Phase 1 trial of ADI-PEG 20 and liposomal doxorubicin in patients with metastatic solid tumors.

BACKGROUND: Arginine depletion interferes with pyrimidine metabolism and DNA damage repair pathways. Preclinical data demonstrated that depletion of arginine by PEGylated arginine deiminase (ADI-PEG 20) enhanced liposomal doxorubicin (PLD) cytotoxicity in cancer cells with argininosuccinate synthase 1 (ASS1) deficiency. The objective of this study was to assess safety and tolerability of ADI-PEG 20 and PLD in patients with metastatic solid tumors. METHODS: Patients with advanced ASS1-deficient solid tumors were enrolled in this phase 1 trial of ADI-PEG 20 and PLD following a 3 + 3 design. Eligible patients were given intravenous PLD biweekly and intramuscular (IM) ADI-PEG 20 weekly. Toxicity and efficacy were evaluated according to the Common Terminology Criteria for Adverse Events (version 4.0) and Response Evaluation Criteria in Solid Tumors (version 1.1), respectively. RESULTS: Of 15 enrolled patients, 9 had metastatic HER2-negative breast carcinoma. We observed no dose-limiting toxicities or treatment-related deaths. One patient safely received 880 mg/m2 PLD in this study and 240 mg/m2 doxorubicin previously. Treatment led to stable disease in 9 patients and was associated with a median progression-free survival time of 3.95 months in 15 patients. Throughout the duration of treatment, decreased arginine and increased citrulline levels in peripheral blood remained significant in a majority of patients. We detected no induction of anti-ADI-PEG 20 antibodies by week 8 in one third of patients. CONCLUSION: Concurrent IM injection of ADI-PEG 20 at 36 mg/m2 weekly and intravenous infusion of PLD at 20 mg/m2 biweekly had an acceptable safety profile in patients with advanced ASS1-deficient solid tumors. Further evaluation of this combination is under discussion.

Phase I study of ADI-PEG20 plus low-dose cytarabine for the treatment of acute myeloid leukemia.

Most acute myeloid leukemia (AML) cells are argininosuccinate synthetase-deficient. Pegylated arginine deiminase (ADI-PEG20) monotherapy depletes circulating arginine, thereby selectively inducing tumor cell death. ADI-PEG20 was shown to induce complete responses in ~10% of relapsed/refractory or poor-risk AML patients. We conducted a phase I, dose-escalation study combining ADI-PEG20 and low-dose cytarabine (LDC) in AML patients. Patients received 20 mg LDC subcutaneously twice daily for 10 days every 28 days and ADI-PEG20 at 18 or 36 mg/m2 (dose levels 1 and 2) intramuscularly weekly. An expansion cohort for the maximal tolerated dose of ADI-PEG20 was planned to further estimate the toxicity and preliminary response of this regimen. The primary endpoints were safety and tolerability. The secondary endpoints were time on treatment, overall survival (OS), overall response rate (ORR), and biomarkers (pharmacodynamics and immunogenicity detection). Twenty-three patients were included in the study, and seventeen patients were in the expansion cohort (dose level 2). No patients developed dose-limiting toxicities. The most common grade III/IV toxicities were thrombocytopenia (61%), anemia (52%), and neutropenia (30%). One had an allergic reaction to ADI-PEG20. The ORR in 18 evaluable patients was 44.4%, with a median OS of 8.0 (4.5-not reached) months. In seven treatment-naïve patients, the ORR was 71.4% and the complete remission rate was 57.1%. The ADI-PEG20 and LDC combination was well-tolerated and resulted in an encouraging ORR. Further combination studies are warranted. (This trial was registered in ClinicalTrials.gov as a Ph1 Study of ADI-PEG20 Plus Low-Dose Cytarabine in Older Patients With AML, NCT02875093).

Arginine metabolism and deprivation in cancer therapy.

Certain cancer cells with nutrient auxotrophy and have a much higher nutrient demand compared with normal human cells. Arginine as a versatile amino acid, has multiple biological functions in metabolic and signaling pathways. Depletion of this amino acid by arginine depletor is generally well tolerated and has become a targeted therapy for arginine auxotrophic cancers. However, the modulatory eff ;ect of arginine on cancer cells is very complicated and still controversial. Therefore, this article focuses on arginine metabolism and depletion therapy in cancer treatment to provide systemical review on this issue.

A phase 1 study of ADI-PEG 20 and modified FOLFOX6 in patients with advanced hepatocellular carcinoma and other gastrointestinal malignancies.

PURPOSE: Arginine depletion interferes with pyrimidine metabolism as well as DNA damage repair pathways. Preclinical data indicates that pairing pegylated arginine deiminase (ADI-PEG 20) with fluoropyrimidines or platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs. METHODS: This is a single-center, open-label, phase 1 trial of ADI-PEG 20 and modified FOLFOX6 (mFOLFOX6) in treatment-refractory hepatocellular carcinoma (HCC) and other advanced gastrointestinal tumors. A 3 + 3 dose escalation design was employed to assess safety, tolerability, and determine the recommended phase 2 dose (RP2D) of ADI-PEG 20. A RP2D expansion cohort for patients with HCC was employed to define the objective response rate (ORR). Secondary objectives were to estimate progression-free survival (PFS), overall survival (OS), and to explore pharmacodynamics and immunogenicity. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI-PEG-20 intramuscularly weekly at 18 (Cohort 1) or 36 mg/m2 (Cohort 2 and RP2D expansion). RESULTS: Twenty-seven patients enrolled-23 with advanced HCC and 4 with other gastrointestinal tumors. No dose-limiting toxicities were observed in cohort 1 or 2. The RP2D for ADI-PEG 20 was 36 mg/m2 weekly with mFOLFOX6. The most common any grade adverse events (AEs) were thrombocytopenia, neutropenia, leukopenia, anemia, and fatigue. Among the 23 HCC patients, the most frequent treatment-related Grade ≥ 3 AEs were neutropenia (47.8%), thrombocytopenia (34.7%), leukopenia (21.7%), anemia (21.7%), and lymphopenia (17.4%). The ORR for this group was 21% (95% CI 7.5-43.7). Median PFS and OS were 7.3 and 14.5 months, respectively. Arginine levels were depleted with therapy despite the emergence of low levels of anti-ADI-PEG 20 antibodies. Arginine depletion at 4 and 8 weeks and archival tumoral argininosuccinate synthetase-1 levels did not correlate with response. CONCLUSIONS: Concurrent mFOLFOX6 plus ADI-PEG-20 intramuscularly at 36 mg/m2 weekly shows an acceptable safety profile and favorable efficacy compared to historic controls. Further evaluation of this combination is warranted in advanced HCC patients.

Application of hydrolases and probiotic Pediococcus acidilactici BaltBio01 strain for cereal by-products conversion to bioproduct for food/feed.

The aim of this study was to apply the enzymatic treatment and fermentation by Pediococcus acidilactici BaltBio01 strain for industrial cereal by-products conversion to food/feed bioproducts with high amount of probiotic lactic acid bacteria (LAB). LAB propagated in potato media and spray-dried remained viable during 12 months (7.0 log10 cfu/g) of storage and was used as a starter for cereal by-products fermentation. The changes of microbial profile, biogenic amines (BAs), mycotoxins, lactic acid (L+/D-), lignans and alkylresorcinols (ARs) contents in fermented cereal by-product were analysed. Cereal by-products enzymatic hydrolysis before fermentation allows to obtain a higher count of LAB during fermentation. Fermentation with P. acidilactici reduce mycotoxins content in fermented cereal by-products. According to our results, P. acidilactici multiplied in potato juice could be used for cereal by-products fermentation, as a potential source to produce safer food/feed bioproduct with high amount of probiotic LAB for industrial production.

Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1-Deficient Thoracic Cancers.

Purpose Pegylated arginine deiminase (ADI-PEG 20) depletes essential amino acid levels in argininosuccinate synthetase 1 (ASS1) -negative tumors by converting arginine to citrulline and ammonia. The main aim of this study was to determine the recommended dose, safety, and tolerability of ADI-PEG 20, cisplatin, and pemetrexed in patients with ASS1-deficient malignant pleural mesothelioma (MPM) or non-small-cell lung cancer (NSCLC). Patients and Methods Using a 3 + 3 + 3 dose-escalation study, nine chemotherapy-naïve patients (five MPM, four NSCLC) received weekly ADI-PEG 20 doses of 18 mg/m2, 27 mg/m2, or 36 mg/m2, together with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 which were given every three weeks (maximum of six cycles). Patients achieving stable disease or better could continue ADI-PEG 20 monotherapy until disease progression or withdrawal. Adverse events were assessed by Common Terminology Criteria for Adverse Events version 4.03, and pharmacodynamics and immunogenicity were also evaluated. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for NSCLC and by modified RECIST criteria for MPM. Results No dose-limiting toxicities were reported; nine of 38 reported adverse events (all grade 1 or 2) were related to ADI-PEG 20. Circulating arginine concentrations declined rapidly, and citrulline levels increased; both changes persisted at 18 weeks. Partial responses were observed in seven of nine patients (78%), including three with either sarcomatoid or biphasic MPM. Conclusion Target engagement with depletion of arginine was maintained throughout treatment with no dose-limiting toxicities. In this biomarker-selected group of patients with ASS1-deficient cancers, clinical activity was observed in patients with poor-prognosis tumors. Therefore, we recommend a dose for future studies of weekly ADI-PEG 20 36 mg/m2 plus three-weekly cisplatin 75 mg/m2 and pemetrexed 500 mg/m2.

Phase I Trial of Arginine Deprivation Therapy with ADI-PEG 20 Plus Docetaxel in Patients with Advanced Malignant Solid Tumors.

PURPOSE: This phase I study examined the toxicity and tolerability of pegylated arginine deiminase (ADI-PEG 20) in combination with docetaxel in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: Eligible patients had histologically proven advanced solid malignancies, with any number of prior therapies, Zubrod performance status 0-2, and adequate organ function. Patients received ADI-PEG 20 weekly intramuscular injection ranging from 4.5 to 36 mg/m(2) and up to 10 doses of docetaxel (75 mg/m(2)) every 3 weeks. Primary endpoints were safety, toxicity, and a recommended phase II dose. Circulating arginine levels were measured before each cycle. Tumor response was measured as a secondary endpoint every 6 weeks on study. RESULTS: Eighteen patients received a total of 116 cycles of therapy through four dose levels of ADI-PEG 20. A single dose-limiting toxicity (grade 3 urticarial rash) was observed at the 1st dose level, with no additional dose-limiting toxicities observed. Hematologic toxicities were common with 14 patients experiencing at least one grade 3 to 4 leukopenia. Fatigue was the most prevalent toxicity reported by 16 patients. Arginine was variably suppressed with 10 patients achieving at least a 50% reduction in baseline values. In 14 patients with evaluable disease, four partial responses (including 2 patients with PSA response) were documented, and 7 patients had stable disease. CONCLUSIONS: ADI-PEG 20 demonstrated reasonable toxicity in combination with docetaxel. Promising clinical activity was noted, and expansion cohorts are now accruing for both castrate-resistant prostate cancer and non-small cell lung cancer at a recommended phase II dose of 36 mg/m(2).

[Systemic enzymotherapy in the combined treatment of infectious endocarditis in drug addicts].

The aim of this study was to elucidate effects of systemic enzymotherapy on the clinical course of infectious endocarditis and the frequency of thromboembolic complications in drug addicts compared with controls. Another objective was to develop an optimal regime of enzymotherapy depending on the severity of the disease. Inclusion of wobenzyme in the combined treatment of infectious endocarditis permitted to accelerate the achievement of clinical improvement, normalize blood rheologic characteristics, reduce severity of intoxication and systemic inflammation, decrease the frequency of septic thromboembolia of the pulmonary artery.

Phase II study of pegylated arginine deiminase for nonresectable and metastatic hepatocellular carcinoma.

PURPOSE: It is well known that hepatocellular carcinoma (HCC) is an arginine auxotroph due to argininosuccinate synthetase I deficiency. This study's purpose was to evaluate the effects of pegylated arginine deiminase (ADI) in terms of toxicity, tumor response, alpha-fetoprotein (AFP) levels, and serum arginine levels. PATIENTS AND METHODS: Eighty patients were randomly assigned to receive either 80 IU/m(2) or 160 IU/m(2) of ADI weekly for up to 6 months. Adverse events, serum arginine, AFP levels, and antibody production against ADI were measured on a regular basis. In addition, disease response and time to progression according to the Response Evaluation Criteria in Solid Tumors (RECIST) and survival rates were evaluated. RESULTS: Four patients were excluded from the survival analysis because they developed exclusion criteria after randomization, but before first treatment. The number of patients in the two cohorts were similar (n = 37 in the low-dose cohort, n = 39 in the high-dose cohort). Mean (+/-SE) survival for all subjects was 15.8 months (474 days +/- 39 days) from time of diagnosis of unresectable disease. Arginine levels remained below baseline for 50 days while antibodies against ADI reached a plateau at approximately the same time. There were no deaths attributed to ADI treatment. Only two patients were withdrawn for immunogenic-related adverse events. Grade 2, 3, or 4 toxicities were recorded in 92, 19, and 0 patients, respectively. CONCLUSION: Pegylated ADI is a promising drug that capitalizes on a significant enzymatic deficiency in HCC. It is safe, well tolerated, and may benefit patients with unresectable HCC.

[EFFECT OF THE POLYENZYME DRUG WOBENZYM ON THE ACTIVITY OF A DESTRUCTIVE INFLAMMATORY PROCESS IN THE COMPLEX THERAPY OF PULMONARY TUBERCULOSIS].

Ninety patients with new-onset pulmonary tuberculosis were examined prior to therapy The patients were randomized into 2 groups: 1) 20 patients receiving the standard antibiotic therapy regimen; 2) 70 patients taking the standard antibiotic therapy and the polyenzyme drug Wobenzym. The use of the latter in the complex therapy of patients with pulmonary tuberculosis was shown to cause an increase in the activity of the destructive inflammatory process and to regulate the function of the immune system as compared with those during the standard therapy.

Peak expiratory flow analysis in workers exposed to detergent enzymes.

AIMS: To study serial peak expiratory flow (PEF) responses in a group of symptomatic detergent enzyme-exposed workers. METHODS: Workers were recruited from a biological detergent formulating and packaging company. Those with occupational asthma symptoms and/or specific IgE to a detergent enzyme were asked to complete 2 hourly PEF measurements for 4 weeks. Outputs from the Oasys program (Oasys score, rest-work score and rest-work difference in diurnal variation) assessed PEF response. These were then related to the levels of sensitization and current occupational exposure to detergent enzymes. RESULTS: In all, 67/72 workers returned PEF records; 97% were able to return a record with at least four readings per day and 87% at least 3 weeks in length. Of total, 79% (n = 27) of those with a final diagnosis of occupational asthma had peak flow records confirming the disease using Oasys. PEF response was similar in those with high, medium and low levels of exposures and those with negative, low-moderate and high specific IgE levels. CONCLUSIONS: The Oasys program is a sensitive tool for the diagnosis of detergent enzyme occupational asthma, but the levels of exposure and specific IgE sensitization to enzymes do not affect the magnitude of PEF response in symptomatic workers.

Drug evaluation: ADI-PEG-20--a PEGylated arginine deiminase for arginine-auxotrophic cancers.

Pheonix is developing ADI-PEG-20, a PEGylated arginine deiminase for the potential treatment of hepatocellular carcinoma, for which the Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products have granted the drug Orphan Drug status, and melanoma, for which the FDA has also awarded ADI-PEG-20 Orphan Drug status. ADI-PEG-20 is also being investigated for the potential treatment of influenza virus infection and hepatitis C virus infection.

[Experimental systemic enzyme therapy of gouty and primary glomerulonephritis]. / Sistemnaia énzimoterapiia podagricheskogo i pervichnogo khronicheskogo glomerulonefritov v éksperimente.

The influence of a systemic enzymotherapy on the morphological, biochemical, and functional manifestations of the kidney damage during the experimental gouty and primary glomerulonephritis is described in comparison to the results obtained by traditional methods.

Postpartum thiamine deficiency in a Karen displaced population.

BACKGROUND: Before its recognition, infantile beriberi was the leading cause of infant death in camps for displaced persons of the Karen ethnic minority on Thailand's western border. OBJECTIVE: This study aimed to document thiamine status in the peripartum period to examine the current supplementation program and the correlation between the clinical manifestations of thiamine deficiency and a biochemical measure of thiamine status. DESIGN: Women were enrolled prospectively at 30 wk of gestation and were followed up weekly until delivery and at 3 mo postpartum. Thiamine supplementation during pregnancy was based on patient symptoms. RESULTS: At 3 mo postpartum, thiamine deficiency reflected by an erythrocyte transketolase activity (ETKA) > or = 1.20% was found in 57.7% (15/26) of mothers, 26.9% (7/26) of whom had severe deficiency (ETKA > 1.25%). No significant associations between ETKA and putative maternal symptoms or use of thiamine supplements were found. CONCLUSIONS: Biochemical postpartum thiamine deficiency is still common in Karen refugee women. This situation may be improved by educating lactating women to reduce their consumption of thiaminase-containing foods and by implementing an effective thiamine supplementation program.

Inhibition of proteasome activity by the TED4 protein in extracellular space: a novel mechanism for protection of living cells from injury caused by dying cells.

In maturation process of tracheary element (TE) differentiation, many hydrolases are activated to execute programmed cell death of TEs. Such hydrolases are released from maturing TEs into extracellular space. The release of hydrolases should be harmful to surrounding cells. The TED4 protein, a tentative plant non-specific lipid transfer protein that is expressed preferentially in TE-induced culture of zinnia (Zinnia elegans L.), is secreted into the apoplastic space prior to and associated with morphological changes of TEs. Our studies on the interrelationship between the TED4 protein and proteolytic activities using an in vitro TE differentiation system of zinnia revealed the following facts. (1) Active proteasome is released into medium at maturation stage of TE differentiation. (2) The TED4 protein forms a complex with proteasome in culture medium. (3) The TED4 protein inhibits proteasome activity in the medium and crude extracts of zinnia cells. (4) The depletion of the TED4 protein from culture medium results in an increase in mortality of other living cells. These results strongly suggest that the secreted TED4 protein acts as an inhibitor of proteasome to protect other cells from undesirable injury due to proteolytic activities exudated from dying TEs.

Immune response to enzyme replacement therapy in lysosomal storage disorder patients and animal models.

The lysosomal storage disorders (LSD) are a group of severe multiple pathology disorders characterized by enzyme deficiencies which cause the lysosomal accumulation of undegraded or partially degraded macromolecules. Enzyme replacement therapy (ERT) has been developed as a therapy for LSD patients. However, immune responses to ERT have been reported in some individuals from LSD animal model and LSD human patient studies. Antibodies can have adverse effects during ERT, which include hypersensitivity/anaphylactic reactions, enzyme inactivation, altered targeting, and increased enzyme turnover. The monitoring of antibody production during replacement therapy is an important consideration for patient management, as high-titer antibodies can affect the safety and efficacy of the therapy.

[The pathogenetic basis for and clinical use of systemic enzyme therapy in traumatology and orthopedics]. / Patogeneticheskoe obosnovanie i klinicheskoe primenenie sistemnoi fermentoterapii v travmatologii i ortopedii.

The authors have generalized their experiences with using "Wobenzym" in 140 patients. Schemes of the effective systemic enzyme therapy are proposed for patients of the orthopedic-traumatological profile.

[The effect of the preparation Wobenzym on the antioxidant protection indices and on the functional-morphological properties of the erythrocytes in a toxic lesion of the liver]. / Vplyv preparatu "Vobenzym" na pokaznyky protyoksydantnoho zakhistu ta deiaki funktsional'no-morfolohichni vlastyvosti erytrotsytiv pry toksychnomu urazhenni pechinky.

Based on the analysis of results of examination of 60 patients with toxic affections of the liver particular features of the anti-radical defence decompensation mechanisms have been established together with changes in morphofunctional properties of red cells in toxic hepatitis in patients with pulmonary tuberculosis. It was considered expedient to include the polyenzymic preparation Wobenzyme into the therapeutic complex since it had been shown to make for normalization of the red cells' ability to undergo deformation, lowering the degree of viscosity of RBC suspension in the above patients.