Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms.

PURPOSE: To define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of the novel protein kinase inhibitor, UCN-01 (7-hydroxystaurosporine), administered as a 72-hour continuous intravenous infusion (CIV). PATIENTS AND METHODS: Forty-seven patients with refractory neoplasms received UCN-01 during this phase I trial. Total, free plasma, and salivary concentrations were determined; the latter were used to address the influence of plasma protein binding on peripheral tissue distribution. The phosphorylation state of the protein kinase C (PKC) substrate alpha-adducin and the abrogation of DNA damage checkpoint also were assessed. RESULTS: The recommended phase II dose of UCN-01 as a 72-hour CIV is 42.5 mg/m(2)/d for 3 days. Avid plasma protein binding of UCN-01, as measured during the trial, dictated a change in dose escalation and administration schedules. Therefore, nine patients received drug on the initial 2-week schedule, and 38 received drug on the recommended 4-week schedule. DLTs at 53 mg/m(2)/d for 3 days included hyperglycemia with resultant metabolic acidosis, pulmonary dysfunction, nausea, vomiting, and hypotension. Pharmacokinetic determinations at the recommended dose of 42.5 mg/m(2)/d for 3 days included mean total plasma concentration of 36.4 microM (terminal elimination half-life range, 447 to 1176 hours), steady-state volume of distribution of 9.3 to 14.2 L, and clearances of 0.005 to 0.033 L/h. The mean total salivary concentration was 111 nmol/L of UCN-01. One partial response was observed in a patient with melanoma, and one protracted period ( > 2.5 years) of disease stability was observed in a patient with alk-positive anaplastic large-cell lymphoma. Preliminary evidence suggests UCN-01 modulation of both PKC substrate phosphorylation and the DNA damage-related G(2) checkpoint. CONCLUSION: UCN-01 can be administered safely as an initial 72-hour CIV with subsequent monthly doses administered as 36-hour infusions.

A high-performance liquid chromatography method using ultraviolet and fluorescence detection for the quantitation of UCN-01, 7-hydroxystaurosporine, from human plasma and saliva.

UCN-01, 7-hydroxystaurosporine, is an antagonist of protein kinase C, as well as causing cell cycle arrest. We developed and validated an HPLC assay method for the quantitation of UCN-01. Plasma and saliva standard curves were prepared at concentrations ranging from 0.2 to 20.0 microgram/mL and 4.0 to 200.0 ng/mL, respectively. The sample preparation consisted of acetonitrile precipitation. Separation was accomplished on a phenyl column and a C-18 precolumn insert utilizing a gradient-profile consisting of ammonium acetate and acetonitrile. UV detection was set at 295 nm for UCN-01 and 323 nm for umbelliferone, the internal standard. For fluorescence detection, excitation occurred at 290 nm, while emission was at 400 nm. The retention times were around 4 min for umbelliferone and 9.1 for UCN-01. Inter- and intra-assay errors of accuracy were less than 7. 0% and 10.7%, respectively, for the plasma standard curve and less than 7.1% and 6.7%, respectively, for the saliva standard curve. The recoveries of UCN-01 and umbelliferone from saliva were 81.4 +/- 0. 9% and 106.3 +/- 10.2%, respectively. The recovery of UCN-01 from plasma was 97.9 +/- 7.1% and for umbelliferone was 103.3 +/- 2.3%. This method is suitable for quantifying UCN-01 in patient samples and further characterizing the clinical pharmacology of this compound. Published in 2000 by John Wiley & Sons, Ltd.

A phase II trial of gallium nitrate in patients with androgen-metastatic prostate cancer.

INTRODUCTION: Due to in vitro data suggesting antitumor activity with gallium nitrate, we sought to evaluate the safety and activity in patients with androgen-independent prostate cancer. METHOD: Patients were eligible for this study if they had an ECOG performance status of < or = 2, stage D2 metastatic prostate cancer that was progressing following combined androgen ablation (medical or surgical castration plus antiandrogen) and had failed antiandrogen withdrawal. Therapy consisted of gallium nitrate (200 mg/m(2)/day) as a continuous infusion for 7 days, administered every 21 days, with hydration (100 ml/m(2)/h). Individuals that had previously received suramin were treated at a dose of 150 mg/m(2)/day of gallium nitrate. RESULTS: Eight patients were enrolled: 4 patients at the 200 mg/m(2)/day dose level and 4 patients at the lower dosage (150 mg/m(2)/day). One of 8 patients had a >75% decline in prostate-specific antigen (PSA), 3 patients had stable PSA values for 17, 18 and 22 weeks, and 4 patients had progression by PSA (>50% increase over baseline). Anemia requiring transfusion occurred in 5 of 8 patients (63%). Two patients (25%) developed grade 4 toxicity: 1 patient developed complete blindness with partial reversal over 12 months, and another patient had pulmonary infiltrates, hypoxemia, and fever. Serious adverse events were not correlated to prior suramin exposure, or gallium plasma concentrations (total or free), but appeared to be related to cumulative cycles of gallium nitrate. Remaining adverse events were grade 1 or 2. No patients developed renal or neurological toxicity. CONCLUSION: This trial was prematurely terminated because repeated administration of gallium nitrate was poorly tolerated in an elderly population with androgen-independent prostate cancer. Gallium had modest clinical activity in this disease.

Pharmacokinetics of cisplatin administered by continuous hyperthermic peritoneal perfusion (CHPP) to patients with peritoneal carcinomatosis.

The pharmacokinetics of cisplatin administered by continuous hyperthermic peritoneal perfusion (CHPP) was characterized in patients with peritoneal carcinomatosis. Cisplatin was added into the perfusate with escalating doses from 100 mg/m2 to 400 mg/m2. The hyperthermic perfusion was maintained for 90 minutes with a flow rate of 1.5 L/min and a target peritoneal temperature of 42.5 degrees C after a tumor debulking procedure. Samples of both the perfusate and blood were obtained during the perfusion and 30 minutes after the perfusion. Cisplatin plasma and perfusate concentrations were determined by flameless atomic absorption spectrometry with a lower limit of detection of 2 ng/ml and a coefficient of variation (CV) < 10%. Fifty-six patients were enrolled in the study. The mean (+/- SD) percentage of cisplatin present in the perfusate at the completion of perfusion was 27.8% +/- 20% of the total dose. The maximum cisplatin concentrations in the perfusate were 10 times higher than those in plasma. The area under the concentration-time curve (AUC) of the perfusate was 13 times higher than the AUC of plasma. A two-compartment model with an additional peritoneal cavity compartment fits to the data best based on the Akaike information criterion. However, the interpatient variability was considerably high (CV < 100%). In conclusion, cisplatin administered by hyperthermic peritoneal perfusion resulted in a pharmacological advantage by obtaining higher and direct drug exposure to the tumor in the peritoneal cavity while limiting systemic absorption and toxicity. Using a complex two-compartment model, the authors were able to characterize the pharmacokinetics of cisplatin given intraperitoneally via this technique.

Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms.

PURPOSE: We conducted a phase I trial of the cyclin-dependent kinase inhibitor, flavopiridol (National Service Center [NSC] 649890), to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacology of flavopiridol given as a 72-hour infusion every 2 weeks. PATIENTS AND METHODS: Seventy-six patients with refractory malignancies with prior disease progression were treated with flavopiridol, with first-cycle pharmacokinetic sampling. RESULTS: Forty-nine patients defined our first MTD, 50 mg/m2/d x 3 with dose-limiting toxicity (DLT) of secretory diarrhea at 62.5 mg/kg/d x 3. Subsequent patients received antidiarrheal prophylaxis (ADP) to define a second MTD, 78 mg/m2/d x 3 with DLT of hypotension at 98 mg/m2/d x 3. Other toxicities included a proinflammatory syndrome with alterations in acute-phase reactants, particularly at doses >50 mg/ m2/d x 3, which in some patients prevented chronic therapy every 2 weeks. In some patients, ADP was not successful, requiring dose-deescalation. Although approximately 70% of patients displayed predictable flavopiridol pharmacology, we observed unexpected interpatient variability and postinfusion peaks in approximately 30% of cases. At the two MTDs, we achieved a mean plasma flavopiridol concentration of 271 nM (50 mg/m2/d x 3) and 344 nM (78 mg/m2/d x 3), respectively. One partial response in a patient with renal cancer and minor responses (n=3) in patients with non-Hodgkin's lymphoma, colon, and renal cancer occurred. CONCLUSION: The MTD of infusional flavopiridol is 50 mg/m2/d x 3 with dose-limiting secretory diarrhea at 62.5 mg/m2/d x 3. With ADP, 78 mg/m2/d x 3 was the MTD, with dose-limiting hypotension at 98 mg/m2/d x 3. Based on chronic tolerability, 50 mg/m2/d x 3 is the recommended phase II dose without ADP. Antitumor effect was observed in certain patients with renal, prostate, and colon cancer, and non-Hodgkin's lymphoma. Concentrations of flavopiridol (200 to 400 nM) needed for cyclin-dependent kinase inhibition in preclinical models were achieved safely.

A phase II study of 5-aza-2'deoxycytidine (decitabine) in hormone independent metastatic (D2) prostate cancer.

AIMS AND BACKGROUND: Decitabine (5-aza-2'-deoxycytidine) is an S-phase-specific pyrimidine analog with hypomethylation properties. In laboratory models of prostate cancer (PC-3 and DU-145), decitabine induces cellular differentiation and enhanced expression of genes involved in tumor suppression, immunogenicity, and programmed cell death. METHODS: We conducted a phase II study of decitabine in 14 men with progressive, metastatic prostate cancer recurrent after total androgen blockade and flutamide withdrawal. Decitabine was administered at a dose of 75 mg/m2/dose i.v. as a 1 hour infusion every 8 hours for three doses. Cycles of therapy were repeated every 5 to 8 weeks to allow for resolution of toxicity. RESULTS: Two of 12 patients evaluable for response had stable disease with a time to progression of more than 10 weeks. This activity was seen in 2 of 3 African-American patients. Toxicity was similar to previously reported experience. No significant changes in urinary concentrations of the angiogenic factor bFGF, a potential biomarker of tumor activity, were identified over time in 7 unselected patients with progressive disease. CONCLUSIONS: We conclude that decitabine is a well tolerated regimen with modest clinical activity against hormone-independent prostate cancer. Further investigations in patients of African-American origin may be warranted.

Elevated carcinoembryonic antigen in patients with androgen-independent prostate cancer.

BACKGROUND: Extraordinarily high serum carcinoembryonic antigen (CEA) values have been reported to be associated with many malignant disorders, including carcinoma with primary sites in the colon, pancreas, stomach, bile duct, lung, and breast. This study was undertaken to determine if a marked elevation of serum CEA levels in androgen-independent prostate cancer patients exists, and to evaluate the potential of using CEA monitoring as a marker for disease progression. METHODS: Records from 141 patients with progressive androgen-independent prostate cancer who were treated at the National Cancer Institute from 1990 to 1996 were analyzed. Serum CEA concentrations were measured using a micro-particle enzyme immunoassay. RESULTS: Among these cases of prostatic carcinoma, 69 (48.9%) had abnormally elevated plasma CEA values (greater than the normal upper limit of 2.5 ng/mL) at some time during their treatment on a clinical investigation protocol. No correlation was found between the elevated CEA concentrations and prostate specific antigen (PSA). In comparison, 32.5% of patients with elevated CEAs had disease that had metastasized to soft tissue (adenopathy, etc) versus 22.2% with normal CEA who had soft tissue involvement (p = 0.3 X2). We examined the CEA values with respect to survival time, defined as the interval from the date of the earliest CEA level to the date of death and found no association (p > 0.3). CONCLUSIONS: Based on these observations, it appears that in the context of androgen-independent prostate cancer, CEA can be elevated but is an inviable surrogate marker of disease progression with minimal prognostic value.

Pharmacokinetics and relative bioavailability of carboxyamido-triazole with respect to food and time of administration: use of a single model for simultaneous determination of changing parameters.

Carboxyamido-triazole (CAI) is an anti-invasive, antimetastatic, antiangiogenic agent in clinical development for cancer treatment. It has been postulated that food might enhance the oral absorption of micronized CAI based on an apparent discrepancy in steady state maximum concentrations when taken without regard to meals vs. fasting. The purpose of this study was to determine if a standardized meal affects the absorption and pharmacokinetics of this agent. Twelve patients with refractory cancers and good end organ function were randomized to receive two doses of CAI (250 mg/m2) with and without a standardized high fat meal. One cohort of 6 patients received these doses at 9 AM, and the remaining 6 patients received CAI at 9 PM. Blood was obtained prior to each dose, and serially thereafter. A series of pharmacokinetic (PK) models were fit to the concentration-time data. PK parameters were ultimately calculated using a model which allows simultaneous estimation of parameters from both test doses using nonlinear least squares analysis with ADAPT II. This model estimates independent absorption rate constants and relative fraction absorbed for each condition. AUC0-t was determined using the trapezoidal method, extrapolated to infinity, and used to calculate the relative bioavailability. No significant differences in PK parameters were noted between the morning and evening cohorts. However, the relative bioavailability, as measured by AUC0-infinity, of CAI was significantly increased when administered with a high fat meal compared to fasting (138.9 vs. 52.2 micrograms * hr/ml; p = 0.0005). The magnitude of the increase in relative bioavailability of CAI taken with food could have profound implications for patients who may inadvertently take this medication shortly after eating.

Pharmacometric analysis of the effect of furosemide on suramin pharmacokinetics.

STUDY OBJECTIVE: To characterize the effects of furosemide on the pharmacokinetics of suramin, a renally eliminated investigational antineoplastic agent. DESIGN: Retrospective population pharmacokinetic analysis. SETTING: Government biomedical research facility. PATIENTS: Twenty-six men with hormone-refractory prostate cancer and one with adrenocortical carcinoma. INTERVENTIONS: Patients received suramin by continuous or intermittent infusion with and without concomitant furosemide. MEASUREMENTS AND MAIN RESULTS: Optimum suramin regimens were achieved by adaptive feedback control, and pharmacokinetic data were collected both in the presence and absence of furosemide. Suramin concentrations were determined by high-performance liquid chromatography (coefficient of variation < 8%). Suramin concentrations were fit to a three-compartment linear model with six coefficients and two rate inputs, which allowed furosemide to affect suramin pharmacokinetics. Individual and population parameter estimates were determined using the iterative two-stage approach. Concomitant furosemide was associated with a median decrease in total body clearance of suramin by 36% (range 0-63%, p < 0.0001). No other parameter was significantly altered, and there was no trend for change in any pharmacokinetic value with time. Suramin plasma concentrations were simulated with and without prolonged furosemide therapy in 26 patients for 12 weeks. The average suramin concentration increased by greater than 33% in 12 patients; 2 patients had a greater than 67% increase in this extreme case model. CONCLUSION: Coadministration of furosemide with suramin can cause an increase in suramin concentrations; however, due to suramin's long half-life, its rate of accumulation is very slow. Nonetheless, in individuals receiving suramin by nonadaptive control, appropriate precautions should be taken when prolonged furosemide therapy is begun.

Continuous hyperthermic peritoneal perfusion with cisplatin for the treatment of peritoneal mesothelioma.

PURPOSE: Peritoneal mesothelioma remains a difficult therapeutic challenge. Aggressive debulking combined with continuous hyperthermic peritoneal perfusion (CHPP) using cisplatin (CDDP) is a novel strategy for the treatment of peritoneal mesothelioma, allowing high regional delivery of chemotherapeutics and hyperthermia while minimizing systemic toxicity. PATIENTS AND METHODS: From June 1993 to May 1996, 10 patients with peritoneal mesothelioma (six men, four women; mean age 40 years, range 15-57) underwent tumor debulking followed by a 90-minute CHPP. CHPP parameters included mean initial CDDP of 120 micrograms/mL (range 81-166), perfusate volume 5.2 L (range 4-7), flow 1.5 L/min, intraperitoneal temperature at three locations-41.5 degrees C, 40.5 degrees C, 41.1 degrees C, and core temperature 38.4 degrees C (range 37.2 degrees C-39.5 degrees C). Nine of 10 patients had malignant peritoneal mesothelioma, eight with associated ascites, while the tenth had a symptomatic, multiply recurrent benign peritoneal mesothelioma. Nine of 10 patients were optimally debulked. Pharmacokinetics were performed on blood and perfusate samples on nine patients; CDDP levels were quantitated by atomic absorption spectroscopy. RESULTS: Total perfusate cisplatin AUC was a mean of 21-fold higher (range 2- to 116-fold) than total serum cisplatin AUC, and serum CDDP behaved similarly to systemically administered CDDP. Median follow-up after CHPP is 10 months (range 2-32), with no treatment-related mortality. In eight optimally debulked patients there is no evidence of recurrent disease clinically or by CT or MRI. Seven patients with symptomatic ascites have been completely palliated. CONCLUSIONS: CHPP with CDDP is well tolerated with no significant regional toxicity. Because favorable CDDP pharmacokinetics suggest the potential for enhanced CDDP tumoricidal effect during CHPP, tumor debulking and CHPP may represent an effective strategy for the treatment of peritoneal mesothelioma.

Initial pharmacokinetics and bioavailability of PSC 833, a P-glycoprotein antagonist.

Resistant cancer cells have been shown to overexpress a 170-kd membrane glycoprotein called P-glycoprotein. P-glycoprotein, a product of the multidrug resistance 1 gene, functions as an energy-dependent efflux pump that decreases intracellular drug concentrations. A variety of nonchemotherapeutic agents have been shown to inhibit P-glycoprotein-dependent drug efflux including cyclosporin. PSC 833 is a nonimmunosuppressive derivative of cyclosporin D with the ability to reverse multidrug resistance because of P-glycoprotein overexpression in vitro. As part of early clinical development of PSC 833, the authors investigated the bioavailability of an oral formulation of PSC 833. PSC 833 (3 mg/kg) was administered as a 2-hour intravenous infusion on day 1 of the treatment cycle. Serial blood samples for the determination of PSC 833 whole blood concentrations were obtained after both the intravenous and oral doses. On day 5 of the study, patients received a single oral dose (9 mg/kg) of PSC 833. A total of 14 patients were treated. The intravenous data were best described by a two-compartment open model. The oral data also were described using a two-compartment model, with oral absorption incorporating a lag time to account for possible delays in absorption. There was large intra- and interpatient variability in the pharmacokinetics of PSC 833 in these patients. The absolute bioavailability of PSC 833 was 34% but ranged from 3% to 58% of the administered dose. The clearance (CI) of PSC 833, in general, was consistent between the two dose forms administered. The pharmacokinetic behavior of PSC 833 appears to be similar to that of cyclosporine.

In vitro effect of gallium nitrate when combined with ketoconazole in the prostate cancer cell line PC-3.

Secondary hormonal manipulations are common following the failure of combined androgen blockade in patients with metastatic prostate cancer. Ketoconazole has been shown to have activity in this disease by inhibiting cytochrome P450 steroid hormone biosynthesis, thus inducing androgen deprivation. Gallium nitrate has been reported to target tumor tissue in vitro and some preliminary data suggests activity in patients with prostate cancer. Thus, we conducted a Phase II study of gallium nitrate in patients with androgen-independent prostate cancer. Two patients with progressive prostate cancer were removed from this study and subsequently placed on ketoconazole, as a palliative agent. Surprisingly, both of these patients had a greater than 50% decline in their prostate specific antigen (PSA) with this secondary endocrine maneuver. Based on this clinical observation, we conducted the following in vitro study to determine if there was a substantial additive effect of gallium nitrate followed by ketoconazole. Gallium nitrate or ketoconazole was added to the androgen-independent prostatic epithelial cell line, PC-3. One hundred and twenty hours (120 h) following the addition of one of the agents, the media was aspirated and the second agent was added to the wells. One plate was assayed every 24 h for cell viability using a non-isotopic cell proliferation assay kit. Cells treated with gallium nitrate followed by ketoconazole were 70-100% of control at the end of the gallium nitrate treatment; ketoconazole was then added and viability either remained constant or dropped steadily. Gallium nitrate by itself had a weak inhibitory effect on cell viability that only became apparent at the highest concentration evaluated. Ketoconazole, on the other hand, showed a substantial growth inhibition that was concentration-dependent. Cells treated with this agent alone showed a pronounced steady decrease in viability. Exposure to ketoconazole for 120 h followed by incubation in culture medium alone for 120 h caused a decrease in cell viability to 26.0% of control. Our in vitro results suggest that the combination of gallium nitrate and ketoconazole has no additive activity in the PC-3 cell line. Furthermore, this study confirms that ketoconazole added to prostate cancer cells has antiproliferative activity. The in vitro activity of ketoconazole has traditionally been thought to result from its inhibition of cytochrome P450-dependent enzymes responsible for steroidogenesis; however, an alternative hypothesis is necessary to explain the cytotoxic effect in the absence of adrenal and testicular androgen production as found in an in vitro system.

The pharmacokinetics of TNP-470, a new angiogenesis inhibitor.

STUDY OBJECTIVE: To characterize the pharmacokinetic profile of TNP-470, a synthetic analog of fumagillin that is a potent inhibitor of angiogenesis and inhibits neovascularization in several solid tumor models. DESIGN: A dose-escalation phase I clinical trial. SETTING: The National Institutes of Health. PATIENTS: Patients with human immunodeficiency virus-associated Kaposi's sarcoma. INTERVENTIONS: The TNP-470 dosage was increased in 13 sequential cohorts using a modified Fibonacci escalation scheme (4.6, 9.3, 15.4, 23.2, and 43.1 mg/m2). The drug was administered as a 1-hour intravenous infusion. Serial blood samples were collected and assayed by reverse-phase high-performance liquid chromatography and the pharmacokinetics were characterized. MEASUREMENTS AND MAIN RESULTS: There was a linear relationship between the dose of TNP-470 and both area under the curve to infinity (AUC[inf]) and time to maximum concentration (Cmax). The Cmax ranged between 6.6 ng/ml at the lowest dosage (4.6 mg/m2) and 597.1 ng/ml at the highest dosage (43.1 mg/m2). The agent was rapidly cleared from the circulation with a short terminal half-life (0.88 +/- 2.5 hr), which is consistent with preclinical data. Peak plasma concentrations of AGM-1883, an active metabolite, ranged between 0.4 and 158.1 ng/ml. CONCLUSION: Concentrations of TNP-470 that have in vitro activity were achievable in vivo. The drug was rapidly cleared from the circulation after a single 1-hour infusion. There was considerable interpatient variability in the clearance, but no evidence of saturable elimination. If more prolonged exposure is necessary for activity, administration of TNP-470 by continuous infusion may be suitable.

Apoptosis: its role in the development of malignancies and its potential as a novel therapeutic target.

OBJECTIVE: To review the current literature regarding the role of apoptosis in the development of malignant cells and how the induction of this pathway could be used in cancer therapy. DATA SOURCE: A MEDLINE search of basic science articles pertinent to the understanding of the normal physiologic process of apoptosis was conducted. STUDY SELECTION: Because of the rapidly growing literature regarding apoptosis, only articles describing key processes in the biology of the cell and the genetic control of apoptosis were included. DATA SYNTHESIS: Apoptosis is imperative for host survival since it discards unwanted, damaged, and atypical cells. The process is therefore implicated in the continuous regulation of development, differentiation, and homeostasis. Furthermore, apoptosis is a response to physiologic and pathologic stresses that disrupt the balanced rates of cell generation and elimination. In a disease such as cancer, there is a lack of equilibrium between the rates of cell division and cell death; agents that promote or suppress apoptosis can manipulate these rates, influencing the anomalous accumulation of neoplastic cells. Pharmacologic manipulation of apoptosis can manipulate these rates, influencing the anomalous accumulation represents a novel approach in targeting malignant cells and has far-reaching implications for new directions in cancer therapy. CONCLUSIONS: Apoptosis is a highly organized physiologic mechanism of destroying injured and abnormal cells as well as maintaining homeostasis in multicellular organisms. Both the activation and inhibition of apoptosis are tightly controlled. Pharmacologic manipulation of this pathway is a novel therapeutic target in cancer therapy.

Plasma protein binding of phenylacetate and phenylbutyrate, two novel antineoplastic agents.

Phenylacetate and phenylbutyrate, two novel inducers of tumor cytostasis and differentiation, are currently in clinical trials for the treatment of cancer in adults. The purpose of our study was to evaluate the plasma protein-binding characteristics of phenylacetate and phenylbutyrate in the plasma of normal volunteers and that of patients with cancer. Drug plasma protein-binding analysis was examined using three separate devices: a micropartition system and two equilibrium dialysis systems, all of which exhibited similar results. Phenylacetate and phenylbutyrate concentrations were determined by high-performance liquid chromatography. Both drugs exhibited concentration-dependent binding. Our results showed sodium phenylacetate to have a higher free fraction than sodium phenylbutyrate at corresponding concentrations (> 0.442 +/- 0.008 and > 0.188 +/- 0.001, respectively). Plasma pH did not greatly affect protein binding of either drug. As albumin concentration decreased, an increase in free fraction of both drugs was observed, however alpha 1-acid glyco-protein showed no change in free fraction as its concentration increased. Patients with cancer with lower levels of albumin showed an increase in free fraction with both phenylacetate and phenylbutyrate. When phenylacetate and phenylbutyrate were added together in plasma, the free fraction of phenylacetate increased, whereas the phenylbutyrate free fraction slightly decreased. We conclude that phenylacetate and phenylbutyrate have high free fractions that change with varying albumin levels and when both phenylacetate and phenylbutyrate are present together in plasma.

A phase I study of pentosan polysulfate sodium in patients with advanced malignancies.

BACKGROUND: Pentosan polysulfate (xylanopolyhydrogensulfate) is a semi-synthetic sulfated heparinoid polysaccharide which has been used as an anticoagulant for nearly thirty years in Europe. It antagonizes the binding of bFGF to cell surface receptors and has thus been evaluated for antitumor activity in several animal models and human tumor cell lines. In two angiogenic models pentosan has been shown to inhibit bFGF stimulation of angiogenesis. Previous clinical studies have determined the coagulation effects of pentosan to be the dose-limiting toxicity. PATIENTS AND METHODS: We conducted a phase I study designed to define the duration-limiting toxicity associated with progressive prolongation of a continuous intravenous infusion (three, five, and eight weeks). This study was not designed to escalate the dose of pentosan beyond that required to maintain the activated partial thromboplastin time (aPTT) between 1.8 and 2.2 times the baseline value. RESULTS: Thirteen patients with advanced stage metastatic cancer were enrolled (median age 50 years, range 34 to 61 years). Four patients were treated in cohort #1 (three weeks of infusional therapy), five patients were treated in cohort #2 (five weeks of therapy), and four patients in cohort #3 (eight weeks of therapy). All patients experienced a progressive prolongation of their aPTT and PT. Furthermore, all patients experienced at least grade I thrombocytopenia. Other complications were, in general, mild. One patient developed grade III liver abnormalities while receiving the eight-week infusion and another patient developed grade IV thrombocytopenia while receiving the same regimen. One patient with colon cancer had stable disease for 24 weeks, while the remaining 12 patients had no objective evidence of response. CONCLUSION: Pentosan was well tolerated when doses were adjusted for aPTT prolongations and a five-week cycle appeared to be the maximum tolerated duration of infusion (initially 4 mg/kg/day). One patient had stable disease, but there was no objective tumor response noted in the remaining 12 patients.

Suramin-induced neutropenia.

This paper presents a retrospective review of 6 cases of severe neutropenia attributed to suramin, the response to granulocyte-colony stimulating factor (G-CSF) and the possible mechanism. Plasma suramin concentrations, G-CSF, platelet-derived growth factor-AB (PDGF-AB) and fibroblast growth factor basic (FGF basic) levels were measured and correlated with neutropenic course. The time course of neutropenia was unpredictable and occurred both during and following discontinuation of suramin. Neutropenia rapidly resolved with G-CSF. Neither the measured growth factor levels nor plasma suramin concentrations correlated with neutropenia. We conclude that neutropenia secondary to suramin is unpredictable and responds to G-CSF administration permitting further suramin therapy. The mechanism remains unknown.

A phase I study of bolus versus continuous infusion of the anti-CD19 immunotoxin, IgG-HD37-dgA, in patients with B-cell lymphoma.

IgG-HD37-SMPT-dgA is a deglycosylated ricin A chain (dgA)-containing immunotoxin (IT) prepared by conjugating the monoclonal murine (MoAb) anti-CD19 antibody, HD37, to dgA using the heterobifunctional hindered disulfide linker, N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyldithio) toluene (SMPT). In this report, we have used two regimens for the administration of IgG-HD37-SMPT-dgA to patients with non-Hodgkin's lymphoma (NHL) in two concomitant phase I trials. One trial examined four intermittent bolus infusions administered at 48-hour intervals. The other studied a continuous infusion (CI) administered over the same 8-day period. In the intermittent bolus regimen, the maximum tolerated dose (MTD) was 16 mg/m2/8 d and the dose-limiting toxicity (DLT) consisted of vascular leak syndrome (VLS), aphasia, and evidence of rhabdomyolysis encountered at 24 mg/m2/8 d. Using the CI regimen, the MTD was defined by VLS at 19.2 mg/m2/8 d. At the MTD of both regimens, a novel toxicity, consisting of acrocyanosis with reversible superficial distal digital skin necrosis in the absence of overt evidence of systemic vasculitis, occurred in 3 patients. Of 23 evaluable patients on the bolus schedule, there was 1 persisting complete response (CR; > 40 months) and 1 partial response (PR). Of 9 evaluable patients on the continuous infusion regimen, there was 1 PR. Pharmacokinetic parameters for the bolus regimen at the MTD showed a mean maximum serum concentration (Cmax) of 1,209 +/- 430 ng/mL, with a median T1/2 beta for all courses of 18.2 hours (range, 10.0 to 80.0 hours), a volume of distribution (Vd) of 10.9 L (range, 3.1 to 34.5 L), and a clearance (CL) of 0.45 L/h (range, 0.13 to 2.3 L/h). For the CI regimen at MTD, the mean Cmax was 963 +/- 473 ng/mL, with a median T1/2 beta for all courses of 22.8 hours (range, 24.1 to 30.6 hours), a Vd of 9.4 L (range, 4.4 to 19.5 L), and a CL of 0.32 L/h (range, 0.12 to 0.55 L/h). Twenty-five percent of the patients on the bolus infusion regimen and 30% on the CI regimen made antibody against mouse Ig (HAMA) and/or ricin A chain antibody (HARA). We conclude that this IT can be administered safely and that both regimens achieve comparable peak serum concentrations at the MTD; these concentrations are similar to those achieved previously using other regimens with IgG-dgA ITs at their respective MTDs. Thus, toxicity is related to the serum level of the IT and does not differ with different targeting MoAbs.

The mutated androgen receptor and its implications for the treatment of metastatic carcinoma of the prostate.

Androgen deprivation is the most effective therapy for patients with advanced prostatic carcinoma. The lack of androgen stimulation on these cells causes them to become apoptotic. Although therapeutic efficacy of initial androgen deprivation in prostate cancer is high, the emergence of androgen-independent cancer is inevitable. Withdrawal of the antiandrogen flutamide elicits surprising activity in these cancers. In numerous studies the response rates cell line harbors a mutation in codon 877 of the androgen receptor. The mutant receptor loses androgen specificity and is activated by various steroids as well as flutamide. Identical and similar mutations have now been isolated from human prostate cancer tissue. The discovery of the mutated androgen receptor sheds light on the emergence of androgen-independent cancer and should facilitate the development of more efficacious therapies.