioration of HIV-induced myelosuppression.

Drug discovery and development in the pharmaceutical industry.

The discovery and development of new anticancer drugs is a complex and largely empirical process. New compounds can be discovered by screening, modification of existing compounds, rational drug design, and serendipitous basic research observations. Selection of compounds for clinical trials depends on assays of uncertain predictive value. In the pharmaceutical industry, priorities for development of potentially active entities are set and available resources allocated based on the availability and cost of supplies, patent status, potential spectrum of activity, ability to meet regulatory requirements, and market assessments. Competition for resources also occurs from noncancer drugs, eg, cardiovascular agents. Clinical development (testing and approval for commercial distribution) requires close attention to the requirements of national regulatory agencies such as the United States Food and Drug Administration. The arbitrary nature by which compounds with antitumor potential are chosen for development means that some that would be useful never reach clinical trial and others are never made generally available. This article reviews the decision making process in the pharmaceutical industry by which compounds are identified and selected for clinical trial, the regulations in the United States that govern such trials, and what is required to have the drug approved for commercial distribution.

Phase I trial and clinical pharmacology of elsamitrucin.

Elsamitrucin (BMY-28090) is an antitumor antibiotic first described in 1985 that has significant oncolytic activity against a number of murine tumors including P388, L1210, B16 and M5076, as well as against MX1 and HCT116 xenografts. Preclinical toxicology studies of elsamitrucin revealed edema of multiple organs associated with hypoproteinemia and, at lethal doses, severe multiorgan toxicity. We conducted a phase I clinical trial (31 patients) of elsamitrucin administered as a 10-min i.v. infusion every 3 weeks. The starting dose (0.6 mg/m2) was 1/3 of the dog low toxic dose. The maximum tolerated dose was 30 mg/m2. Dose-limiting toxicity was reversible hepatic dysfunction manifested by elevated transaminase levels not associated with bilirubin, alkaline phosphatase, or lactate dehydrogenase elevations. Other toxicities included nausea, vomiting, malaise, and phlebitis. Because the hepatic toxicity was brief and reversible, a subsequent study (18 patients) was conducted with elsamitrucin administered every 2 weeks. Reversible grade 3 hepatotoxicity was again observed at 30 mg/m2. Plasma and urine samples from patients receiving doses of 0.6-36 mg/m2 were analyzed for drug content. The maximum plasma concentration and area under the plasma concentration versus time curve values increased linearly with doses up to 25 mg/m2 but not at higher doses. The terminal half-lives, total body clearances, and volume of distribution were 36-60 h, 10-19 liters/h/m2, and 400-1100 liters/m2, respectively. Less than 5% was excreted in the urine in 24 h as parent compound. Bile was collected from one patient with an indwelling biliary catheter. Approximately 22% of the dose was excreted in 48 h, suggesting that biliary excretion of elsamitrucin may be an important route of drug elimination. Based on reversible hepatic toxicity, the phase II recommended dose of elsamitrucin is 25 mg/m2 every 2 weeks.

Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group.

PURPOSE: The trial was undertaken to determine (1) the relative efficacy/toxicity of two commonly used combination chemotherapy regimens in patients with extensive small-cell lung cancer (SCLC) and (2) whether the rapid alternation of these two regimens could provide superior therapeutic results compared with either regimen alone. PATIENTS AND METHODS: In this phase III trial, 437 eligible patients were stratified by performance status (PS) and sex and were randomly assigned to receive either 12 weeks of cisplatin and etoposide (EP); 18 weeks of cyclophosphamide, doxorubicin, and vincristine (CAV); or 18 weeks of alternation of these two regimens (CAV/EP). RESULTS: There were no significant differences in treatment outcome for EP, CAV, or CAV/EP in terms of response rate (61%, 51%, 59%, respectively), complete response rate (10%, 7%, 7%, respectively), or median survival (8.6 months, 8.3 months, 8.1 months, respectively), with a non-statistically significant trend toward a longer median time to progression with alternating therapy (4.3 months, 4.0 months, 5.2 months, respectively). Crossover second-line chemotherapy given at progression produced low response rates and short survival, regardless of the regimen used. Myelosuppression was the dose-limiting toxicity for all patients, although the pattern and severity differed among the treatment arms. CONCLUSIONS: The combination regimens EP and CAV can be considered equivalently effective induction therapies in extensive SCLC, and these two regimens are, to some degree, crossresistant. Alternating therapy provides no therapeutic advantage compared with the use of either of these regimens alone and should not be considered as standard treatment in this clinical setting.

Overview of hormonal therapy in advanced breast cancer.

Hormonal therapy of breast cancer is widely used and effective. Although never curative in advanced disease, significant palliation and durable remissions can be obtained with a wide variety of hormonal manipulations. Historically, surgical ablation was used to reduce endogenous hormone levels, but this invasive procedure has been largely supplanted by drugs that reduce hormone secretion or block steroid hormone activity. A number of such antagonists are available, with tamoxifen probably the most widely used. Response can also be achieved with hormone agonists. Estrogens and androgens or their congeners have about the same level of activity as surgical ablation or drug antagonists (20% to 30% overall response rate). The progestins, another class of agonists, are also effective in the palliation of advanced breast cancer. Megestrol acetate, in part because of its oral formulation, is probably the most commonly used progestational drug for the treatment of breast cancer. Reports of 16 trials involving 1,342 patients show a response rate of 26% in patients with advanced breast cancer treated with megestrol acetate. The drug has proved active in a small number of male patients and, in randomized trials, it has been shown to be comparable with tamoxifen in efficacy (30% response for megestrol acetate v 35% for tamoxifen). Studies are currently under way to evaluate the possibility that high doses of megestrol acetate may increase response rates, and to determine whether weight gain, a well-described effect of this drug, may prove beneficial in cancer treatment.

Anagrelide: a new drug for treating thrombocytosis.

Anagrelide is a member of the imidazo (2,1-b) quinazolin-2-one series of compounds, with a powerful antiaggregating effect on platelets. During studies in humans, anagrelide in small doses has produced thrombocytopenia. We therefore evaluated it in the treatment of thrombocytosis, and to date, platelet levels in 15 of 17 patients with primary thrombocythemia, 2 patients with polycythemia vera and thrombocytosis, and 1 patient with chronic granulocytic leukemia and thrombocytosis have been well controlled with the use of this agent. Induction doses of 1.0 to 1.5 mg given orally every six hours have produced a decrease in the platelet count, starting on day 5 and reaching a normal level by day 12. Side effects of anagrelide have been minimal. Maintenance therapy with 1.5 to 4.0 mg a day has continued to control the platelet count in patients for up to 28 months. This new agent appears promising in the treatment of thrombocytosis in patients with chronic myeloproliferative disease.

Generation of superoxide anion and hydrogen peroxide by erythrocytes from individuals with sickle trait or normal haemoglobin.

To test the hypothesis that the resistance of sickle trait (AS Hgb) erythrocytes (rbcs) to malaria may be mediated by increased production of activated oxygen species, the production of superoxide anion (O2-) and hydrogen peroxide (H2O2) by AS rbcs and normal (AA Hgb) rbcs was measured under defined conditions. Formation of O2- and H2O2 was time, temperature and oxygen saturation dependent. Reproducible measurement of O2- formation required the presence of 0.2 mmol l-1 KCN to inhibit a cytochrome oxidase activity found in the cytochrome C preparation used. There was an inverse relationship between cell concentration and O2- and H2O2 formation. Use of the inhibitor of superoxide dismutase (SOD), diethyldithiocarbamic acid, increased the amount of O2- measured. When rbcs from blacks with AS Hgb and with AA Hgb were incubated under standardized conditions, significantly (P less than 0.05) more O2- was formed by AS than AA cells (24.3 v. 14.5 mmol per mol Hgb). These findings show that AS rbcs can generate more O2- than AA rbcs. The increased formation of O2- by rbcs containing AS Hgb may contribute to the resistance of AS rbcs to malarial parasitism.

Well-differentiated lymphocytic lymphoma with peripheral blood involvement, osteolytic bone lesions, and hypercalcemia. A case report and review of the literature.

It is rare for small lymphocytic B-cell malignancies to be associated with osteolytic bone lesions and/or hypercalcemia. The authors present an unusual case of well-differentiated lymphocytic lymphoma (DWDL) in a 70-year-old man who had osteolytic bone lesions and subsequently developed severe refractory hypercalcemia. The possible etiologic mechanisms responsible for these findings are discussed, and a brief review of the literature is presented.

Red cell superoxide dismutase and sickle cell anemia symptom severity.

Patients with sickle cell anemia vary in the severity of their symptoms but the basis of this variability is unknown. We have tested the hypothesis that this variability is related to differences in the activity of the antioxidant superoxide dismutase (SOD). The amount of superoxide dismutase I (SOD) enzyme activity in red cells of patients with different degrees of symptom severity and healthy black and white controls was measured and correlated with symptom severity in SCA patients. Blacks with normal (AA) hemoglobin had significantly (p less than .001) more SOD activity (1.82 U/mg Hb) than white controls (1.44 U/mg Hb). Patients with moderate or severe symptoms had less SOD activity (1.16 and 0.95 U/mg Hb, respectively) than control blacks or SCA patients with mild symptoms (1.62 U/mg Hb). The correlation of SOD activity and symptom severity was not a function of age or sex and was unrelated to reticulocyte count or fetal hemoglobin level.

Measurement of free radical oxygen generation by cytochrome c reduction requirement for cytochrome c oxidase blockade.

Data is presented showing that one commercial preparation of cytochrome c, used to trap and measure free radical superoxide anion, can be contaminated with cytochrome c oxidase activity. This activity can vary from lot to lot, can introduce variability into the measurement of superoxide anion and can result in falsely low estimations of free radical formation. This cytochrome c oxidase activity can be inhibited by low (0.2 mM) concentrations of KCN. Blockade of the cytochrome c oxidase activity allows reproducible measurement of superoxide anion formation at low levels by red cells.

Phase II trial of 5-fluorouracil, adriamycin, mitomycin C, and streptozotocin (FAM-S) in pancreatic carcinoma.

Twenty-five patients with unresectable and metastatic pancreatic carcinoma were treated with the combination of 5-fluorouracil, Adriamycin, mitomycin C and streptozotocin (FAM-S). Twelve of 25 patients responded (48%) and four patients demonstrated stable disease. Median survival of all patients was 6.75 months, and seven of 25 patients survived more than 12 months. Hematologic toxicity was moderate, and the predominant side effect recorded was nausea and vomiting (80% patients). Combination chemotherapy in pancreatic carcinoma may provide palliation and randomized trials are warranted to confirm these results.

Elevated superoxide dismutase in black alcoholics.

Superoxide dismutase concentrations in lysates of erythrocytes from black alcoholics were higher than those of white alcoholics and of nonalcoholics of both races. Higher concentrations of enzyme protein, as determined by competition radioimmunoassay, correspond to proportionately higher enzyme activity. Elevated superoxide dismutase levels were not related to any other clinical, historical, or demographic variables. Increased superoxide dismutase levels may delay or prevent some of the pathological sequelae of alcoholism and may be a useful biological marker for alcohol abuse.