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Biomedical subjects

G C Jayson

Publications and source records attributed to G C Jayson.

At least 37 records · Page 2Linked to original sources

Intra-tumoural microvessel density in human solid tumours.

Over the last decade assessment of angiogenesis has emerged as a potentially useful biological prognostic and predictive factor in human solid tumours. With the development of highly specific endothelial markers that can be assessed in histological archival specimens, several quantitative studies have been performed in various solid tumours. The majority of published studies have shown a positive correlation between intra-tumoural microvessel density, a measure of tumour angiogenesis, and prognosis in solid tumours. A minority of studies have not demonstrated an association and this may be attributed to significant differences in the methodologies employed for sample selection, immunostaining techniques, vessel counting and statistical analysis, although a number of biological differences may account for the discrepancy. In this review we evaluate the quantification of angiogenesis by immunohistochemistry, the relationship between tumour vascularity and metastasis, and the clinicopathological studies correlating intra-tumoral microvessel density with prognosis and response to anti-cancer therapy. In view of the extensive nature of this retrospective body of data, comparative studies are needed to identify the optimum technique and endothelial antigens (activated or pan-endothelial antigens) but subsequently prospective studies that allocate treatment on the basis of microvessel density are required.

Antibodies, Monoclonal↗

The clinical development of the bryostatins.

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.

Animals↗

Heparan sulfate proteoglycans and cancer.

Heparan sulfate proteoglycans (HSPGs) are widely distributed in mammalian tissues and involved in a number of processes related to malignancy. They are composed of a core protein to which chains of the glycosaminoglycan, heparan sulfate (HS), are attached. The existence of various classes of core protein, in addition to highly polymorphic HS chains, creates a superfamily of macromolecules with considerable diversity of structure and function. HSPGs interact with many proteins including growth factors, chemokines and structural proteins of the extracellular matrix to influence cell growth, differentiation, and the cellular response to the environment. The recent identification of two inherited syndromes that are associated with an increased cancer risk, and caused by mutations in HSPG-related genes, has intensified interest in these molecules. This review describes our current understanding of HSPGs in cancer and highlights new possibilities for therapeutic control.

Animals↗

A phase II trial of bryostatin 1 in patients with non-Hodgkin's lymphoma.

Bryostatin 1 is a naturally occurring macrocyclic lactone with promising antitumour and immunomodulatory function in preclinical and phase I clinical investigations. In this phase II study, 17 patients with progressive non-Hodgkin's lymphoma of indolent type (NHL), previously treated with chemotherapy, received a median of 6 (range 1-9) intravenous infusions of 25 microg/m(2) bryostatin 1 given once weekly over 24 hours. In 14 evaluable patients no responses were seen. Stable disease was attained in one patient for 9 months. The principal toxicities were myalgia and phlebitis. Treatment was discontinued early because of toxicity alone (phlebitis) in 2 patients, toxicity in addition to progressive disease in 3 patients (myalgia and phlebitis n = 2; thrombocytopenia n = 1) and progressive disease in 5 patients. The results fail to demonstrate efficacy of this regimen of bryostatin 1 in the treatment of NHL. In light of preclinical data that demonstrate synergy between bryostatin 1 and several cytotoxic agents and cytokines, clinical studies to investigate bryostatin 1 in combination are warranted. We also present data to demonstrate that central venous lines may be used in future studies to avoid phlebitis.

Adult↗

VEGF antagonists.

The majority of cancer have an absolute requirement for angiogenesis, the process by which new blood vessels are formed. The most potent angiogenic cytokine is vascular endothelial growth factor (VEGF) and there has been substantial research into the development of VEGF/VEGF receptor (VEGFR) antagonists. To date these strategies have included gene therapy techniques that deliver antisense oligonucleotides, soluble VEGFRs that function in a dominant negative fashion and ribozymes. Additional strategies have included the development of receptor tyrosine kinase (RTK) inhibitors and monoclonal antibodies (mAbs) directed against VEGF or the signalling receptor. The most promising agents appear to be the monoclonal anti-VEGF antibodies and the RTK inhibitors as these have demonstrated broad spectrum antitumour activity in vivo and single agent activity in early phase clinical trials in patients with advanced pre-treated breast and colorectal carcinoma and Kaposi's sarcoma. The RTK inhibitors are of particular interest as they can be administered by mouth. Collation of the early clinical trial data suggests that VEGF antagonists are largely well-tolerated but may be associated with vascular toxicities such as haemorrhage and thromboembolic events. Combination studies of chemotherapy and VEGF antagonists are underway but the benefit of these regimens will need to be established in adequately powered Phase III studies. Potentially these agents may play a role in the treatment of both early (adjuvant) and advanced cancer. The efficacy of the drugs will be explored in a number of non-malignant conditions including rheumatoid arthritis (RA), psoriasis, diabetic retinopathy and possibly as non-steroidal contraceptives but the overall clinical development of these agents can only be optimised if appropriate biological end points are identified and incorporated into clinical trials.

Adult↗

Metallothionein expression in epithelial ovarian cancer: effect of chemotherapy and prognostic significance.

BACKGROUND AND PURPOSE: Regimens containing platinum drugs continue to be amongst the most effective therapies for ovarian cancer. However, despite high initial response rates most patients relapse and die of their disease. Elevation of metallothionein has been implicated as a mechanism by which tumour cells become resistant to platinum anticancer drugs, although most of these studies have been carried out in vitro. This study was carried out to determine whether metallothionein expression was associated with response or survival in patients with epithelial ovarian cancer. METHODS: Metallothionein was determined by radioimmune assay using frozen ovarian tumour tissue taken either before or following cytotoxic chemotherapy. RESULTS: An increase in expression of metallothionein was seen in tumour tissue from patients who had undergone cytotoxic chemotherapy, although this did not attain significance. However, a preliminary study using biopsy material from the same patient, taken both before and after chemotherapy, showed a statistically significant increase in metallothionein. An analysis of these data showed that the level of metallothionein expression was not associated with survival or response. CONCLUSION: These data do not support the hypothesis that metallothionein expression is a determinant of response in ovarian cancer. There is some preliminary evidence from the study of paired samples which indicates that cytotoxic chemotherapy may increase metallothionein expression. An increase in metallothionein was also seen in the study using unmatched biopsies although this did not attain statistical significance, due in part to the large inter-patient variability in expression of this protein.

Adult↗

p53 and related proteins in epithelial ovarian cancer.

We conducted a retrospective immunohistochemical evaluation of the prognostic significance of the expression of p53 and the related proteins Bax, Bcl-2, growth arrest and DNA damage (Gadd45), murine double minute 2 (Mdm2) and p21(WAF1/CIP1) in chemonaive tumours taken from 66 patients with ovarian cancer. Ki-67 expression (a marker of cell proliferation) was also evaluated immunohistochemically, while apoptosis within malignant cells was determined with the terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling (TUNEL) assay. The expression of each of the following proteins was significantly associated in the tumours (P < 0.05 unless otherwise stated): Bax with Bcl-2 (P < 0.01); Bax with Mdm2; p21(WAF1/CIP1) with Gadd45 (P < 0.01); p21(WAF1/CIP1) with p53; p53 with Mdm2. Univariate analysis showed that expression of p53, Bax, bulk residual disease and International Federation of Gynecology and Obstetricians (FIGO) stage were all strongly correlated with response to chemotherapy (P < 0.01). Similarly, the FIGO stage and Ki-67 expression (P < 0.01), as well as pathological subtype and bulk residual disease (P < 0.05), were prognostic factors for disease progression. The FIGO stage and Ki-67 expression were significant prognostic factors for overall survival (P < 0.01), with Gadd45 expression and pathological subtype also significant (P < 0.05) in a univariate analysis. Multivariate analysis for response to chemotherapy showed that expression of p53, Bax and FIGO stage were all independent prognostic factors (P < 0.01). The FIGO stage was the most important independent prognostic factor for progression and survival on multivariate analysis (P < 0.01). However, Ki-67 expression was also an independent prognostic factor for disease progression (P < 0.05) and approached significance for survival (P = 0.055). Taken together, these data suggest that determination of Ki-67 expression could supplement established prognostic factors.

Adult↗

Randomised phase II study of cisplatin-etoposide versus infusional carboplatin in advanced non-small-cell lung cancer and mesothelioma.

BACKGROUND: A randomised phase II study was performed to compare standard combination chemotherapy containing cisplatin and etoposide with infusional carboplatin. PATIENTS AND METHODS: One hundred twenty patients with locally advanced/metastatic non-small-cell lung cancer or mesothelioma were enrolled. All were chemotherapy-naïve and had a Karnofsky performance status of > or = 50. Patients were randomised to either four cycles of bolus therapy of cisplatin 80 mg/m2 day 1, etoposide 120 mg/m2 day 1-3, or continuous infusion of carboplatin 100/mg/m2/week for six weeks. RESULTS: No patients on infusional therapy incurred grade 3-4 toxicity while in the bolus arm, grade 3 and grade 4 leucopenia occurred in 17% and 35% of patients, respectively. Grade 4 thrombocytopenia occurred in 8% of patients and there were two instances of grade 3 renal toxicity. No responses occurred in the pump arm. Eight of forty-six patients with non-small-cell lung cancer responded to treatment (response rate 17.3%) with two complete responses and six partial responses. Only one patient with mesothelioma responded to bolus therapy. There was no difference in survival for the subset of NSCLC patients. Survival for mesothelioma patients in the pump arm was superior but this was likely to be a result of early deaths in the bolus arm. CONCLUSIONS: The pump arm was well-tolerated but not active, whilst combination platinum-based therapy demonstrated activity but significantly more toxicity than the pump arm. Further studies of infusional carboplatin with this schedule are not warranted.

Adult↗

Prospective evaluation of oral mucositis in patients receiving myeloablative conditioning regimens and haemopoietic progenitor rescue.

Four hundred and twenty-nine patients received myeloablative chemotherapy for solid and haematological malignancies in a bone marrow transplantation unit. Regimens appropriate to the tumour type were administered and haemopoietic reconstitution was achieved with peripheral blood progenitor cells (PBPC; n = 275), autologous bone marrow (auto-BMT; n = 69) or allogeneic bone marrow (allo-BMT; n = 85). World Health Organization (WHO) oral mucositis scores were collected prospectively from the start of chemotherapy (d 1) until d 28 or discharge. Oral mucositis (OM) was experienced by 425 (99%) patients and in 289 (67.4%) this was grade III or IV. Strong opiate analgesia was prescribed for a median of 6 d to 47% of patients. Univariate analysis suggested that the area under the OM curve (AUC; sum of daily mucositis grades, d 1-28) was associated with the myeloablative regimen, haemopoietic progenitor source (PBPC > allo-BMT > auto-BMT), use of myeloid growth factors and age. Multivariate analysis showed that the only independent risk factor for mucositis was the conditioning regimen (P < 0.00005). The mean OM AUC for high-dose melphalan (HDM) regimens (52 grade-days) exceeded busulphan (41), busulphan-cyclophosphamide (35), cyclophosphamide-total body irradiation (TBI) (34), cyclophosphamide-carmustine (BCNU) (20) and cyclophosphamide-etoposide-carmustine (CVB) (19). HDM regimens resulted in the highest mean peak OM (3.6), followed by busulphan regimens (2.6), cyclophosphamide/TBI (2.3) and cyclophosphamide-carmustine and CVB (1.4). Busulphan produced significantly delayed OM (median 3 d; P < 0.00005). There was a linear association between the area under the OM curve for each treatment group and the time to reach grade 3 OM (P < 0.00005), but no association with the time to reach grade 4 neutropenia (P = 0.24) or thrombocytopenia (P = 0.73), implying that haematological and mucosal toxicity are not associated. The cytotoxic regimen is the most significant determinant of OM. Studies investigating agents to ameliorate mucosal toxicity should be stratified according to cytotoxic regimen.

Adolescent↗

Requirement for expert histopathological assessment of ovarian cancer and borderline tumors.

The distinction between borderline ovarian tumours (BOT) and ovarian carcinoma is made by histopathological assessment. Of 64 patients managed according to institutional BOT protocols, 27 (42%) had been referred with a diagnosis of ovarian carcinoma that was subsequently changed to BOT following histopathological review. The 70% 6-year event-free survival of the patients with a revised diagnosis was not significantly different from those who were referred with a diagnosis of BOT. This change in diagnosis is important as it avoids the need for chemotherapy for most patients and results in patients receiving appropriate information concerning prognosis. Interestingly, 24 patients (38.1%) reported a family history of epithelial cancer, a finding that has not been reported previously. Campaign

Adult↗

Coordinated modulation of the fibroblast growth factor dual receptor mechanism during transformation from human colon adenoma to carcinoma.

Basic fibroblast growth factor (bFGF) is dependent on heparan sulphate for its ability to activate the cell surface signal transducing receptor. We have investigated the FGF dual receptor mechanism in a novel model of the transformation from human colon adenoma to carcinoma in vitro. Reverse transcription-polymerase chain reaction showed that mRNA for FGF receptors 1 and 2 were expressed in both the adenoma and carcinoma cells whereas immunocytochemistry showed that the expression of the FGF R1 was reduced significantly in the carcinoma cells. We have reported previously that the composition and sequence of human colon adenoma and carcinoma heparan sulphate (HS) differ in a defined and specific manner. The functional significance of these changes was assessed by affinity co-electrophoresis, which showed that the affinity of adenoma HS for bFGF was 10-fold greater than that of the carcinoma HS (Kd 220 nM vs. 2493 nM, respectively). In addition, Northern studies of the expression of syndecan 1 and 4 mRNA showed that proteoglycan core protein expression was reduced significantly in the carcinoma cells. These findings were associated with a reduced biological response to bFGF in the carcinoma cells that could be partially reversed by the addition of exogenous heparin, suggesting that both the proteoglycan and signal transducing receptor control the cells' response to bFGF.

Adenoma↗

An audit of primary surgical treatment for women with ovarian cancer referred to a cancer centre.

Ovarian cancer is the commonest cause of gynaecological cancer death in the UK, and guidelines for initial surgery and staging of this disease are widely available. We report a retrospective audit of the surgical management of patients with newly diagnosed ovarian cancer referred to the Christie Cancer Centre in Manchester in 1996. The aim was to assess compliance with surgical guidelines. The authors found that the majority of patients (92%) presented via an outpatient clinic and for these individuals surgery was therefore elective. This mode of presentation should allow management by a small number of dedicated gynaecologists at each hospital, but up to seven consultants in each hospital performed surgery on a relatively small number of patients. Furthermore, less than half the patients underwent the recommended surgical procedure. Although some patients may have 'inoperable' disease, these data suggest that a greater compliance with national and international guidelines are required to provide an optimal level of care.

Adult↗

Heparan sulfate undergoes specific structural changes during the progression from human colon adenoma to carcinoma in vitro.

We report a detailed analysis of heparan sulfate (HS) structure using a model of human colon carcinogenesis. Metabolically radiolabeled HS was isolated from adenoma and carcinoma cells. The chain length of HS was the same in both cell populations (Mr 20,000; 45-50 disaccharides), and the chains contained on average of two sulfated domains (S domains), identified by heparinase I scission. This enzyme produced fragments of approximate size 7 kDa, suggesting that the S domains were evenly spaced in the intact HS chain. The degree of polymer sulfation and the patterns of sulfation were strikingly different between the two HS species. When compared with adenoma HS, the iduronic acid 2-O-sulfate content of the carcinoma-derived material was reduced by 33%, and the overall level of N-sulfation was reduced by 20%. However, the level of 6-O-sulfation was increased by 24%, and this was almost entirely attributable to an enhanced level of N-sulfated glucosamine 6-O-sulfate, a species whose data implied was mainly located in the mixed sequences of alternating N-sulfated and N-acetylated disaccharides. The results indicate that in the transition to malignancy in human colon adenoma cells, the overall molecular organization of HS is preserved, but there are distinct modifications in both the S domains and their flanking mixed domains that may contribute to the aberrant behavior of the cancer cell.

Adenoma↗

A randomized phase II trial of interleukin 2 and interleukin 2-interferon alpha in advanced renal cancer.

A randomized phase II trial was performed to compare the efficacy and toxicity of interleukin 2 (IL-2) with an IL-2 and interferon alpha (IFN-alpha) regimen for the treatment of metastatic renal carcinoma. Sixty patients with recurrent renal cell carcinoma (RCC) who had previously undergone a nephrectomy were randomized to receive three cycles of IL-2 or IL-2 with IFN-alpha2b. Eighteen MU of IL-2 were administered subcutaneously on Mondays-Fridays for 3 weeks out of 4. Those patients randomized to receive the combination received the same regimen of IL-2 with 9 MU of IFN-alpha2b subcutaneously on Mondays, Wednesdays and Fridays for 3 weeks out of 4. Thirty patients were randomized to receive each arm. Twenty-nine were evaluable in each arm. Twenty-two patients received three cycles of IL-2 but only 14 patients received three cycles of IL-2/IFN-alpha because of the greater toxicity of the combination. The principal toxicities included nausea, fatigue and fever. There were no complete responses in either arm and only two patients who were treated with IL-2 attained a partial response. Twelve patients in each arm had stable disease and 15 patients in the IL-2 arm and 16 patients in the IL-2/IFN-alpha arm progressed through treatment. There were no significant differences in survival. Ten patients who received IL-2 are alive with a median follow-up of 266 days, whereas six patients who received IL-2/IFN-alpha are alive after a median of 278 days. The median survival from the time of identification of metastatic disease is 444 days in the IL-2 arm and 381 days in the IL-2/IFN-alpha arm. The IL-2/IFN-alpha combination is more toxic than IL-2 alone and this resulted in a reduced number of cycles of treatment. However, the median survival of the two groups was the same, suggesting that further evaluation of the IL-2/IFN-alpha combination should be confined to large prospective randomized clinical trials.

Adult↗

The treatment of nephrotic syndrome caused by primary (light chain) amyloid with vincristine, doxorubicin and dexamethasone.

Three out of four patients with primary (light chain) amyloid nephrotic syndrome treated with vincristine, doxorubicin and dexamethasone (VAD) induction obtained a partial response and are alive in continuing remission at 4.1, 6.5 and 9.3 years. These preliminary results are of considerable interest and suggest that prospective evaluation of this regimen is warranted in patients with this condition.

Aged↗

Heparin oligosaccharides: inhibitors of the biological activity of bFGF on Caco-2 cells.

A number of growth factors, including members of the fibroblast growth factor (FGF) family - hepatocyte growth factor, vascular endothelial growth factor and heparin-binding epidermal growth factor - are dependent on heparan sulphate (HS) for biological activity mediated through their high-affinity signal-transducing receptors. This obligate requirement for HS prompted the search for antagonists of HS function that could be used as anti-growth factor drugs for the treatment of cancer. Basic FGF (bFGF) was the focus of this study. Caco-2, a human colon carcinoma cell line, was adapted to growth in serum-free medium so that investigation of its growth factor requirements for growth and migration could be performed in defined conditions (Jayson GC, Evans GS, Pemberton PW, Lobley RW, Allen T 1994, Cancer Res, 54, 5718-5723). This cell line multiplied and moved in a dose-dependent manner in response to bFGF. Here, we show that the mitogenic response to bFGF is dependent on the presence of heparan sulphate. A library of heparin oligosaccharides with uniform composition but variable length was generated [general formula [IdoA(2S)-GlcNS(6S)n], and oligosaccharides of defined lengths were tested for their ability to inhibit the biological activity of bFGF. While intact heparin and heparin-derived fragments of 12 monosaccharide units did not affect bFGF-induced cell division or bFGF-induced cell migration, octasaccharides and decasaccharides potently inhibited the bFGF-induced growth and migration responses. In particular, octasaccharides completely inhibited these biological activities at 10 microg ml-, a clinically achievable and tolerable concentration. This study shows that the length of an oligosaccharide determines its ability to block the biological activity of bFGF. The observation that the biological activity of cell-surface heparan sulphate can be antagonized in this way in a human carcinoma cell line suggests that oligosaccharides should be investigated further as anti-growth factor agents for the treatment of cancer. In addition, the results suggest that the clinical evaluation of low-molecular weight heparin (LMWH) as an anti-cancer agent might benefit from subfractionation of the LMWH, to remove oligosaccharides of 12 or more residues.

Animals↗