bryostatin-1 and Adenocarcinoma

To determine the efficacy and toxicity of the protein kinase C inhibitor bryostatin-1 plus paclitaxel in patients with advanced pancreatic carcinoma.. Each treatment cycle consisted of paclitaxel 90 mg/m by intravenous infusion over 1 hour on days 1, 8, and 16, plus bryostatin 25 mcg/m as a 1-hour intravenous infusion on days 2, 9, and 15, given every 28 days. Patients were evaluated for response after every 2 treatment cycles, and continued therapy until disease progression or prohibitive toxicity. The primary objective was to determine whether the combination produced a response rate of at least 30%.. Nineteen patients with locally advanced or metastatic pancreatic adenocarcinoma received a total of 52 cycles of therapy (range: 1-10). Patients received the combination as first-line therapy for advanced disease (N = 5) or after prior chemotherapy used alone or in combination with local therapy. No patients had a confirmed objective response. The median time to treatment failure was 1.9 months (95% confidence intervals: 1.2, 2.6 months). Reasons for discontinuing therapy included progressive disease or death in 14 patients (74%) or because of adverse events or patient choice in 5 patients (26%). The most common grade 3 to 4 toxicities included leukopenia in 26%, anemia in 11%, myalgias in 11%, gastrointestinal bleeding in 11%, infection in 10%, and thrombosis in 10%.. The combination of weekly paclitaxel and bryostatin-1 is not an effective therapy for patients with advanced pancreatic carcinoma.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bryostatins; Female; Humans; Male; Middle Aged; Neoplasm Staging; Paclitaxel; Pancreatic Neoplasms; Protein Kinase C; Survival Rate; Treatment Outcome; Young Adult

We sought to determine the response rate and toxicity profile of sequential paclitaxel and bryostatin-1, a novel, selective inhibitor of protein kinase C, in patients with advanced esophageal cancer.. Patients with advanced esophageal and gastroesophageal junction cancer were enrolled. All gave informed consent. They were initially treated with paclitaxel 90 mg/m(2) intravenously on Day 1 and bryostatin-1 50 microg/m2 on Day 2 weekly for three consecutive weeks out of four. Because of severe myalgias, dosing was reduced to paclitaxel 80 mg/m2 with bryostatin-1 40 microg/m2 and then to paclitaxel 80 mg/m2 with bryostatin-1 25 microg/m2.. Twenty-four patients were enrolled, with 22 assessable for response. The partial response rate was 27%. 10 patients treated with bryostatin-1 40-50 microg/m2 had a response rate of 40 versus 17% at bryostatin-1 25 microg/m2 (p-value = 0.3). Median time-to-progression was 3.7 months and median survival was 8.3 months. Grade 3/4 myalgias were seen in 50% of patients. Myalgias appeared to be related to bryostatin-1 dose. Because of toxicity, the trial was closed prior to full accrual.. Despite potential anti-tumor activity of this combination in patients with advanced esophageal cancer, further development is not warranted, given the severe toxicity, especially myalgias, that were seen.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bryostatins; Carcinoma, Squamous Cell; Disease Progression; Esophageal Neoplasms; Female; Humans; Male; Middle Aged; Paclitaxel

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.. 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.. 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.. 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.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bryostatins; Disease Progression; Dose-Response Relationship, Drug; Esophageal Neoplasms; Esophagogastric Junction; Female; Humans; Macrolides; Male; Middle Aged; Neoplasm Staging; Paclitaxel; Survival Analysis

Bryostatin-1 is a macrocyclic lactone, which exhibits pleiotropic biological effects via protein kinase C and has shown preclinical synergy with paclitaxel for enhanced tumor cell apoptosis.. Patients had stage IIIB (pleural effusion)/IV non-small cell lung cancer, measurable disease, performance status 0-2 Eastern Cooperative Oncology Group, adequate organ function, and no prior chemotherapy. Patients received dexamethasone premedication followed by paclitaxel at a dose of 90 mg/m(2) on days 1, 8, and 15 along with bryostatin-1 50 microg/m(2) on days 2, 9, and 16 every 28 days until disease progression. Correlative assays measuring serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and T-lymphocyte numbers were performed based on a previous study showing cytokine induction in vivo by bryostatin-1. Fifteen patients were enrolled.. Thirty cycles of the bryostatin-1 and paclitaxel were delivered with a median of 2 per patient (range 1-4). Myalgia was the predominant non-hematologic toxicity encountered as 3 patients developed grade 4 and 1 patient developed grade 3 myalgia. Four patients were removed from the study during cycle 1 for rapid disease progression or myalgia. Eleven patients could be evaluated for response. Five patients had stable disease, two had a mixed response, and four had progressive disease. Ten patients received second-line chemotherapy after leaving the study. Median survival was 31 weeks (95% confidence interval: 5.4-49.3). Correlative data showed a trend towards decreased plasma IL-6 and TNF-alpha after each cycle of therapy presumably due to the dexamethasone premedication and/or paclitaxel.. This drug combination showed no significant clinical response and was associated with reproducible toxicity. The predominance of myalgia in the absence of elevated serum cytokines suggests a non-inflammatory etiology of this toxicity.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Bryostatins; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Drug Administration Schedule; Female; Glucocorticoids; Humans; Interleukin-6; Lactones; Lung Neoplasms; Macrolides; Male; Middle Aged; Paclitaxel; Premedication; Survival Rate; T-Lymphocytes; Tumor Necrosis Factor-alpha

Protein kinase C (PKC) is involved in tumor growth and apoptosis and hence represents a potential target for cancer therapy. This study investigated the expression of PKC in pancreatic tumor tissue in comparison to adjacent normal tissue and determined the modulation of PKC by bryostatin-1 (BRYO) on pancreatic cancer cell lines.. Pancreatic tissue was obtained from 18 patients who had a resection (14 with ductal adenocarcinoma and 4 with adenoma and high-grade dysplasia). Cytosolic and nuclear membrane PKCs in the paired samples were determined by immunoblotting. HPAC cells were treated with gemcitabine and BRYO and in sequential and concomitant combination. To evaluate cell viability, apoptosis, and electrophoretic mobility shift assay, 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, enzyme-linked immunosorbent assay, and nuclear factor kappaB (NF-kappaB) assays were used.. As compared with the adjacent normal tissue, PKC-alpha, PKC-beta1, and PKC-delta were higher in the tumor; PKC-epsilon was higher in the normal tissue. Pretreatment with gemcitabine followed by BRYO resulted in decreased cell viability, increased apoptosis, and inhibited NF-kappaB than either agent alone or BRYO followed by gemcitabine.. Protein kinase C is overexpressed and activated in pancreatic cancer as compared with normal tissue. Inhibition of PKC could sensitize pancreatic cancer cell lines to the effects of gemcitabine. The potentiation of gemcitabine by BRYO is sequence-dependent and mediated through inhibition of PKC-dependent activation of NF-kappaB.

Topics: Adenocarcinoma; Adenoma; Antineoplastic Combined Chemotherapy Protocols; Bryostatins; Cell Survival; Deoxycytidine; Gemcitabine; Humans; Isoenzymes; Pancreatic Neoplasms; Protein Kinase C; Protein Kinase Inhibitors; Reference Values

Bryostatin-1 is a new chemotherapeutic agent that inhibits protein kinase C. The most common side effect and the dose limiting toxicity is myalgia. The cutaneous side effects reported during the phase I and II trials were alopecia, mucositis, nonspecific "rash," "bronzing," and hyperpigmentation in sun exposed areas. No specific acute drug eruptions have been reported. We present the first reported case of a morbilliform drug eruption with histologic features of intraepidermal and subcorneal spongiotic pustules containing eosinophils secondary to bryostatin-1.

Topics: Adenocarcinoma; Antineoplastic Agents; Bryostatins; Clinical Trials as Topic; Drug Eruptions; Humans; Lactones; Macrolides; Male; Middle Aged; Protein Kinase C; Stomach Neoplasms

Adenocarcinoma of the pancreas generally remains an incurable disease by available treatment modalities, demanding the development of a suitable cell-culture/animal model and the discovery and evaluation of novel therapeutic agents. We report the clonal preservation of a human pancreatic cell line (KCI-MOH1) established from a 74-year-old African-American man diagnosed with pancreatic cancer. Initially the human primary tumor was grown as a xenograft in SCID mice and, subsequently, a cell line was established from tumors grown as a xenograft as reported in our earlier publication. The molecular characterization of the primary tumor, the tumors grown as xenograft, and the cell line all revealed similar genotypic properties. By using an automated DNA sequencer, a K-ras mutation (codon 12, GGT to CGT, Gly to Arg) was detected in the pancreatic tumor tissue taken from the patient, whereas no p53 mutation was detected. The same K-ras mutation and unaltered p53 was also found in the xenograft tumor and in the KCI-MOH1 cell line. Chromosome analysis of the cultured cells revealed: 42,XY,add(3)(p11.2),der(7)t(7;12) (p22;q12),-10,-12,add (14)(p11),-18,add (20)(q13),-22/84, idemx2, which is the same chromosome complement found in xenograft tumors. The KCI-MOH1 cell line grows well in tissue culture and forms tumors in the SCID mice when implanted subcutaneously, as well as in orthotopic sites. The KCI-MOH1 cell line-derived SCID mouse xenograft model was used for efficacy evaluation of bryostatin 1, auristatin-PE, spongistatin 1, and gemcitabine alone and in combination. Tumor growth inhibition (T/C expressed as percentage), tumor growth delay (T - C), and log 10 kill for these agents were 38%, 22 days, and 0.53; 15%, 30 days, and 0.80; 24%, 25 days, and 0.66; and 10%, 33 days, and 0.90, respectively. When given in combination, two of seven gemcitabine + auristatin-PE-treated animals were free of tumors for 150 days and were considered cured. Animals treated with a combination of bryostatin 1 and gemcitabine and a combination of spongistatin and gemcitabine produced remissions in only one of seven mice. From these results, we conclude that (a) this is the first study illustrating that clonal characteristics of primary pancreatic tumors remained unchanged when implanted in mice and as a permanent cell line grown in vitro; and (b) there is a synergistic effect between gemcitabine and selected marine products tested in this study, which is more apparent in the gemcita

Topics: Adenocarcinoma; Aged; Animals; Antineoplastic Agents; Bryostatins; Deoxycytidine; DNA Mutational Analysis; Ethers, Cyclic; Gemcitabine; Genes, p53; Genes, ras; Humans; Karyotyping; Lactones; Macrolides; Male; Mice; Mice, SCID; Neoplasm Transplantation; Oligopeptides; Pancreatic Neoplasms; Tumor Cells, Cultured

Butyrate is a potentially selective therapeutic agent for many adenocarcinomas. Butyrate causes reversible growth arrest as well as some death of VACO 5 colon cancer cells. Combined treatment with butyrate and the phorbol ester TPA leads instead only to cell death, while TPA causes little death on its own. Cells dying during treatment with TPA and butyrate, as well as those dying in the presence of butyrate alone, exhibit features typical of apoptosis, including detachment, shrinkage and internucleosomal DNA cleavage. Pre-treating VACO 5 cell cultures with TPA for as little as 6 hr prior to butyrate addition led to a markedly diminished enhancement of butyrate-induced apoptosis. Treatment with a distinct PKC activator, bryostatin 1, was ineffective in enhancing butyrate-induced death and, furthermore, counteracted the death-enhancing actions of TPA. Such antagonism was apparent when bryostatin was added after 12 hr of TPA/butyrate treatment but was much less effective thereafter. The duration of TPA/butyrate treatment required for depressing cell survival by >95% was thereby estimated to be 24 hr. Other colon cancer cell lines were examined for the extent of cell death following treatment with TPA/butyrate. In each of these lines, butyrate inhibited cell replication in a reversible manner, similar to that seen in VACO 5. However, the combination of butyrate and TPA led to high levels of cell death in only a subset of these lines. TPA/butyrate-treated cultures of COLO 201 exhibited extensive apoptosis, similar in timing and magnitude to the response by VACO 5, whereas HCT 116 was reversibly growth-arrested. Our findings indicate that the PKC system plays a critical role in maintaining cell survival during butyrate-induced growth arrest.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Bryostatins; Butyrates; Butyric Acid; Cell Division; Colonic Neoplasms; Drug Interactions; Enzyme Activation; Humans; Kinetics; Lactones; Macrolides; Protein Kinase C; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

Bryostatin 1 (Bryo) is a naturally occurring macrocyclic lactone with antineoplastic activity. Like the phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate (TPA) it directly activates the calcium- and phospholipid-dependent protein kinase C (PKC), thus generating a number of different cellular responses. We investigated the effects of Bryo and TPA on DNA synthesis, proliferation, viability and c-myc protooncogene expression of the human carcinoma cell lines COLO-320, MEL-HO, and KB-3-1. TPA inhibited [3H]-thymidine incorporation in all three cell lines in a dose-dependent manner, whereas Bryo only inhibited the DNA synthesis in MEL-HO, but not in KB-3-1 and COLO-320 cells. Within the concentration ranges used, TPA and Bryo were found to have a low toxicity. Counting of the cells confirmed the observed inhibition of cell proliferation. However, the enzymatic conversion of MTT, applied as a colorimetric proliferation assay, was not significantly affected by both biomodulators. Time-course experiments revealed a rapid onset of the inhibitory effect on DNA synthesis. Bryo was further able to antagonize the TPA-mediated effects on proliferation suggesting an (at least partially) different mode of action of these PKC activators. Incubation of MEL-HO and COLO-320 cells with either of the two biomodulators resulted in a rapid and strong increase of c-myc mRNA. The present study emphasizes Bryo as an interesting, natural substance for the study of PKC-mediated biological effects.

Topics: Adenocarcinoma; Antineoplastic Agents; Bryostatins; Cell Division; Cell Survival; DNA; Dose-Response Relationship, Drug; Female; Gene Expression Regulation, Neoplastic; Genes, myc; Humans; Lactones; Macrolides; Melanoma; Protein Kinase C; Proto-Oncogene Proteins c-myc; RNA, Messenger; Sigmoid Neoplasms; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured; Uterine Cervical Neoplasms

We have examined the ability of bryostatin 1 to inhibit the in vitro growth and in vivo development of a panel of four murine tumors of diverse tissue origins. A wide range of antiproliferative responses was observed for the four tumors. At 100 ng/ml the in vitro growth of the Renca renal adenocarcinoma, the B16 melanoma, the M5076 reticulum cell sarcoma, and the L10A B-cell lymphoma were inhibited by 0, 40, 40, and 94% respectively. All three cell lines sensitive to bryostatin in vitro responded to multiple dose, 1 microgram/injection/day in vivo i.p., bryostatin therapy. Only the in vitro resistant Renca tumor failed to respond to bryostatin in vivo. The correlation between in vitro and in vivo antitumor efficacy suggests a direct mechanism of antitumor activity for bryostatin. Both local regional therapy (M5076 i.p.) and systemic therapy (B16 lung metastases and L10A s.c. tumors) with bryostatin were successful at prolonging survival time. Multiple i.p. doses of bryostatin at a minimum level of 0.5-1.0 microgram/injection were required to observe significant in vivo antitumor effects. The success of in vivo administration of bryostatin in mice bearing 8-10-mm s.c. masses of L10A lymphoma (5-10 x 10(9)) and our further observation that five of a panel of six human B-cell lymphoma cell lines were sensitive to the growth inhibitory effects of bryostatin in vitro suggest that bryostatin may be effective in treating lymphoid malignancies in humans.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Bryostatins; Drug Resistance; Drug Screening Assays, Antitumor; Female; Kidney Neoplasms; Lactones; Lymphoma, B-Cell; Macrolides; Male; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Tumor Cells, Cultured