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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 levels, none showed an increase in these cytokines.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

Natural killer (NK) cell activity and lymphokine activated killer (LAK) cell cytotoxicity were measured in patients receiving recombinant interleukin 2 (rIL-2) and flavone acetic acid (FAA) for treatment of progressing metastatic melanoma. NK activity was increased in 23 of 26 patients and LAK activity induced in 13 of 26 patients. However, levels of cytotoxicity in the present study were not significantly greater than a previous study using rIL-2 alone. LAK cell precursors demonstrated by in vitro incubation of pretreatment lymphocytes with IL-2 and subsequent cytotoxicity were no different in the patients compared to normal controls. Analysis of cell surface phenotypes failed to reveal any significant changes in the cell populations examined, including IL-2R and Leu 19. Although five patients had tumour response, one being complete, there was no correlation with the immunological parameters examined.

The stability of cisplatin (DDP) solutions (1 and 1.6 mg/ml in saline-mannitol) in plastic infusion bags was studied for up to 14 days at 25° C, 37° C and 60° C. Small changes in the solution were observed, but no evidence of any decomposition product was seen. Some precipitation of DDP was seen in the 1.6-mg/ml solution at the lower temperatures. Fluid loss from the bags was significant at the higher temperatures.

One hundred and fifty-nine previously untreated patients with small cell lung cancer (SCLC), who were not eligible for intensive chemotherapy, were entered into a randomised study of intravenous (i.v.) doxorubicin and ifosfamide (with mesna) and oral etoposide. The i.v. drugs were given either by bolus therapy or by a continuous infusion (CI) pump over 7 days via a central venous line. Therapy was given for 6 weeks only. On weeks 1, 3 and 5 IV doxorubicin 35 mg m-2 was given with 5 days of oral etoposide 100 mg m-2 daily. On weeks 2, 4 and 6 IV ifosfamide 5 g m-2 was given with equidose mesna. The overall median survival was 25 weeks for patients in the bolus arm and 30 weeks for the CI therapy (P = 0.45). The overall response rate was 64% (18% complete response-CR) and 69% (30% CR) respectively (P = 0.13). The median WHO score for haematological toxicity was 4 for bolus therapy and 3 for CI therapy (P = 0.0007). Despite a trend for less supportive care for patients on CI therapy there were no significant differences in the use of i.v. antibodies and blood or platelet transfusions. There were fewer treatment delays due to myelotoxicity in the CI arm (P = 0.04). The median WHO score for non-haematological toxicity was 2 in both treatment groups. There was significantly less nausea (P = 0.037) but more mucositis (P = 0.01) in the CI arm. Weekly chemotherapy using CI treatment was as effective as bolus therapy. It was well accepted by patients. The assessment of quality of life in a subgroup of patients showed a statistically significant reduction in anxiety and depression for both groups of patients during therapy.

Bryostatin 1 is a novel macrocyclic lactone activator of protein kinase C (PKC) which has clinical potential as an anti-cancer agent. The mechanism of action of this agent is unknown, but protein kinase C has been implicated. In order to investigate this possibility, we have developed P388 sublines resistant to bryostatin 1, by continuous challenge of the parent cell line with increasing incremental concentrations of the drug over 4 months. Cell lines were established at monthly intervals yielding four sublines: P388/BR/A, which were removed at 1 month; P388/BR/B, obtained after 2 months; P388/BR/C, obtained after 3 months; and P388/BR/D, which were established after 4 months. All four P388/BR sublines show an equal degree of resistance to the growth inhibitory effects of bryostatin 1, with a relative resistance ratio (RR) IC50 of approximately 4,000. The ability of the cytosol of cells to phosphorylate PKC-specific substrate is decreased by 41% for BR/A, 57% for BR/B 80% for BR/C and 94% for BR/D compared with the parental cell line, even when grown in the absence of bryostatin 1 for up to 4 weeks. Similar decreases are seen for cytosolic phorbol ester binding and whole-cell PKC isoenzyme expression. All four P388/BR sublines show high and equal levels of cross-resistance to the PKC activatory phorbol ester, phorbol 12-myristate 13-acetate (PMA). There is no loss of resistance to either bryostatin 1 or PMA up to 3 months after termination of exposure of the sublines to bryostatin 1. There was no significant degree of cross-resistance to daunorubicin in the bryosatin 1-resistant cell lines, P388/BR/A, B, C or D, when compared with the parent cell line, P388.

This audit was designed to assess whether existing UK vaccination programmes mean that patients receiving chemotherapy are being vaccinated against influenza. One hundred and ten adult patients receiving chemotherapy at a south London tertiary referral centre were interviewed when they attended for their chemotherapy. Thirty‐six of the 110 (33%) patients had received their influenza vaccination at the time of the study. Vaccination rates were significantly higher in those patients older than 65 years (53% vs17%, p<0.001), and in those with co‐morbidities (49% vs25%, p<0.05). The vaccination rate in this at‐risk population is lower than the overall national uptake in those aged 65 and over. Those patients most likely not to receive their influenza vaccination are those who have no indication for vaccination other than the fact they are receiving chemotherapy. Increased awareness of the benefits of influenza vaccine and its safety is needed among general practitioners, patients and oncologists.

Between 11/88 and 1/95,44 patients (3_51 years, meidan 32) With AML in first remission underwent BMT from HLA-identical siblings after 110mg/m2melphalan and 950 cGy (n=6) or 1050 cGy (n=38) singlefraction TBI. Cyclosporine and methotrexate were used for GVHD prophylaxis. Myeloid engraftment was achieved in. all patients. Acute GVHD was seen in 34 patients (77%), and chrome GVHD m 12 of 29 (41%) of patients at risk. 14 (32%) patients died of toxieity 21–300 days (median 72) post-transplant; all had received 1050 cGy TBI (P=.072). 3 patients relapsed; 1 died of leukemia, and the other 2 are alive in CR with chronic GVHD after immunotherapy with donor cells±interferon-α. 25 patients are alive in continuous remission at 2_52 months (median 20); 6 with chronic GVHD requiting therapy. The overall survival is 66% (29/44). We conclude that melphalan-TBI is an active conditioning regimen for AML and pennits consistent alloengraftment. Although the toxicity is considerable, the risk of relapse is low. Decreasing the TBI to 950 cGy appears to have controlled the toxicity, but the experience is still limited and longer fullow-up is required to see if relapse rates increase.

Summary 159 “poor risk” patients with previously untreated small cell lung cancer were entered into a randomised study of intravenous bolus versus continuous infusion chemotherapy with doxorubicin on weeks 1,3,5 and ifosfamide with mesna on weeks 2, 4, 6. Oral etoposide was given on days 1–5, 15–19, and 29–33. There was no difference in response rate or survival. However, patients treated with continuous infusion therapy had significantly less haematological toxicity (P=0.0007), and less nausea and vomiting (P=0.03).

8 patients (20–50 years, median 36) relapsing 2–27 months (median 5) after BMT from HLA-matched sibling (n=3) or unrelated (n=3), or HLA-mismatched sibling (n=2) donors were treated with interferon-α (IFN) ± donor cells ± IL-2. The plan was to administer IFN alone first. 100% lymphoid cells and 0–90% myeloid cells were of donor origin at relapse. The diagnoses at BMT were: secondary AML (n=2), primary refractory AML (n=3; one relapsing after a previous allograft), AML in first remission (n=2), and ALL in refractory relapse (n=1). Marrow from mismatched donors (n=2) was depleted of T-cells. Response to immunotherapy was not evaluable in 2 patients who died of treatmentrelated toxicity. Of 6 responders, 2 relapsed and died of toxicity of further therapy, and 1 died of acute hepatic GVHD but with improvement in the clinical signs of the disease. Two other patients developed acute skin GVHD which resolved. 3 patients are alive in remission 2, 8 and 18 months after therapy; all with evidence of chronic GVHD. We conclude that remission can be attained after immunotherapy in acute leukemia relapsing post-allograft, and long-term survival may be achieved. IFN alone may have significant activity, especially with patient-donor HLA disparity (unrelated or mismatch).