bryostatin-1 and Neoplasms

Natural compounds derived from marine organisms have shown a wide variety of anti-tumor effects and a lot of attention has been drawn to further development of the isolated compounds. A vast quantity of individual chemical structures from different organisms has shown a variety of apoptosis inducing mechanisms in a variety of tumor cells. The bis-steroidal cephalostatin 1 for example, induces apoptosis via activation of caspases whereas the polyketide discodermolide inhibits cell growth by binding to and stabilizing microtubule and salisporamide A, the product of an actinobacterial strain, is an inhibitor of the proteasome. This great variety of mechanisms of action can help to overcome the multitude of resistances exhibited by different tumor specimens. Products from marine organisms and their synthetic derivates are therefore an important source for new therapeutics for single agent or combined therapy with other chemotherapeutics to support the struggle against cancer.

Topics: Alkaloids; Alkanes; Animals; Anti-Bacterial Agents; Antineoplastic Agents; Apoptosis; Aquatic Organisms; Biological Products; Bryostatins; Carbamates; Cell Proliferation; Depsipeptides; Dioxoles; Drug Screening Assays, Antitumor; Humans; Lactones; Macrolides; Microtubules; Models, Chemical; Neoplasms; Phenanthrolines; Phenazines; Proteasome Endopeptidase Complex; Pyrones; Pyrroles; Quinolines; Spiro Compounds; Steroids; Tetrahydroisoquinolines; Thiazoles; Trabectedin

Marine antitumor drugs have been the research focus in the world. Recently, advancement has been made in the investigation of six types of compounds including bryostatin-1, ecteinascidin-743, dolastatin, didemnin B, psammaplin and halichondrin B. In this review, we summarized the recent research progress of the above mentioned marine antitumor drugs and their derivatives. Also, the development tendency of marine antitumor drugs was discussed.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biological Products; Bryostatins; Cell Line, Tumor; Depsipeptides; Dioxoles; Disulfides; Ethers, Cyclic; Humans; Macrolides; Marine Biology; Neoplasms; Tetrahydroisoquinolines; Trabectedin; Tyrosine

Topics: Animals; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Bryostatins; Clinical Trials, Phase I as Topic; Depsipeptides; Dioxoles; Drug Screening Assays, Antitumor; Humans; Isoquinolines; Lactones; Macrolides; Marine Biology; Neoplasms; Oligopeptides; Peptides, Cyclic; Tetrahydroisoquinolines; Trabectedin

The bryostatins are a group of novel macrocyclic lactones derived from the marine bryozoan, Bugula neritina. In vitro evidence indicates that their main mechanism of action is modulation of protein kinase C (PKC) activity. Phase I studies suggested significant antineoplastic activity against several tumor types and defined the main dose-limiting toxicity as myalgia. Bryostatin-1 has subsequently been investigated extensively in phase II clinical trials as a single agent, although trial design has been hampered by lack of human pharmacokinetic data. Results have been generally disappointing but in vitro and animal data suggests an important role for bryostatin-1 in combination with cytotoxic agents. Preliminary results of phase I studies support these observations but further work needs to be done to define the future role of the bryostatins in the clinic.

Topics: Animals; Antineoplastic Agents; Bryostatins; Clinical Trials as Topic; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Humans; Immunotherapy, Adoptive; Lactones; Macrolides; Neoplasms

Various active anticancer agents are derived from plants and terrestrial microorganisms. The isolation of C-nucleosides from the Caribbean sponge, Cryptotheca crypta, four decades ago, provided the basis for the synthesis of cytarabine, the first marine-derived anticancer agent to be developed for clinical use. Cytarabine is currently used in the routine treatment of patients with leukaemia and lymphoma. Gemcitabine, one of its fluorinated derivatives, has also been approved for use in patients with pancreatic, breast, bladder, and non-small-cell lung cancer. Over the past decade, several new experimental anticancer agents derived from marine sources have entered preclinical and clinical trials. This field has expanded significantly as a result of improvements in the technology of deep-sea collection, extraction, and large-scale production through aquaculture and synthesis. In this paper, examples of marine-derived experimental agents that are currently undergoing preclinical and early clinical evaluation are briefly discussed. A summary of the available information on the results of phase I and II trials of agents such as aplidine, ecteinascidin-734 (ET-734), dolastatin 10 and bryostatin 1 is also presented.

Topics: Animals; Antineoplastic Agents; Bryostatins; Clinical Trials as Topic; Drug Evaluation, Preclinical; Forecasting; Humans; Lactones; Macrolides; Neoplasms; Urochordata

Bryostatins are a class of antineoplastic compounds isolated from the bryozoans Bugula neritina. A wide range of scientific research is currently underway, studying different aspects of the bryostatins. In this review we try to summarize the latest findings, including all the topics involved, from marine biology to medicinal chemistry.

Topics: Animals; Antineoplastic Agents; Bryostatins; Bryozoa; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Enzyme Activation; Humans; Lactones; Macrolides; Molecular Structure; Neoplasms; Protein Kinase C

Topics: Antineoplastic Agents; Apoptosis; Bryostatins; Cytarabine; Drug Synergism; Enzyme Inhibitors; Humans; Lactones; Macrolides; Neoplasms; Protein Kinase C; Protein-Tyrosine Kinases; Signal Transduction

Topics: Animals; Antineoplastic Agents; Bryostatins; DNA Topoisomerases, Type I; Drug Resistance; Enzyme Inhibitors; Humans; Lactones; Macrolides; Neoplasms; Protein Kinase C; Tetradecanoylphorbol Acetate

New drug discovery continues to follow the time-honored paths of screening and novel target identification combined with analogue development and serendipity. The agents selected here reflect these various approaches. They include drugs already showing significant antitumor activity, eg, anthrapyrazoles, temozolomide, camptothecin analogues, and taxotere, and updated information is provided on their development. Other drugs just entering or currently in phase I trials include rhizoxin, which seems capable of overcoming multidrug resistance; the novel bioreductive agent EO9 [corrected]; and bryostatin, a highly potent protein kinase C agonist. Sequence specificity could well prove to be an important factor in the development of DNA-interactive agents, and information is provided on the progress with distamycin mustard and the new cyclopropylpyrroloindole analogues carzelesin and adozelesin.

Topics: Antineoplastic Agents; Bryostatins; Camptothecin; Docetaxel; Humans; Lactones; Macrolides; Neoplasms; Paclitaxel; Taxoids

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adjuvants, Immunologic; Animals; Bryostatins; Growth Inhibitors; Humans; Immunologic Factors; Lactones; Macrolides; Neoplasms; Phosphatidylethanolamines; Picibanil; Polysaccharides

Topics: Animals; Antineoplastic Agents; Bryostatins; Humans; Lactones; Macrolides; Molecular Conformation; Molecular Structure; Neoplasms

Preclinical data suggested that bryostatin-1 (bryo) could potentiate the cytotoxicity of cisplatin when given prior to this drug. We designed a phase I study to achieve tolerable doses and schedules of bryo and cisplatin in combination and in this sequence.. Patients with non-hematologic malignancies received bryo followed by cisplatin in several schedules. Bryo was given as an 1 and a 24 h continuous infusion, while cisplatin was always given over 1 h at 50 and 75 mg/m(2); the combined regimen was repeated on an every 3-week and later on an every 2-week schedule. Bryo doses were escalated until recommended phase II doses were defined for each schedule. Patients were evaluated with computerized tomography every 2 cycles.. Fifty-three patients were entered. In an every 2-week schedule, the 1-h infusion of bryo became limited by myalgia that was clearly cumulative. With cisplatin 50 mg/m(2) its recommended phase II dose was 30 microg/m(2). In the 3-week schedule, dose-limiting toxicities were mostly related to cisplatin effects while myalgias were tolerable. Pharmacokinetics unfortunately proved to be unreliable due to bryo's erratic extraction. Consistent inhibition of PKC isoform eta (eta) in peripheral blood mononuclear cells was observed following bryo.. Bryo can be safely administered with cisplatin with minimal toxicity; however, only four patients achieved an objective response. Modulation of cisplatin cytotoxicity by bryo awaits further insight into the molecular pathways involved.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bryostatins; Cisplatin; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Protein Kinase C

Accurate response assessment is essential for evaluating new cancer treatments. We evaluated the impact of Response Evaluation Criteria in Solid Tumors (RECIST), World Health Organization (WHO) criteria and tumor shape on response assessment in patients with metastatic esophageal cancer.. In 19 patients with metastatic esophageal cancer in a phase II trial of bryostatin-1 and paclitaxel, response was retrospectively assessed for 89 lesions with RECIST and WHO criteria on baseline and serial follow-up CT scans. The eccentricity factor (EF) was introduced for measuring the degree to which tumor shape diverges from a perfect sphere [EF = radical1-(LPD/MD)(2), where LPD is the largest perpendicular diameter and MD is the maximal diameter].. The disagreement rate in best overall response categorization between RECIST (unidimensional) and WHO (bidimensional) criteria was 26.3%. Change in eccentricity was significantly greater (P < 0.01) for patients with disagreement (mean 0.31, range 0-0.91). When the short axis was used for unidimensional lymph node measurement, disagreement between WHO and RECIST lessened.. Response assessment by WHO and RECIST differs substantially. Greater change in eccentricity is associated with greater discordance between WHO and RECIST. The discordance between WHO and RECIST may impact on how effective a therapy is judged to be.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bryostatins; Esophageal Neoplasms; Female; Follow-Up Studies; Humans; Lymphatic Metastasis; Macrolides; Male; Middle Aged; Neoplasm Staging; Neoplasms; Paclitaxel; Retrospective Studies; Tomography, X-Ray Computed; Treatment Outcome

Bryostatin 1 is a macrocyclic lactone with protein kinase C inhibitory activity. Gemcitabine is a nucleotide analogue with a broad spectrum of anticancer activity. Bryostatin 1 enhanced the activity of antitumor agents including gemcitabine in preclinical models. The primary objective of this phase I study was to determine the recommended doses for phase II trials of bryostatin 1 and gemcitabine.. Eligible patients had histologic or cytologic diagnosis of nonhematologic cancer refractory to conventional treatment; life expectancy of >3 months; normal renal, hepatic, and bone marrow function; and a Southwest Oncology Group performance status of 0 to 2. Gemcitabine was administered i.v. over 30 minutes and was followed by bryostatin 1 by i.v. infusion over 24 hours on days 1, 8, and 15 of a 28-day cycle. Bryostatin 1 (microg/m(2)) and gemcitabine (mg/m(2)) doses were escalated as follows: 25/600, 25/800, 25/1,000, 30/1,000, 35/1,000, and 45/1,000, respectively.. Thirty-six patients (mean age, 57 years; male/female 15:21) were treated. The median number of treatment cycles per patient was 3 (range, 0-24). Four patients developed dose limiting toxicities: myalgia, 2; myelosuppression, 1; and elevation of serum alanine aminotransferase levels, 1. Ten grade 3 toxicities were observed (anemia, 2; neutropenia, 5; thrombocytopenia, 3). No treatment-related death was seen. The recommended doses for phase II trials for bryostatin 1 and gemcitabine were 35 microg/m(2) and 1,000 mg/m(2), respectively. Two heavily pretreated patients with breast and colon cancer experienced partial responses lasting 22 and 8 months, respectively. Eight patients had stable disease.. The combination of bryostatin 1 and gemcitabine seemed to be well tolerated with limited grade 3 toxicity. The recommended dose of bryostatin 1 in combination with full doses of gemcitabine was 35 microg/m(2).

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bryostatins; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Gemcitabine; Humans; Injections, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Treatment Outcome

Adoptive immunotherapy (AIT) of cancer with T lymphocytes may be limited by the need to activate tumor antigen-sensitized cells in vitro. In murine models, we have shown that AIT with tumor-sensitized T cells that have been pharmacologically activated with bryostatin 1 and ionomycin plus interleukin-2 can induce tumor regression. A Phase I clinical trial was carried out to assess the feasibility and toxicity associated with using tumor- or vaccine-draining lymph node cells, activated pharmacologically and expanded in culture with low-dose interleukin-2 and infused intravenously, followed by IL-2 infusion. Nine patients were entered into the trial, and six were treated as planned. Average expansion of cell numbers over 13 to 27 days in culture was 118-fold. No patient's cells reached the target cell number (2.5 x 10(10)). Infusion of these cells did not result in any unexpected toxicities. The toxicities observed were related to IL-2 infusion, and conformed to the expected range of side-effects. Based on these Phase I results, additional trials, with tumor antigen vaccine-sensitized DLN and technical modifications of the culture technique, are planned.

Topics: Adult; Bryostatins; Cells, Cultured; Female; Humans; Immunotherapy, Adoptive; Interleukin-2; Ionomycin; Lactones; Lymph Nodes; Lymphocyte Activation; Macrolides; Male; Middle Aged; Neoplasms; Pilot Projects; T-Lymphocytes

Bryostatin-1, a macrocyclic lactone, appears to elicit a wide range of biological responses including modulation of protein kinase C (PKC). PKC, one of the major elements in the signal transduction pathway, is involved in the regulation of cell growth, differentiation, gene expression, and tumor promotion. Because of the potential for a unique mechanism of interaction with tumorgenesis, a Phase I trial of bryostatin-1 was performed in children with solid tumors to: (a) establish the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD); (b) establish the pharmacokinetic profile in children; and (c) document any evidence of antitumor activity. A 1-h infusion of bryostatin-1 in a PET formulation (60% polyethylene glycol 400, 30% ethanol, and 10% Tween 80) was administered weekly for 3 weeks to 22 children (age range, 2-21 years) with malignant solid tumors refractory to conventional therapy. Doses ranged from 20 to 57 microg/m2/ dose. Pharmacokinetics were performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. Twenty-two patients on five dose levels were evaluable for toxicities. At the 57 microg/m2/dose level dose-limiting myalgia (grade 3) was observed in three patients; two of those patients also experienced photophobia or eye pain, and one experienced headache. Symptoms occurred in all patients within 24-72 h after the second dose of bryostatin-1 with resolution within 1 week of onset. Other observed toxicities (grades 1 and 2) included elevation in liver transaminases, thrombocytopenia, fever, and flu-like symptoms. The bryostatin-1 infusion was typically well tolerated. Although stable disease was noted in several patients, no complete or partial responses were observed. The recommended Phase II dose of bryostatin-1 administered as a 1-h infusion weekly for 3 of every 4 weeks to children with solid tumors is 44 microg/m2/dose. Myalgia, photophobia, or eye pain, as well as headache, were found to be dose limiting.

Topics: Adolescent; Adult; Antineoplastic Agents; Bryostatins; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Lactones; Macrolides; Male; Neoplasms; Thrombocytopenia

A Phase Ib trial of bryostatin 1, a macrocyclic lactone and protein kinase C (PKC) activator, was conducted in patients with refractory nonhematological malignancies with the primary goal of determining whether down-regulation of peripheral blood mononuclear cell (PBMNC) PKC activity could be achieved in vivo in humans. Patients (four patients/cohort) received bryostatin 1 (25 microg/m2) as a 1-h infusion weekly three times every 4 weeks, but to study the schedule dependence of pharmacokinetics and pharmacodynamics, the first dose was administered according to one of three schedules: (a) a 1-h infusion; (b) a 24-h infusion; or (c) a split course (12.5 microg/m2 as a 30-min infusion) on days 1 and 4. Conventional toxicities (grades I-III) included myalgias, fever, anemia, fatigue, phlebitis, and headache; in addition, two patients in cohort 3 experienced transient elevations in liver function tests, although these patients had preexisting liver metastases. No objective clinical responses were encountered. Effects on PBMNC PKC activity were heterogeneous. Several patients in cohorts 1 and 2 experienced significant declines in activity (approximately 50%) that were sustained in some cases for periods of > or = 72 h. Comparison of 72-h with baseline values for all three patient cohorts combined revealed a trend toward PKC down-regulation (P = 0.06; signed rank test). For each schedule, plasma bryostatin 1 levels were below the level of detection of a platelet aggregation-based bioassay (3-4 nm). Bryostatin 1 administration failed to produce consistent alterations in lymphocyte immunophenotypic profiles, interleukin 2-induced proliferation, or cytotoxicity, although two of three samples from patients in cohort 3 did show significant posttreatment increases in proliferation. Moreover, in some patients, bryostatin 1 treatment increased lymphokine-activated killer cell activity. These findings indicate that bryostatin 1 doses of 25 microg/m2 can induce in vivo PBMNC PKC down-regulation in at least a subset of patients and raise the possibility that higher bryostatin 1 doses may be more effective in achieving this effect.

Topics: Adult; Aged; Antineoplastic Agents; Bryostatins; Cohort Studies; Cytotoxicity, Immunologic; Drug Administration Schedule; Female; Humans; Immunophenotyping; Infusions, Intravenous; Interleukin-2; Lactones; Lymphocyte Activation; Lymphocytes; Lymphoma; Macrolides; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Patient Selection; Platelet Aggregation; Protein Kinase C

Bryostatin 1 is a macrocyclic lactone derived from the marine invertebrate Bugula neritina. In vitro, bryostatin 1 activates protein kinase C (PKC), induces the differentiation of a number of cancer cell lineages, exhibits anti-tumour activity and augments the response of haemopoietic cells to certain growth factors. In vivo, bryostatin 1 is also immunomodulatory, but the range of tumours which respond to bryostatin 1 in xenograft tumour models is mostly the same as the in vitro tumour types, suggesting a direct mode of action. Nineteen patients with advanced malignancy were entered into a phase I study in which bryostatin 1 was given as a 24 h intravenous infusion, weekly, for 8 weeks. Myalgia was the dose-limiting toxicity and the maximum tolerated dose was 25 micrograms m-2 per week. The myalgia was cumulative and dose related, and chiefly affected the thighs, calves and muscles of extraocular movement. The mechanism of the myalgia is unknown. CTC grade 1 phlebitis affected every patient for at least one cycle and was caused by the diluent, PET, which contains polyethylene glycol, ethanol and Tween 80. Most patients experienced a 1 g dl-1 decrease in haemoglobin within 1 h of commencing the infusion which was associated with a decrease in haematocrit. Radiolabelled red cell studies were performed in one patient to investigate the anaemia. The survival of radiolabelled red cells during the week following treatment was the same as that seen in the week before treatment. However, there was a temporary accumulation of radiolabelled red cells in the liver during the first hour of treatment, suggesting that pooling of erythrocytes in the liver might account for the decrease in haematocrit. Total or activated PKC concentrations were measured in the peripheral blood mononuclear cells (PBMCs) of three patients for the first 4 h of treatment and during the last hour of the infusion. This showed that PKC activity was significantly modulated during the infusion. Bryostatin 1 is immunomodulatory in vitro, and we have confirmed this activity in vivo. An investigation of the first three cycles of treatment in seven patients showed an increased IL-2-induced proliferative response in peripheral blood lymphocytes and enhanced lymphokine-activated killer (LAK) activity. A previously reported rise in serum levels of interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF 1) was not confirmed in our study; of nine patients in this study, including patients at all dose l

Topics: Adult; Aged; Anemia; Antineoplastic Agents; Bryostatins; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hematocrit; Humans; Infusions, Intravenous; Interleukin-6; Killer Cells, Lymphokine-Activated; Lactones; Leukocytes, Mononuclear; Macrolides; Male; Middle Aged; Neoplasms; Phlebitis; Protein Kinase C; Tumor Necrosis Factor-alpha

Bryostatin 1 is a protein kinase C activator that inhibits growth of tumour cells and activates lymphocytes in vitro, properties that have encouraged its use in phase 1 clinical studies as an anticancer agent. We investigated interleukin-2(IL-2)-induced proliferation and lymphokine-activated killer (LAK) cell activity in peripheral blood mononuclear cells (PBMC) from cancer patients receiving Bryostatin intravenously. After Bryostatin administration both LAK generation and proliferation were enhanced when patients' PBMC were stimulated with IL-2 in vitro. However, when normal donors' PBMC were cultured in vitro in the presence Bryostatin and IL-2, LAK induction was inhibited while IL-2-driven proliferation was increased. These effects were also seen following only 2 h exposure to Bryostatin and could be elicited by conditioned medium from Bryostatin-pretreated cells. Neither IL-4 nor interferon gamma was detected in the conditioned medium. Bryostatin in vitro was found to increase expression of IL-2 receptors on CD4+, CD8+ and CD56+ cells and augment the proportion of CD8+ cells in conjunction with IL-2. We conclude that Bryostatin in combination with IL-2 in vitro enhances proliferation and IL-2 receptor expression on lymphocytes, favouring CD8+ cells while suppressing the generation of LAK activity. Intravenous administration of Bryostatin increases the potential of IL-2 to induce proliferation and LAK activity in lymphocytes which, taken together with its putative direct antitumour effect, makes Bryostatin an interesting candidate for clinical trials in combination with IL-2.

Topics: Adjuvants, Immunologic; Adult; Antineoplastic Agents; Bryostatins; CD8-Positive T-Lymphocytes; Cell Division; Cells, Cultured; Culture Media, Conditioned; Drug Interactions; Female; Humans; Infusions, Intravenous; Interleukin-2; Killer Cells, Lymphokine-Activated; Lactones; Lymphocyte Activation; Lymphocytes; Macrolides; Male; Middle Aged; Neoplasms; Receptors, Interleukin-2

Many oncogenes have been shown to code for growth factor receptors that are involved in regulation of cell growth and proliferation and can activate transcription via protein kinase C. Bryostatin 1, a partial agonist of protein kinase C, has demonstrated potent antitumor activity in vitro and in vivo in human tumor xenografts.. The aim of this phase I study was to determine the optimal dosage and toxicity profile of bryostatin 1 and its influence on cytokine release in vivo.. Three successive cohorts consisting of 35 patients with various malignant tumors were treated with bryostatin 1 by intravenous infusion over 1 hour as follows: cohort A--35 micrograms/m2 (three patients) or 50 micrograms/m2 (eight patients) once every 2 weeks; cohort B--25 micrograms/m2 once a week (eight patients); and cohort C--25 micrograms/m2 once a week for 3 weeks, with no treatment during the 4th week (16 patients). Plasma levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) were measured by immunoradiometric assay and by radioimmunoassay, respectively.. The dose-limiting toxicity was grade 3 or 4 myalgia in four of 11 patients in cohort A, in two of eight in cohort B, and in none of 16 in cohort C. Occurrence of myalgia was dose related. There was no significant myelosuppression, apart from a small and transient fall in platelet count. Six patients experienced acute but transient skin flushing, dyspnea, hypotension, and bradycardia, probably related to the bryostatin 1 vehicle. TNF-alpha and IL-6 were detected in plasma at 2 and 24 hours after treatment, respectively, and the levels were dose related (P = .02). Two patients with metastatic malignant melanoma had partial remission after three or four cycles of therapy; remission lasted 6 weeks and 10+ months, respectively.. The dose-limiting toxicity of bryostatin 1 was myalgia. Plasma IL-6 and TNF-alpha concentrations were increased within 24 hours of therapy. Antitumor activity against malignant melanoma was observed early in the course of treatment.. The recommended dosage of bryostatin 1 for phase II studies is 25 micrograms/m2 by intravenous infusion for 1 hour once a week for 3 weeks, with no treatment in the 4th week. IL-6 and TNF-alpha plasma concentrations may be useful in monitoring biological activity of bryostatin 1. Future studies should explore use of this drug with other conventional immune modulators and conventional cytotoxic drugs.

Topics: Adult; Aged; Antineoplastic Agents; Bryostatins; Drug Administration Schedule; Female; Humans; Interleukin-6; Lactones; Macrolides; Male; Middle Aged; Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

Bryostatin 1 is a novel antitumour agent derived from Bugula neritina of the marine phylum Ectoprocta. Nineteen patients with advanced solid tumours were entered into a phase I study to evaluate the toxicity and biological effects of bryostatin 1. Bryostatin 1 was given as a one hour intravenous infusion at the beginning of each 2 week treatment cycle. A maximum of three treatment cycles were given. Doses were escalated in steps from 5 to 65 micrograms m-2 in successive patient groups. The maximum tolerated dose was 50 micrograms m-2. Myalgia was the dose limiting toxicity and was of WHO grade 3 in all three patients treated at 65 micrograms m-2. Flu-like symptoms were common but were of maximum WHO grade 2. Hypotension, of maximum WHO grade 1, occurred in six patients treated at doses up to and including 20 micrograms m-2 and may not have been attributable to treatment with bryostatin 1. Cellulitis and thrombophlebitis occurred at the bryostatin 1 infusion site of patients treated at all dose levels up to 50 micrograms m-2, attributable to the 60% ethanol diluent in the bryostatin 1 infusion. Subsequent patients treated at 50 and 65 micrograms m-2 received treatment with an intravenous normal saline flush and they did not develop these complications. Significant decreases of the platelet count and total leucocyte, neutrophil and lymphocyte counts were seen in the first 24 h after treatment at the dose of 65 micrograms m-2. Immediate decreases in haemoglobin of up to 1.9g dl-1 were also noted in patients treated with 65 micrograms m-2, in the absence of clinical evidence of bleeding or haemodynamic compromise. No effect was observed on the incidence of haemopoietic progenitor cells in the marrow. Some patients' neutrophils demonstrated enhanced superoxide radical formation in response to in vitro stimulation with opsonised zymosan (a bacterial polysaccharide) but in the absence of this additional stimulus, no bryostatin 1 effect was observed. Lymphocyte natural killing activity was decreased 2 h after treatment with bryostatin 1, but the effect was not consistently seen 24 h or 7 days later. With the dose schedule examined no antitumour effects were observed. We recommend that bryostatin 1 is used at a dose of 35 to 50 micrograms m-2 two weekly in phase II studies in patients with malignancies including lymphoma, leukaemia, melanoma or hypernephroma, for which pre-clinical investigations suggest antitumour activity.

Topics: Adult; Aged; Antineoplastic Agents; Bone Marrow; Bryostatins; Colonic Neoplasms; Colony-Forming Units Assay; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Killer Cells, Natural; Lactones; Leukocytes; Macrolides; Mesothelioma; Middle Aged; Neoplasms; Neutrophils; Ovarian Neoplasms; Phagocytosis; Sarcoma

New drug discovery continues to follow the time-honored paths of screening and novel target identification combined with analogue development and serendipity. The agents selected here reflect these various approaches. They include drugs already showing significant antitumor activity, eg, anthrapyrazoles, temozolomide, camptothecin analogues, and taxotere, and updated information is provided on their development. Other drugs just entering or currently in phase I trials include rhizoxin, which seems capable of overcoming multidrug resistance; the novel bioreductive agent EO9 [corrected]; and bryostatin, a highly potent protein kinase C agonist. Sequence specificity could well prove to be an important factor in the development of DNA-interactive agents, and information is provided on the progress with distamycin mustard and the new cyclopropylpyrroloindole analogues carzelesin and adozelesin.

Topics: Antineoplastic Agents; Bryostatins; Camptothecin; Docetaxel; Humans; Lactones; Macrolides; Neoplasms; Paclitaxel; Taxoids

Bryostatin 1 is a marine natural product under investigation for HIV/AIDS eradication, the treatment of neurological disorders, and enhanced CAR T/NK cell immunotherapy. Despite its promising activity, bryostatin 1 is neither evolved nor optimized for the treatment of human disease. Here we report the design, synthesis, and biological evaluation of several close-in analogs of bryostatin 1. Using a function-oriented synthesis approach, we synthesize a series of bryostatin analogs designed to maintain affinity for bryostatin's target protein kinase C (PKC) while enabling exploration of their divergent biological functions. Our late-stage diversification strategy provides efficient access to a library of bryostatin analogs, which per our design retain affinity for PKC but exhibit variable PKC translocation kinetics. We further demonstrate that select analogs potently increase cell surface expression of CD22, a promising CAR T cell target for the treatment of leukemias, highlighting the clinical potential of bryostatin analogs for enhancing targeted immunotherapies.

Topics: Bryostatins; Cell Line, Tumor; Humans; Immunotherapy; Leukemia; Models, Molecular; Neoplasms; Protein Kinase C; Sialic Acid Binding Ig-like Lectin 2; T-Lymphocytes

The 18-deoxy derivative (3) of a simplified analogue (1) of aplysiatoxin with antiproliferative activity was synthesized to examine the role of the phenolic hydroxyl group at position 18 in the biological activities of 1. Compound 3 as well as 1 showed significant affinity for protein kinase Cδ (PKCδ), and the antiproliferative activity of 3 was slightly higher than that of 1. However, the anti-tumor-promoting activity of 3 was less than that of 1 in vitro, suggesting that the phenolic hydroxyl group of 1 is necessary for the anti-tumor-promoting activity but not for the binding of PKCδ and antiproliferative activity. Moreover, PKC isozyme selectivity of 3 was similar to that of 1, suggesting non-PKC receptors for these compounds to play some roles in the anti-tumor-promoting activity of 1.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Humans; Hydroxyl Radical; Lyngbya Toxins; Neoplasms; Protein Kinase C

K-Ras associates with the plasma membrane (PM) through farnesylation that functions in conjunction with an adjacent polybasic sequence. We show that phosphorylation by protein kinase C (PKC) of S181 within the polybasic region promotes rapid dissociation of K-Ras from the PM and association with intracellular membranes, including the outer membrane of mitochondria where phospho-K-Ras interacts with Bcl-XL. PKC agonists promote apoptosis of cells transformed with oncogenic K-Ras in a S181-dependent manner. K-Ras with a phosphomimetic residue at position 181 induces apoptosis via a pathway that requires Bcl-XL. The PKC agonist bryostatin-1 inhibited the growth in vitro and in vivo of cells transformed with oncogenic K-Ras in a S181-dependent fashion. These data demonstrate that the location and function of K-Ras are regulated directly by PKC and suggest an approach to therapy of K-Ras-dependent tumors with agents that stimulate phosphorylation of S181.

Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Apoptosis; bcl-X Protein; Bryostatins; Cell Line; Cell Membrane; Genes, ras; Humans; Intracellular Membranes; Intracellular Signaling Peptides and Proteins; Macrolides; Membrane Proteins; Mice; Mice, Nude; Mitochondria; Molecular Sequence Data; Myristoylated Alanine-Rich C Kinase Substrate; Neoplasms; Protein Isoforms; Protein Kinase C; Recombinant Fusion Proteins; Serine; Signal Transduction; Static Electricity; T-Lymphocytes

Dendritic cells (DC) play a major role in priming naive T cells and modulating the immune response. We have previously reported that bryostatin-1, a potent immune modulator with antitumor activity, activates monocytes and lymphocytes to produce cytokines. Studies have shown that tumor-bearing hosts have a Th1/Th2 cytokine pattern that is associated with decreased production of IFN-gamma. We investigated the expression of IFN-gamma in bryostatin-1-treated human DC. Bryostatin-1 induced both IFN-gamma and T-bet mRNA expression in a dose- and time-dependent manner. As little as 1 ng/ml bryostatin-1 induced IFN-gamma and T-bet transcripts within 3 h and protein at 12 h. Treatment of DC with cycloheximide revealed that bryostatin-1-induced T-bet expression requires de novo protein synthesis, but bryostatin-1-induced IFN-gamma expression is independent of protein synthesis. Furthermore, dexamethasone inhibits bryostatin-1-induced IFN-gamma mRNA expression but increases bryostatin-1-induced T-bet mRNA expression. Experiments with ERK-1/2 inhibitors demonstrated that bryostatin-1 induction of IFN- gamma and T-bet was ERK-dependent and IL-12-independent. Similar results were obtained from both normal donors and cancer patients. In summary, our results suggest that bryostatin-1-induced IFN-gamma expression is T-bet independent. They also suggest for the first time that IFN- gamma and T-bet can be induced in human DC through an ERK-dependent pathway. Bryostatin-1-induced IFN- gamma may play a crucial role in the initiation of the immune response, before specific recognition by T cells that could be beneficial in the treatment of cancer.

Topics: Adjuvants, Immunologic; Antineoplastic Agents; Bryostatins; Cells, Cultured; Dendritic Cells; Gene Expression Regulation, Neoplastic; Humans; Interferon-gamma; Interleukin-12; Macrolides; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neoplasms; RNA, Messenger; T-Box Domain Proteins; Transcription Factors

Bryostatin-1 (Bryo-1), a protein kinase C modulator with antineoplastic activity, may exert some of its antitumor activity through activation of the immune response. Studies in tumor-bearing hosts have indicated that the T cell response, particularly IFN-gamma production, is impaired. To evaluate whether Bryo-1 plus IL-2 may affect the activation pattern of T cells, we investigated the expression of IFN-gamma mRNA and protein in human primary T cells. Northern blot analysis and ELISAs demonstrated that Bryo-1 and IL-2 synergized to induce both IFN-gamma mRNA and protein expression. This synergistic induction was seen within 3 h of treatment and with as little as 10 U/ml IL-2 and 1.0 ng/ml Bryo-1. In vitro transcription assays revealed that Bryo-1 plus IL-2 induced transcriptional activation of the IFN-gamma gene. Furthermore, mRNA stability studies indicated that this treatment also enhanced the IFN-gamma mRNA half-life. Both CD4(+) and CD8(+) T cells responded to the treatment with IFN-gamma expression. The induction of the IFN-gamma expression was decreased by a specific p38 mitogen-activated protein kinase inhibitor, but not by a protein kinase C inhibitor. Our results demonstrate for the first time that Bryo-1 in combination with IL-2 control IFN-gamma gene expression at both the transcriptional and post-transcriptional levels through a p38 mitogen-activated protein kinase-dependent process. Given the pivotal role that IFN-gamma plays in the orchestration of an effective Th1 type of response, our results suggest that Bryo-1 plus IL-2 may be a valuable combined therapy for cancer treatment.

Topics: Bryostatins; Cycloheximide; Dexamethasone; Drug Synergism; Humans; Interferon-gamma; Interleukin-13; Interleukin-2; Interleukin-4; Lactones; Macrolides; Mitogen-Activated Protein Kinases; Neoplasms; p38 Mitogen-Activated Protein Kinases; Protein Kinase C; RNA, Messenger; T-Lymphocytes

Topics: Antineoplastic Agents; Bryostatins; Clinical Protocols; Clinical Trials as Topic; Humans; Lactones; Leukemia; Lymphoma; Macrolides; Melanoma; Neoplasms; United States

Topics: Antineoplastic Agents; Bryostatins; Humans; Lactones; Macrolides; Neoplasms; Oceans and Seas