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Showing papers in "Investigational New Drugs in 2006"


Journal ArticleDOI
TL;DR: It is concluded that 13 g of oral silybin-phytosome daily, in 3 divided doses, appears to be well tolerated in patients with advanced prostate cancer and is the recommended phase II dose.
Abstract: Silibinin is a polyphenolic flavonoid isolated from milk thistle with anti-neoplastic activity in several in vitro and in vivo models of cancer, including prostate cancer Silybin-phytosome is a commercially available formulation containing silibinin This trial was designed to assess the toxicity of high-dose silybin-phytosome and recommend a phase II dose Silybin-phytosome was administered orally to prostate cancer patients, giving 25-20 g daily, in three divided doses Each course was 4 weeks in duration Thirteen patients received a total of 91 courses of silybin-phytosome Baseline patient characteristics included: median age of 70 years, median baseline prostate specific antigen (PSA) of 43 ng/ml, and a median ECOG performance status of 0 The most prominent adverse event was hyperbilirubinemia, with grade 1-2 bilirubin elevations in 9 of the 13 patients The only grade 3 toxicity observed was elevation of alanine aminotransferase (ALT) in one patient; no grade 4 toxicity was noted No objective PSA responses were observed We conclude that 13 g of oral silybin-phytosome daily, in 3 divided doses, appears to be well tolerated in patients with advanced prostate cancer and is the recommended phase II dose Asymptomatic liver toxicity is the most commonly seen adverse event

272 citations


Journal ArticleDOI
TL;DR: Can patients whose tumors have a specific set of molecular properties be identified prospectively, and matched with the pharmacological properties of an agent, i.e. can therapy of individual patients be tailored?
Abstract: • Are multiple intracellular targets better than one? Does inhibition of dihydrofolate reductase (DHFR), thymidylate synthase (TS) or enzymes of the purine biosynthetic pathway confer an advantage? Alternatively, is inhibition of purine biosynthesis a safety liability rather than an advantage? • Can a lipophilic molecule rather than one that uses the folate carrier mechanisms, i.e. the folate binding protein (FBP) and or the reduced folate carrier (RFC), circumvent intrinsic or acquired resistance? • Can tumor selectivity be increased by exploiting knowledge of different patterns of RFC versus FBP expression or of variations in FBP isoform expression? • How does a patient’s functional folate status or supplemental folic acid modulate efficacy and or toxicity? • Does an antifolate that is a good substrate for the intracellular enzyme folylpolyglutamate synthase (FPGS) have a selective advantage? Does polyglutamation of the antifolate confer a therapeutic advantage because it results in increased potency against the target enzyme, and increased polarity leading to increased cellular retention? Alternatively, is it a disadvantage with respect to safety of the molecule because of prolonged intracellular retention times or the potential for resistance? • Does an increase in the potency of binding to the target enzyme confer a therapeutic advantage? • Resistance mechanisms include decreased cellular accumulation due to impaired transport, decreased retention inside the cell as a consequence of a lack of polyglutamate formation, or an increase in gamma glutamyl hydrolase (GGH) activity, an increase in expression of the target enzyme, or a mutation in the target enzyme. Which of these is clinically relevant, and how does knowledge of these resistance mechanisms aid selection of the appropriate antifolate for treatment of an individual patient? • How do pharmacokinetic variables contribute to safety and efficacy? Do the newer antifolates have fewer propensities for drug-drug interactions? • Is there an intrinsic limit to the clinical activity of an antifolate as a single agent? Can antitumor activity be increased, or can an increase in activity only be achieved by combining antifolates with other anticancer drugs (either other antifolates which target different folate requiring enzymes or compounds with different mechanisms of action)? Similarly, can the spectrum of clinical activity be increased? • Can patients whose tumors have a specific set of molecular properties be identified prospectively, and matched with the pharmacological properties of an agent, i.e. can therapy of individual patients be tailored? • Can toxicity be decreased and quality of life improved? • Can patients at risk of serious toxicity to a given agent be identified before or during therapy and managed in the light of that knowledge? • Are there mechanisms for rescuing patients from toxicity, and not from antitumor activity? • What improvements can be made in the administration schedule and therefore convenience to patients?

150 citations


Journal ArticleDOI
TL;DR: At the dose and schedule used in this trial, 17-AAG did not achieve objective response in the treatment of clear cell or papillary renal cell carcinoma patients.
Abstract: The aim of this study was to determine the antitumor activity of 17-(Allylamino)-17-demethoxyge-ldanamycin (17-AAG), a heat shock protein 90(hsp90) inhibitor in patients with metastatic papillary renal cell carcinoma (RCC) or metastatic clear cell RCC. Eligible patients were divided into 2 cohorts based on histological subtype: papillary or clear cell RCC. All patients had advanced RCC with measurable disease, a Karnofsky performance status of at least 70, and no evidence of brain metastases. Twelve patients with clear cell RCC and 8 patients with papillary RCC were treated with 17-AAG on this phase II trial. 17-AAG was given intravenously at 220 mg/m2 twice weekly for 2 weeks followed by a week of rest. Cycle length was 21 days. No patient in either cohort achieved a complete or partial response. Toxicities included elevated liver function tests, optic neuritis, dyspnea, fatigue, and gastrointestinal side effects. Six of the 20 patients required dose reduction. At the dose and schedule used in this trial, 17-AAG did not achieve objective response in the treatment of clear cell or papillary renal cell carcinoma patients.

144 citations


Journal ArticleDOI
TL;DR: 2ME2, alone or in combination with docetaxel, was well tolerated in patients with MBC but systemic exposure remained below the expected therapeutic range.
Abstract: Purpose: We report the first phase I trials of 2-methoxyestradiol (2ME2, Panzem® Capsules, EntreMed, Rockville, MD), alone and in combination with docetaxel, in patients with metastatic breast cancer (MBC).

127 citations


Journal ArticleDOI
TL;DR: No objective responses were seen in this two-stage phase II trial of MG98, a second generation antisense oligodeoxynucleotide inhibitor of human DNMT 1 in patients with metastatic renal carcinoma, and a conclusive pattern of decreased DNMT1 activity in PBMCs was detected post MG98 treatment.
Abstract: DNA methyltransferases (DNMTs) methylate DNA, promoting local chromatin condensation and consequent repression of gene expression. The purpose of this two-stage phase II trial was to assess the antitumor activity of MG98, a second generation antisense oligodeoxynucleotide inhibitor of human DNMT 1, in patients with metastatic renal carcinoma (MRC). Untreated adult patients with measurable MRC were treated with MG98 at a dose of 360 mg/m2 via 2-h iv infusion twice weekly for three consecutive weeks out of four. The primary endpoint was objective response or absence of progression for at least eight weeks. Pharmacokinetics and DNMT1 mRNA levels in peripheral blood mononuclear cells (PBMCs) were also analyzed at pre-specified intervals. Seventeen eligible patients received a median of two cycles of treatment (range, 1–7), and no objective responses were seen. Nine patients had progressive disease, six had stable disease, and the study was stopped after the first stage. The most common symptomatic toxicities were rigors, fatigue, fever, and nausea. Hematological toxicity was mild. Seven patients treated with prior nephrectomy had grade 3 or 4 elevations in hepatic transaminases. Significantly higher Cmax and AUC(0→inf) values were observed in these patients. No conclusive pattern of decreased DNMT1 activity in PBMCs was detected post MG98 treatment. The lack of objective responses observed may be explained by a lack of target effect or the choice of tumor type. Transaminitis was observed in patients with prior nephrectomy and appeared to be associated with altered drug exposure in these patients.

118 citations


Journal ArticleDOI
TL;DR: Single-agent arsenic trioxide using this dose schedule is not active against advanced HCC, and three patients had disease stabilization for at least six months.
Abstract: Background: Arsenic trioxide induces growth inhibition and apoptosis in human hepatocellular carcinoma (HCC) cell lines. A phase II trial was conducted to evaluate the efficacy and toxicity of single-agent arsenic trioxide in patients with HCC. Methods: Inclusion criteria included advanced HCC patients to whom no standard palliative treatment can be offered, good organ function and liver function reserve. Patients received arsenic trioxide 0.16–0.24 mg/kg per day for 5–6 days per week for 3–4 weeks, followed by one-week rest. Tumor response was assessed every 2 cycles. Primary endpoint was the percentage of patients with 6-month disease stabilization. Results: Twenty-nine patients (median age, 59) with locally advanced or metastatic HCC received a total of 61 cycles (median, 2; range, 1–6). One patient had partial response. Three patients had disease stabilization for at least six months. The 6-month tumor stabilization rate was 14% (95% CI, 1–27). The median overall survival was 4.8 months (95% CI, 1.4–8.2) and one-year survival was 30%. Conclusion: Single-agent arsenic trioxide using this dose schedule is not active against advanced HCC.

105 citations


Journal ArticleDOI
TL;DR: A focused overview of the function of the Wnt-dependent signaling pathways and their role in oncogenesis and cancer development is presented and information on a selection of potential drug targets within these pathways for oncology drug discovery is provided.
Abstract: Our current understanding of the Wnt-dependent signaling pathways is mainly based on studies performed in a number of model organisms including, Xenopus, Drosophila melanogaster, Caenorhabditis elegans and mammals. These studies clearly indicate that the Wnt-dependent signaling pathways are conserved through evolution and control many events during embryonic development. Wnt pathways have been shown to regulate cell proliferation, morphology, motility as well as cell fate. The increasing interest of the scientific community, over the last decade, in the Wnt-dependent signaling pathways is supported by the documented importance of these pathways in a broad range of physiological conditions and disease states. For instance, it has been shown that inappropriate regulation and activation of these pathways is associated with several pathological disorders including cancer, retinopathy, tetra-amelia and bone and cartilage disease such as arthritis. In addition, several components of the Wnt-dependent signaling pathways appear to play important roles in diseases such as Alzheimer’s disease, schizophrenia, bipolar disorder and in the emerging field of stem cell research. In this review, we wish to present a focused overview of the function of the Wnt-dependent signaling pathways and their role in oncogenesis and cancer development. We also want to provide information on a selection of potential drug targets within these pathways for oncology drug discovery, and summarize current data on approaches, including the development of small-molecule inhibitors, that have shown relevant effects on the Wnt-dependent signaling pathways.

97 citations


Journal ArticleDOI
TL;DR: Perifosine when given according to this dosing schedule does not show evidence of activity in a mixed population of adult soft tissue sarcoma patients.
Abstract: Background/Patients and methods: 16 adult patients with untreated measurable locally advanced or metastatic inoperable soft tissue sarcoma were treated with oral perifosine, a synthetic alkylphospholipid, believed to inhibit MAP kinase (MAP-K), protein kinase C (PKC), Akt and other regulatory proteins. Perifosine was administered orally in cycles for 21 days out of 28. Loading doses were given day 1 each cycle (900 mg cycle 1, 300 mg cycle 2+) and 150 mg daily was given days 2–21 of each cycle. Cycles were repeated until disease progression, unacceptable toxicity or patient refusal. Results: Seventeen patients were enrolled; 16 and 15 were evaluable for toxicity and response, respectively. A total of 30 cycles of perifosine were administered. Most toxic effects were grade 1 or 2 and commonly included nausea, vomiting, diarrhea, and fatigue (≥40%). Hematologic toxicity was generally mild. There were no significant biochemical abnormalities due to the drug reported. There were 4 serious adverse events (SAE)—none of which was related to perifosine. No objective responses were seen; 4 patients had stable disease for 1.3 to 8.2 months and the remainder of the patients had progressive disease.Conclusions: Perifosine when given according to this dosing schedule does not show evidence of activity in a mixed population of adult soft tissue sarcoma patients.

92 citations


Journal ArticleDOI
TL;DR: A dose escalating trial to evaluate twice-daily intravenous PBA infusions for two consecutive weeks every month at five dose levels found the therapy was well tolerated overall and the maximum tolerated dose is 300 mg/kg/day.
Abstract: Background: Phenylbutyrate (PBA), and its metabolite phenylacetate (PAA), induce growth inhibition and cellular differentiation in multiple tumor models. However, despite their potential anti-cancer properties, several pharmacodynamic aspects remain unknown. Methods: We conducted a dose escalating trial to evaluate twice-daily intravenous PBA infusions for two consecutive weeks (Monday through Friday) every month at five dose levels (60–360 mg/kg/day). Twenty-one patients with the following malignancies were treated: colon carcinoma 4, non-small cell lung carcinoma 4; anaplastic astrocytoma 3, glioblastoma multiforme 3, bladder carcinoma 2, sarcoma 2, and ovarian carcinoma, rectal hemangiopericytoma, and pancreatic carcinoma 1 each. Results: Conversion of PBA to PAA and phenylacetylglutamine (PAG) was documented without catabolic saturation. Plasma content of PBA ≥1 mM was documented for only 3 h following each dose at the top two dosages. The therapy was well tolerated overall. Common adverse effects included grade 1 nausea/vomiting, fatigue, and lightheadedness. Dose limiting toxicities were short-term memory loss, sedation, confusion, nausea, and vomiting. Two patients with anaplastic astrocytoma and a patient with glioblastoma remained stable without tumor progression for 5, 7, and 4 months respectively. Conclusions: Administration of PBA in a twice-daily infusion schedule is safe. The maximum tolerated dose is 300 mg/kg/day. Study designs with more convenient treatment schedules and specific molecular correlates may help to further delineate the mechanism of action of this compound. Future studies evaluating PBA's ability to induce histone acetylation and cell differentiation alone or in combination with other anti-neoplastics are recommended.

89 citations


Journal ArticleDOI
TL;DR: A phase 1 trial to determine the maximum tolerated dose (MTD) and safety of AnvirzelTM in patients with advanced, refractory solid tumors found it can be safely administered at doses up to 1.2 ml/m2/day, with the amount administered intramuscularly limited by volume.
Abstract: Anvirzel is an aqueous extract of the plant Nerium oleander which has been utilized to treat patients with advanced malignancies. The current study reports a phase 1 trial to determine the maximum tolerated dose (MTD) and safety of Anvirzel in patients with advanced, refractory solid tumors. Patients were randomized to receive this agent by intramuscular injection at doses of 0.1, 0.2, 0.4 ml/m2/day with subsequent patients receiving 0.8 or 1.2 ml/m2/day sequentially. Eighteen patients were enrolled and completed at least one treatment cycle of three weeks. Most patients developed mild injection site pain (78%). Other toxicities included fatigue, nausea, and dyspnea. Traditional dose limiting toxicity was not seen, but the MTD was defined by injection volume as 0.8 ml/m2/day. No objective anti-tumor responses were seen. Anvirzel can be safely administered at doses up to 1.2 ml/m2/day, with the amount administered intramuscularly limited by volume. The recommended phase II dose level is 0.8 ml/m2/day.

86 citations


Journal ArticleDOI
TL;DR: Based on the small number of patients and low statistical power of the study definite conclusions regarding efficacy and safety of carbamazepine for prevention of oxaliplatin-associated neuropathy in patients with advanced colorectal cancer cannot be drawn.
Abstract: Background: Oxaliplatin-induced neurotoxicity is a growing, relevant clinical problem. In this study we evaluated the efficacy and safety of carbamazepine for prevention of oxaliplatin-associated neuropathy in patients with advanced colorectal cancer.

Journal ArticleDOI
TL;DR: Talactoferrin is a promising, well-tolerated new agent that should be evaluated further in patients with refractory metastatic cancer, as well as pharmacokinetics and pharmacodynamics.
Abstract: Background: Lactoferrin is an iron-binding glycoprotein first identified in breast milk as a protein product of mammary epithelial cells. Its immunomodulatory functions include activation of NK and lymphokine-activated killer cells and enhancement of PMN and macrophage cytotoxicity. Studies in animal models have shown promising anti-cancer activity. The purpose of the present study was to evaluate the safety and tolerability of talactoferrin alfa (talactoferrin; TLF) in humans, as well as pharmacokinetics and pharmacodynamics. Methods: Ten adult patients with progressive advanced solid tumors who had failed conventional chemotherapy were administered oral TLF at doses from 1.5 to 9 g/day, using a 2 weeks on, 2 weeks off schedule. Patients were evaluated for drug toxicity, tumor growth rate, talactoferrin pharmacokinetics and cytokine markers. Results: Talactoferrin was very well tolerated. No hematological, hepatic, or renal toxicities were reported. A single patient had Grade 2 diarrhea, and there were no Grade 3 or 4 toxicities. Following oral administration, significant levels of talactoferrin were undetectable in circulation, but a statistically significant increase in circulating IL-18, a pharmacodynamic indicator of talactoferrin activity, was observed. Of the eight patients who were radiologically evaluable, five (63%) had stable disease by RECIST criteria two months after start of therapy, including one patient with a minor response. Seven patients (88%) had a decrease in their tumor growth rate. The three patients with non-small cell lung cancer (NSCLC) all survived for at least one year following the start of talactoferrin monotherapy. Conclusions: Talactoferrin is a promising, well-tolerated new agent that should be evaluated further in patients with refractory metastatic cancer.

Journal ArticleDOI
TL;DR: Considering the novelty of its mechanism of action and impressive preclinical anti-tumor activity, further studies exploiting new formulations of RC-3095 for human use, such as slow-release preparations, and analogues with a more favorable pharmacokinetics are warranted.
Abstract: Bombesin/gastrin-releasing peptides (BN/GRP) were shown to bind selectively to cell surface receptors, stimulating the growth of various types of malignancies in murine and human models. The novel BN/GRP synthetic receptor antagonist, RC-3095, was able to produce long-lasting tumor regressions in murine and human tumor models in vitro and in vivo. Animal toxicology studies showed no detectable organ toxicity apart from local irritation at the injection site. The purpose of this study was to determine the safety and feasibility of the administration of RC-3095 by daily subcutaneous injections in patients with advanced and refractory solid malignancies. Twenty-five patients received RC-3095 once or twice-daily at doses ranging from 8 to 96 ug/kg. Dose was escalated in groups of 3–5 patients per dose level. The only toxicity observed was local discomfort in the injection site at the highest doses. A single dose administration of RC-3095 at the highest dose level (96 ug/kg) was tested in a clearly hypergastrinemic individual with the Zollingen-Ellison syndrome and produced a decrease in plasma gastrin down to 50% of basal levels in 6 h. There was no objective tumor responses in patients included in the study. A short-lasting minor tumor response was observed in a patient with a GRP-expressing progressive medullary carcinoma of the thyroid. Due to problems with the analytical method, plasma pharmacokinetic data was obtained only from two patients included at the highest dose level. In these patients, RC-3095 reached plasma concentrations >100 ng/mL for about 8 h, which were within therapeutic levels on the basis of prior data obtained in mice and rats. The plasma elimination half-life was between 8.6–10.9 h. Due to the occurrence of local toxicity at the injection site, the dose escalation procedure could not be fully evaluated up to a maximum tolerated dose. Thus, a recommended dose of RC-3095 for Phase II trials could not be clearly established. Considering the novelty of its mechanism of action and impressive preclinical anti-tumor activity, further studies exploiting new formulations of RC-3095 for human use, such as slow-release preparations, and analogues with a more favorable pharmacokinetics are warranted.

Journal ArticleDOI
TL;DR: Gefitinib is highly protein bound (∼97%) in human plasma with implications for inter-subject variation in drug toxicity and response.
Abstract: Gefitinib exhibits wide inter-subject pharmacokinetic variability which may contribute to differences in treatment outcome. Unbound drug concentrations are believed to be more relevant to pharmacological and toxicological responses than total drug. Thus it is desirable to determine gefitinib binding in plasma and factors affecting this process. An equilibrium dialysis method using 96-well microdialysis plates was optimized and validated for determining the fraction unbound (fu) gefitinib in human plasma. Gefitinib binding in plasma from four different species and isolated protein solutions as well as drug partitioning in human blood cells were investigated. Unbound gefitinib plasma concentrations were measured in 21 cancer patients receiving daily oral gefitinib 250 mg or 500 mg. It was found that gefitinib was extensively bound in human rat mouse and dog plasma with mean fu values of 3.4%, 3.8%, 5.1% and 6.0% respectively. In isolated protein solutions approximately 90% and 78% of gefitinib was bound to human serum albumin (HSA) (40 mg/dL) and alpha1-acid glycoprotein (AAG) (1.4 mg/dL) with binding constants of 1.85 × 104 M−1 and 1.13 × 105 M−1 respectively. In whole blood 2.8% of gefitinib existed as the free drug while 79.4% and 17.8% was bound to plasma proteins and blood cells respectively. In plasma from cancer patients fu at pre-treatment varied 2.4-fold (mean 3.4 ± 0.6%; range 2.2–5.4%) and fu was constant over the 28-days of treatment (P > 0.05). Pre-treatment AAG concentration was negatively correlated with pre-treatment fu (R2 = 0.28, P = 0.01). In conclusion gefitinib is highly protein bound (∼97%) in human plasma. Variable AAG concentrations observed in cancer patients may affect gefitinib fu with implications for inter-subject variation in drug toxicity and response.

Journal ArticleDOI
TL;DR: ZD6474 was well tolerated at a dose of 100 mg per day and achieved plasma levels predicted to inhibit VEGF signaling, however, this was not reflected in clinical benefit since none of the patients had a reduction in M protein.
Abstract: Multiple myeloma is a disease in which angiogenesis is postulated to be a target for therapy. Based on this hypothesis, we conducted a phase II trial of ZD6474 (Zactima™; a VEGFR inhibitor) 100 mg p.o. daily in patients with relapsed multiple myeloma. The primary efficacy endpoint was objective response as assessed by reduction in M protein. There were 18 patients with a mean age of 64 years. One patient was ineligible and one was not evaluable. Overall, ZD6474 was well tolerated and pharmacokinetic testing demonstrated that adequate drug levels were achieved. The most common drug-related adverse events were nausea, vomiting, fatigue, rash, pruritis, headache, diarrhea, dizziness, and sensory neuropathy, all of which were Grade I–II in severity. There were no drug-related serious adverse events. Laboratory adverse events were infrequent: one patient had Grade III anemia, and there were no Grade III changes in biochemistry. No significant QTc interval changes were seen. There were no responses in M protein levels. In conclusion, ZD6474 was well tolerated at a dose of 100 mg per day and achieved plasma levels predicted to inhibit VEGF signaling. However, this was not reflected in clinical benefit since none of the patients had a reduction in M protein.

Journal ArticleDOI
TL;DR: Treatment with SU5416 in patients with head and neck cancers is feasible, but objective responses are rare, and studies evaluating more potent anti-angiogenic agents in this disease are of interest.
Abstract: Background: SU5416 (semaxanib) is a synthetic small molecule inhibitor of the tyrosine kinase domain of vascular endothelial growth factor receptor 2 (VEGFR2). This Phase II study was conducted to determine the safety and efficacy of SU5416 in patients with recurrent or metastatic head and neck cancers.

Journal ArticleDOI
TL;DR: Ixabepilone shows encouraging activity in patients with advanced pancreatic cancer and should be investigated further in this disease.
Abstract: Purpose: The purpose of this Phase II multi-institutional study was to define the efficacy and toxicity of ixabepilone in patients with advance pancreatic adenocarcinoma.

Journal ArticleDOI
TL;DR: The combination of MTX-HSA with cisplatin is feasible and shows antitumor activity against urothelial carcinomas combined with an acceptable toxicity profile.
Abstract: Purpose: To assess the efficacy, tolerability and safety of MTX-HSA (methotrexate (MTX) covalently linked to human serum albumin (HSA)) combined with cisplatin as first line therapy for advanced bladder cancer.

Journal ArticleDOI
TL;DR: Sequential pac litaxel plus bryostatin-1 resulted in a superior response rate than would be expected of paclitaxel alone in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma.
Abstract: Purpose: Protein Kinase C (PKC), involved in transmembrane signaling of cell surface receptors, promotes carcinogenesis and tumor progression. Bryostatin-1 competes with PKC for phorbol esters (tumor promoters), thus inhibiting tumor progression. Bryostatin-1 also increases cytotoxicity of paclitaxel in a sequential fashion. We studied sequential paclitaxel and bryostatin-1 in patients with untreated, advanced gastric adenocarcinoma. Methods: Patients with histologic proof of gastric or gastroesophageal junction adenocarcinoma with advanced, measurable cancers were eligible. Patients were required to have near normal organ function and ECOG performance status of 0 or 1. All patients gave an informed consent. Patients received paclitaxel 80 mg/m2 in 2 h intravenously on day 1 and bryostatin-1 40 mcg/m2 in 1 h intravenously on day 2 each week for 3 consecutive weeks out of 4. Primary objective was to assess the objective response rate. Results: In a multi-center setting, 37 patients were enrolled and 35 were assessable for response. A confirmed partial response rate was 29%. The median time-to-progression was 4.25 months and the median survival time was 8 months. Grade 3 cumulative myalgias occurred in 55% of patients. Twelve patients discontinued therapy due to myalgias, including 6 patients who had not progressed after achieving a partial response. Other toxic effects were uncommon. Conclusions: Sequential paclitaxel plus bryostatin-1 resulted in a superior response rate than would be expected of paclitaxel alone in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma. Further development of this combination is warranted once an effective method to ameliorate or prevent myalgias can be established.

Journal ArticleDOI
TL;DR: The findings suggest that FK228 is a promising candidate for combining with most anticancer agents except for methotrexate and vincristine, which produce suboptimal effects.
Abstract: FK228 is a novel antitumor depsipeptide that inhibits histone deacetylases and restores the expression of genes aberrantly suppressed in cancer cells. This agent was shown to have broad antitumor activity in preclinical studies, and is currently under phase I/II evaluations. Because of its wide spectrum of actions, it is reasonable to consider the combination with other anticancer drugs in clinical application. We studied the cytotoxic interaction of FK228 in combination with conventional antileukemic agents using human promyelocytic leukemia HL60, Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia KU-812, T-cell lymphoblastic leukemia MOLT3 and Burkitt's lymphoma Raji cell lines. For the combination of FK228 and imatinib, Ph+ leukemia KU812, K562 and TCC-S cell lines were used. The cells were exposed simultaneously to FK228 and other agents for 4 days. Cell growth inhibition was determined by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. We used the isobologram method of Steel and Peckham to evaluate the cytotoxic interaction at the concentration of drugs that produced 80% cell growth inhibition (IC80). FK228 showed an additive effect with cytarabine, carboplatin, doxorubicin, etoposide, 4-hydroperoxy-cyclophosphamide, 6-mercaptopurine and SN-38 (active metabolite of irinotecan) in all cell lines studied. FK228 with methotrexate and vincristine showed an antagonistic effect in three and one of the four cell lines, respectively. FK228 was additive with imatinib in all three Ph+ leukemia cells. Our findings suggest that FK228 is a promising candidate for combining with most anticancer agents except for methotrexate and vincristine, which produce suboptimal effects.

Journal ArticleDOI
TL;DR: Exposure to pixantrone did not worsen pre-existing cardiomyopathy in doxorubicin-pretreated mice, suggesting that pixanrone may be useful in patients pretreated with anthracyclines.
Abstract: Anthracyclines and anthracenediones are important oncotherapeutics; however, their use is associated with irreversible and cumulative cardiotoxicity. A novel aza-anthracenedione, pixantrone (BBR 2778), was developed to reduce treatment-related cardiotoxicity while retaining efficacy. This study evaluates the cumulative cardiotoxic potential of pixantrone compared with equiactive doses of doxorubicin and mitoxantrone in both doxorubicin-pretreated and doxorubicin-naive mice. CD1 female mice were given doxorubicin 7.5 mg/kg (once weekly for 3 weeks) followed 6 weeks later by either sterile 0.9% saline, doxorubicin 7.5 mg/kg, pixantrone 27 mg/kg, or mitoxantrone 3 mg/kg (once weekly for 3 weeks). A second group of CD1 female mice were given 2 cycles of either sterile 0.9% saline, pixantrone 27 mg/kg, doxorubicin 7.5 mg/kg, or mitoxantrone 3 mg/kg (once weekly for 3 weeks). Animals were sacrificed at different time points for histopathologic examination of the heart. In the doxorubicin-pretreated mice, further exposure to doxorubicin or mitoxantrone resulted in a significant worsening of pre-existing degenerative cardiomyopathy. In contrast, pixantrone did not worsen pre-existing cardiomyopathy in these animals. Only minimal cardiac changes were observed in mice given repeated cycles of pixantrone, while 2 cycles of doxorubicin or mitoxantrone resulted in marked or severe degenerative cardiomyopathy. These animal studies demonstrate the reduced cardiotoxic potential of pixantrone compared with doxorubicin and mitoxantrone. Exposure to pixantrone did not worsen pre-existing cardiomyopathy in doxorubicin-pretreated mice, suggesting that pixantrone may be useful in patients pretreated with anthracyclines.

Journal ArticleDOI
TL;DR: Considering response and progression-free rate as the primary endpoints for phase II trials in pretreated STS, gemcitabine has moderate efficacy.
Abstract: Background: The number of effective cytotoxic agents for the treatment of patients with metastatic adult type soft tissue sarcoma (STS) is limited, when patients have failed anthracyline-based chemotherapy. The aim of this trial was to evaluate the efficacy of gemcitabine in this setting. Methods: Between August 2001 and March 2003 19 patients were eligible to enter. Gemcitabine was administered as a 30-minutes infusion at a dosage of 1 g/m2 on day 1, 8 and 15 every 4 weeks. All patients had progressive disease during (n = 12) or shortly after an anthracycline-based regimen (n = 3). Results: Four of 19 patients did not start study treatment because of fulminant progression. Fifteen patients with a median age 47 years (32–72) were assessable. All patients had received at least one prior treatment regimen (range, 1–6) for metastatic disease containing anthracyclines (n = 15) and ifosfamide (n = 11). To date, a total of 72+ cycles have been applied (median; 3, 1–28+). Seven patients (47%) had progressive disease after completion of two cycles at the first response assessment. One patient (6%) attained a partial remission, and 7 patients (47%) achieved disease stabilisations. One patient is still on treatment after more than 2.5 years. The calculated progression-free rate at 3 and 6 months was 46.7% (CI95%, 21.4–71.9) and 13.3% (CI95%, (0–30.5). 95% of the cycles have been applied without any dose modification or treatment delay. Conclusions: Considering response and progression-free rate as the primary endpoints for phase II trials in pretreated STS, gemcitabine has moderate efficacy.

Journal ArticleDOI
TL;DR: The observed increase in vascular permeability may lead to haemoconcentration and increased interstitial pressure, ultimately resulting in an reduction of tumor blood flow and thus a decrease in tumor growth.
Abstract: TNF-alpha may improve drug delivery to tumors by alteration of vascular permeability. However, toxicity precludes its systemic administration in patients. NGR-TNF comprises TNF coupled to the peptide CNGRC, which is a ligand for CD13. CD13 is expressed on tumor vasculature. Therefore, to assess the efficacy of NGR-TNF its biological effect on tumor vasculature should be measured rather than its effect on tumor growth. The aim of this study was to assess the effects of a low dose of NGR-TNF (5 ng/kg) on vascular permeability, tumor hypoxia, perfusion and proliferation in lymphoma bearing mice. MRI measurements with blood pool contrast agent showed an increased leakage of the contrast agent from the vasculature in NGR-TNF treated tumors compared with controls (p < 0.05), suggesting NGR-TNF-induced vascular permeability. Immunohistochemical analysis two hours after NGR-TNF treatment showed a decrease in tumor hypoxia (p < 0.1) and an increase in labeling index of the S-phase marker bromodeoxyuridine (p < 0.1), possibly due to an increase in tumor blood flow after NGR-TNF treatment. Although a decrease in tumor hypoxia and an increase in labeling index could have lead to increased tumor growth, in this experiment after one day a decrease in tumor volume was measured. Possibly, the effects on tumor hypoxia and proliferation two hours after treatment are transient and overruled by other, more longlasting effects. For example, the observed increase in vascular permeability may lead to haemoconcentration and increased interstitial pressure, ultimately resulting in an reduction of tumor blood flow and thus a decrease in tumor growth. A beneficial effect of NGR-TNF in combination with other therapeutical agents may therefore critically depend on the sequence and timing of the regimens. Currently, NGR-TNF is being tested in clinical studies.

Journal ArticleDOI
TL;DR: Although ixabepilone was well-tolerated, the dose of 8–10 mg/m2 daily for 3 days is not an effective therapy in metastatic breast cancer previously exposed to taxanes.
Abstract: Twelve patients with metastatic breast cancer previously exposed to taxanes were treated on a Phase II trial with ixabepilone. Eligible patients had histologically confirmed metastatic breast cancer with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST), and adequate hematopoietic, renal, and hepatic function. Ixabepilone 8 mg/m2/day was given intravenously daily for 3 days for the first 3-week cycle and increased to 10 mg/m2/day for subsequent cycles if patients did not have hematologic or other toxicity after the first cycle. Patients continued treatment until progressive disease or unacceptable toxicity. Three, 29, and 33 of 65 cycles administered were at the 7 mg/m2, 8 mg/m2 and 10 mg/m2 dose levels respectively. Grade 4 leukopenia (n=1), grade 3 neutropenia (n=2), grade 2 neuropathy (n=3), and grade 2 transaminase elevation (n=2) were the most notable toxicities. Ten patients had stable disease for at least 6 weeks. No complete or partial responses were observed in 12 evaluable patients treated with ixabepilone daily for 3 days. Although ixabepilone was well-tolerated, the dose of 8–10 mg/m2 daily for 3 days is not an effective therapy in metastatic breast cancer previously exposed to taxanes.

Journal ArticleDOI
TL;DR: Results of the present study indicate that dietary caraway markedly inhibited DMH-induced colon carcinogenesis and the optimal dose of 60 mg/kg body weight was more effective than the other two doses.
Abstract: Colon cancer has become one of the major causes of cancer mortality. We determined the effect of caraway (Carum carvi L.) on the development of aberrant crypt foci (ACF) and modulation of fecal bacterial enzyme activities in 1,2-dimethylhydrazine (DMH)-induced experimental rat colon carcinogenesis. Male Wistar albino rats were divided into six groups and all the animals were fed 15.8% peanut oil making a total of 20% fat in the diet. Group 1 served as control and group 2 animals received 90 mg/kg body weight caraway p.o. daily for 15 weeks. To induce ACF, DMH (20 mg/kg body weight) was injected subcutaneously once a week for the first four weeks (groups 3–6). In addition caraway was administered at the dose of 30, 60 and 90 mg/kg body weight everyday orally for the entire period of 15 weeks (groups 4–6). First, we analyzed ACF number (incidence), multiplicity and its distribution along the colon in all experimental groups at the end of 15 weeks. Subsequently, we also assayed the fecal bacterial enzyme activities. ACF formation and the fecal bacterial enzyme activities were found to be significantly high in DMH-alone treated group as compared to control group. Caraway supplementation at three different doses significantly suppressed ACF development, bacterial enzyme activities and modulated oxidative stress significantly as compared to the unsupplemented DMH-treated group. Results of our present study indicate that dietary caraway markedly inhibited DMH-induced colon carcinogenesis and the optimal dose of 60 mg/kg body weight was more effective than the other two doses.

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TL;DR: It is suggested that inter-individual variability in 9AC disposition, but not 9NC, may be influenced, in part, by ABCG2 genotype, which is associated with camptothecin resistance.
Abstract: Purpose: The source of the pharmacokinetic variability of 9-nitrocamptothecin (9NC) and its 9-aminocamptothecin (9AC) metabolite is unknown. ATP-binding cassette (ABC) transporters have been reported to modulate camptothecin analogues, are associated with camptothecin resistance, and might also affect 9NC and 9AC pharmacokinetics. The aim of this study was to evaluate the functional consequence of known single nucleotide polymorphisms in the transporter genes ABCB1, ABCC2, and ABCG2 on the pharmacokinetic disposition of 9NC and 9AC. Experimental design: Pharmacokinetic and genotyping studies were performed in 55 patients as part of two phase I studies of 9NC in patients with refractory solid tumors, a phase II study of 9NC in patients with advanced colon cancer, and a study evaluating the disposition of 9NC after administration of a single dose under fasting conditions. DNA was isolated from plasma and analyzed for variants in ABCB1, ABCC2, and ABCG2 genes. The ABCB1 1236C>T (n = 43), ABCB1 2677G>T/A (n = 43), ABCB1 3435C>T (n = 43), ABCC2 3972C>T (n = 39), and ABCG2 421C>A (n = 42) variants were analyzed using Pyrosequencing. Results: The ABCG2 421C>A genotype significantly affected the pharmacokinetics of 9AC. The mean 9AC lactone AUC/dose for wild-type (n = 25) and heterozygous (n = 2) patients were 14.3 ng/mL · h and 51.1 ng/mL. h, respectively (P = 0.032). The mean ± SD 9AC total AUC/dose for wild-type (n = 39) and heterozygous (n = 3) patients were 91.9 ± 78.3 ng/mL · h and 129.0 ± 90.5 ng/mL · h, respectively (P = 0.40). 9NC and 9AC disposition were not significantly influenced by variants in ABCB1, ABCC2, and ABCG2, and ABCB1 and ABCC2, respectively (P>0.05). Conclusion: These findings suggest that inter-individual variability in 9AC disposition, but not 9NC, may be influenced, in part, by ABCG2 genotype. In contrast, there was no evidence for a relationship between ABCG2 and the disposition of 9NC, or for relationships between ABCB1 and ABCC2 genotypes and the disposition of 9NC or 9AC.

Journal ArticleDOI
TL;DR: Fourteen patients with metastatic renal cell carcinoma (RCC) were treated on a Phase II trial with imatinib, and one tumor demonstrated strong, diffuse expression and the rest were negative.
Abstract: Fourteen patients with metastatic renal cell carcinoma (RCC) were treated on a Phase II trial with imatinib. Eligible patients had histologically confirmed RCC, metastatic and measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST), Karnofsky performance status (KPS) of at least 70%, life expectancy of more than 3 months, and adequate hematological, renal, and liver function. Imatinib was given orally at a dose of 400 mg bid. The most common toxicities were Grade II/III nausea (28%) and Grade II renal insufficiency (14%). All patients had tumor tested by immunohistochemistry (IHC) for KIT protein (CD117, DAKO). One tumor (7%) demonstrated strong, diffuse expression and the rest were negative. No complete or partial responses were observed in 12 evaluable patients treated with imatinib.

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TL;DR: A phase I study to evaluate the safety and toxicity of vinflunine administered as a 10 minute intravenous infusion on days 1 and 8 every three weeks found that two of four patients experienced dose limiting toxicities (DLT) at 190 mg/m2 and this was established as the maximum tolerated dose (MTD).
Abstract: Vinflunine is a novel vinca alkaloid developed through the selective modification of vinorelbine using super-acidic chemistry. In preclinical testing, vinflunine demonstrated significantly enhanced anti-tumour activity in human tumour xenograft models when compared to its parent compound. A phase I study was conducted to evaluate the safety and toxicity of vinflunine administered as a 10 minute intravenous infusion on days 1 and 8 every three weeks. Sixteen patients with advanced solid tumours were treated. Two of four patients experienced dose limiting toxicities (DLT) at 190 mg/m2 and this was established as the maximum tolerated dose (MTD). At the MTD, the DLT of vinflunine consisted of constipation and neutropenia. Fatigue was notable but not dose limiting. No objective responses were observed. A dose of 170 mg/m2 given on a day 1 and 8 schedule every three weeks would be suitable for future studies.

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TL;DR: It is postulate that diminished HIF-1α nuclear presence and activity in BP-1 treated EAT cells could be responsible for decreased VEGF expression and antiangiogenic effects.
Abstract: Benzophenones and its analogues are known for wide range of biological properties. Synthetic benzophenone analogue 2-benzoyl -phenoxy acetamide (BP-1) is proven to be potent antitumor and proapoptotic activity against EAT cells in-vivo. In the present report, we studied the antiangiogenic effect of BP-1 in EAT cells induced angiogenesis. Treatment with BP-1 in-vivo was demonstrated by the down regulation of the secretion of VEGF from EAT cells and inhibition of blood vessels formation indicating the potential angioinhibitory effect of BP-1 in EAT cells. HIF-1α protein, a transcription factor known to be key a regulator in hypoxia-induced angiogenesis was also down regulated by BP-1. Our findings indicated that, HIF-1α nuclear sequestration is repressed by BP-1 through inhibition of nuclear translocation. We postulate that diminished HIF-1α nuclear presence and activity in BP-1 treated EAT cells could be responsible for decreased VEGF expression and antiangiogenic effects.

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TL;DR: Evidence that CYP3A4 has a major role in the metabolism of ET-743 in vitro with additional involvement of CYP2C9, 2C19, 2D6, and 2E1 is provided, providing evidence that pharmacokinetic data of clinical trials and prediction of drug-drug interactions could be important.
Abstract: ET-743 is a potent marine anti-cancer drug and is currently being investigated in phase I and II clinical trials, e.g. in combination with other anti-cancer agents. To assess the biotransformation and CYP reaction phenotype and their potential implications for human pharmacology and toxicology, the in vitro metabolism of ET-743 was characterized using incubations with human liver preparations, cytochrome P450 (CYP) and uridine diphosphoglucuronosyl transferase (UGT) supersomes.