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Biomedical subjects

S R Johnston

Publications and source records attributed to S R Johnston.

At least 19 recordsLinked to original sources
PubMed2005

Consensus statement. Workshop on therapeutic resistance in breast cancer: impact of growth factor signalling pathways and implications for future treatment.

Anti-hormones (notably tamoxifen), chemotherapy and modern radiotherapeutic approaches are invaluable in the management of breast cancer, and collectively have contributed substantially to the improved survival in this disease. Moreover, there is promise that these successes will continue with the emergence of other endocrine agents (for example, aromatase inhibitors and pure anti-oestrogens). However, de novo and acquired resistance comprises a significant problem with all treatment approaches examined to date. This Workshop aimed to evaluate the contribution made by growth factor signalling pathways in the various resistant states, primarily focusing on resistance to anti-hormonal strategies and spanning experimental models and, where possible, clinical breast cancer data. The successes and limitations of therapeutic targeting of these pathways with various signal transduction inhibitors (STIs) were evaluated in model systems and from emerging clinical trials (including epidermal growth factor receptor inhibitors such as gefitinib). It was concluded that growth factor signalling is an important contributor in the development of endocrine resistance in breast cancer and that use of STIs provides a promising therapeutic strategy for this disease. However, the cancer cell is clearly able to harness alternative growth factor signalling pathways for growth and cell survival in the presence of STI monotherapy and, as a consequence, the efficacy of STIs is likely to be limited by the acquisition of resistance. A number of strategies were proposed from studies in model systems that appeared to enhance anti-tumour actions of existing STI monotherapy, notably including combination therapies targeting multiple pathways. With the increased availability of diverse STIs and improved drug delivery, there is much hope that the more complex therapeutic strategies proposed may ultimately be achievable in clinical practice.

Breast Neoplasms↗
PubMed2001

Non-invasive antidromic neurostimulation: a simple effective method for improving bladder storage.

Patients with intractably diminished bladder storage function are encountered frequently by neurourologists, occasionally requiring reconstructive surgery for appropriate resolution. Although sacral neuromodulation is a recognized effective therapeutic modality, present techniques are technically demanding, invasive, and expensive. This study investigated the effect of non-invasive third sacral nerve (S3) stimulation on bladder activity during filling cystometry. One hundred forty-six patients underwent standard urodynamic filling cystometry that was then immediately repeated. Patients in the study group (n = 74) received antidromic transcutaneous sacral neurostimulation during the second fill and the control group (n = 72) underwent a second fill without neurostimulation. A statistically significant increase in bladder storage capacity without a corresponding rise in detrusor pressure was observed in the neurostimulated patients. This improvement in functional capacity is an encouraging finding that further supports the use of this non-invasive treatment modality in clinical practice.

Adolescent↗
PubMed2001

Caelyx: phase II studies in ovarian cancer.

While there have been significant advances in first-line chemotherapy for advanced ovarian cancer, most patients still relapse with drug-resistant disease. For patients refractory to the two most active agents (platinum and paclitaxel), there are few salvage regimens that possess significant clinical activity together with minimal treatment-related toxicities. Caelyx is a new treatment for advanced ovarian cancer, which delivers doxorubicin encapsulated in long-circulating Stealth liposomes, resulting in a prolonged circulation and enhanced tumour targeting of the drug, together with a markedly different safety profile compared with native doxorubicin. Recent phase II clinical trials in relapsed ovarian cancer have demonstrated efficacy in patients with platinum-refractory disease (defined as progression on or relapse within 6 months of previous therapy). In those with combined platinum/paclitaxel-refractory disease, the response rate was 14.5% (95% Confidence Interval (CI): 7.8-21.4%), with many patients demonstrating a prolonged duration of response of beyond 6 months. The most frequent severe (grade 3/4) toxicity with Caelyx was palmar-plantar erythrodysesthesia (PPE), which occurred in 25% of patients and was managed by dose modification or lengthening the treatment cycle. The incidence of neutropenia and alopecia was much reduced, and the cardiac safety profile was also improved compared with equivalent cumulative anthracycline doses for native doxorubicin. In summary, the evidence of clinical efficacy in patients with platinum-refractory ovarian cancer together with an improved safety profile are all strongly supportive of a positive benefit-risk profile for Caelyx in the treatment of advanced ovarian cancer following failure of first-line platinum-based therapy

Antineoplastic Agents↗
PubMed2001

Farnesyl transferase inhibitors: a novel targeted tnerapy for cancer.

Activating oncogenic mutations of the RAS gene are common in cancer, occurring in 30% of solid tumours in adults. Inhibitors of the enzyme farnesyl protein transferase prevent a key step in the post-translational processing of the RAS protein, and were developed initially as a therapeutic strategy to inhibit cell signalling in RAS-transformed cells. As more has been learnt about the biological effects of farnesyl transferase inhibitors on cancer cells, it has become increasingly clear that tumours without oncogenic RAS mutations may also be targets for farnesyl transferase inhibitor therapy. Encouraging results from phase I and II clinical trials have emerged, creating both enthusiasm and new challenges for the optimum clinical development of this important new class of anticancer drug.

Alkyl and Aryl Transferases↗
PubMed2001

Recurrent locally advanced breast cancer: the treatment of chest wall disease with further chemotherapy.

Locally recurrent advanced breast cancer is associated with significant morbidity and one aim of treatment is to control chest wall disease. There are no published data on the efficacy of subsequent courses of chemotherapy in this setting. We reviewed the case notes of 22 patients who developed locally recurrent breast cancer despite having received previous surgery, radiotherapy and one prior course of chemotherapy for local disease. These patients were treated with further systemic chemotherapy in an attempt to palliate their symptoms and control recurrent disease. The overall objective response rate observed with chemotherapy was 26% and a further 45% had stabilization of disease during treatment. Time to progression of disease was longest with anthracycline-based regimens; this decreased with subsequent lines of treatment. Chemotherapy was a safe and effective treatment modality in the care of women with locally recurrent breast cancer. A prospective database will now be established to collect further information on this group of patients, including their quality of life.

Adult↗
PubMed2001

Ischemia-reperfusion injury after relief of ureteral obstruction: an animal study.

BACKGROUND AND PURPOSE: The complex series of pathophysiologic alterations associated with obstruction nephropathy includes renal ischemia. Free-radical production follows relief of obstruction. We sought to determine whether free radicals caused additional reduction in blood flow after relief of obstruction. MATERIALS AND METHODS: In White-Landrace pigs, the left ureter was divided 6 cm distal to the ureteropelvic junction, and a nephrostomy tube was passed into the renal pelvis and exteriorized. A catheter was placed in the renal vein and exteriorized. Mean renal blood flow was measured before manipulation and during and after 6 hours of obstruction in animals receiving (N = 7) or not receiving (N = 7) allopurinol. The control groups were not subjected to ureteral obstruction and received (N = 7) or did not receive (N = 7) allopurinol. Free radicals in venous blood were measured by the Fox-1 assay for lipid peroxidation. RESULTS: After obstruction, renal blood flow declined significantly by the sixth hour (-28.73% +/- 1.81). The increase after relief of obstruction was only temporary, and by the third hour, the blood flow was again reduced (-20.14% +/- 2.67). Free radical production was significantly increased, with a peak of +24.63% being found 60 minutes after relief of obstruction. Allopurinol prevented free radical production after relief of obstruction and was associated with a return of blood flow to baseline values. CONCLUSION: Free radicals contribute to renal blood flow reduction after relief of ureteral obstruction. Functional impairment may be preventable by free radical blockade, but further studies are required to confirm this hypothesis.

Allopurinol↗
PubMed2001

Antisense Bcl-2 oligonucleotide uptake in human transitional cell carcinoma.

OBJECTIVES: Antisense oligonucleotides (AO) downregulate Bcl-2 protein expression in various tumours if good target cell uptake is achieved. In this study, uptake of FITC labelled AO (FITC-AO) directed at Bcl-2 was examined in: (1) the RT4 bladder tumour cell line; (2) normal pig urothelium, and (3) human superficial bladder tumours. METHODS: In the RT4 cell line, uptake of FITC-AO, FITC-scrambled and FITC-sense oligonucleotides were quantified by flow cytometry at 4-hour intervals over 24 h. Uptake of FITC-AO was assessed in normal pig urothelium by flow cytometry after FITC-AO was infused for 1 h. Uptake of FITC AO was assessed in samples from 14 human superficial bladder tumours which were maintained in an ex vivo model. In samples from 6 tumours, uptake at 4 h was assessed using fluorescence microscopy. In samples from 8 separate tumours uptake every 4 h within the first 24-hour incubation period was assessed by flow cytometry. RESULTS: In the RT4 cell line the FITC-AO, FITC-scrambled and FITC-sense oligonucleotide uptake was similar. Disaggregated cells from the normal urothelium of the 3 pigs exhibited 33, 46 and 51% of cells staining positively for FITC-AO as determined by flow cytometry. All 6 tumour samples had detectable intracellular FITC-AO by fluorescence microscopy at 4 h. In the 8 tumours examined over the 24-hour incubation period, there was a range of percentages of positively staining cells. However, most tumours had a monotonic increase in intracellular fluorescence intensity that plateaued 16 h post-infusion. CONCLUSION: Antisense Bcl-2 oligonucleotides were readily taken up by superficial bladder cancer cells but the heterogeneous uptake in tumour samples needs to be considered when assessing the bioavailability of these drugs.

Animals↗
PubMed2001

Caelyx: treatment for relapsing ovarian cancer.

Although there have been significant improvements in the first-line treatment of ovarian cancer, the options for patients who relapse have been limited. Caelyx is a new treatment using long-circulating liposomes to target delivery of doxorubicin to the tumour. This article reviews the treatment of ovarian cancer and looks at the place of Caelyx as a new second-line treatment option.

Antineoplastic Agents↗
PubMed2001

Systemic treatment of metastatic breast cancer.

This article reviews recent advances in the treatment of metastatic breast cancer, in particular the results of randomized controlled phase III clinical trials. These have led to the evidence-based introduction of several new drugs including aromatase inhibitors, taxanes and bisphosphonates, some of which have been shown to impact on overall survival.

Antibiotics, Antineoplastic↗
PubMed2001

Farnesyl transferase inhibitors--a novel therapy for breast cancer.

Inhibitors of the enzyme farnesyl protein transferase prevent a key step in the post-translational processing of the Ras protein, and were developed initially as a therapeutic strategy to inhibit cell signalling in ras-transformed cells. As more has been learnt about the biological effects of farnesyl transferase inhibitors (FTIs) on cancer cells, it is clear that tumours without oncogenic ras mutations such as breast cancer may also be targets for FTI therapy. This article reviews the rationale for the development of FTIs, focussing on early preclinical data in breast cancer models together with preliminary results from the first phase II study of an FTI in advanced breast cancer.

Alkyl and Aryl Transferases↗
PubMed2001

The effect of antisense Bcl-2 oligonucleotides on Bcl-2 protein expression and apoptosis in human bladder transitional cell carcinoma.

PURPOSE: Bcl-2 is an important determinant of transitional cell carcinoma of the bladder recurrence and progression as well as a factor in patient response to chemotherapy or radiotherapy. We determined Bcl-2 down-regulation after antisense oligonucleotide therapy and synergism with mitomycin C in transitional cell carcinoma of the bladder. MATERIALS AND METHODS: Bcl-2 protein was quantified using flow cytometry and immunohistochemistry in 4 bladder cancer cell lines, in bladder washings from 6 patients with carcinoma in situ and in 16 patient tumor samples. The synergistic effects of antisense oligonucleotides G3139 and 2009, and mitomycin C were investigated in 4 cell lines, while 2009 down-regulation was examined in 20 tumor explants in an ex vivo model. RESULTS: Bcl-2 protein expression was found in all 4 cell lines and in 5 of the 6 cell populations derived from patients with carcinoma in situ. Of the 16 tumors 7 were classified positive by frozen section immunohistochemistry and quantitative flow cytometry. G3139 and 2009 down-regulated Bcl-2 protein expression in all 4 cell lines and 2009 down-regulated Bcl-2 protein expression in half of the Bcl-2 positive tumor specimens. There was only evidence in 1 cell line, T24/83, that Bcl-2 protein expression down-regulation enhanced mitomycin C induced apoptotic cell death. CONCLUSIONS: Bcl-2 was expressed in a significant proportion of bladder tumors and in carcinoma in situ. Therefore, antisense oligonucleotides represent a viable strategy for Bcl-2 protein down-regulation. However, it may not always translate into an increased level of mitomycin C induced apoptosis in transitional cell carcinoma of the bladder.

Apoptosis↗
PubMed2001

Preclinical antitumor activity and pharmacodynamic studies with the farnesyl protein transferase inhibitor R115777 in human breast cancer.

Antitumor and pharmacodynamic studies were performed in MCF-7 human breast cancer cells and companion xenografts with the farnesyl protein transferase inhibitor, R115777, presently undergoing Phase II clinical trials, including in breast cancer. R115777 inhibited growth of MCF-7 cells in vitro with an IC(50) of 0.31 +/- 0.25 microM. Exposure of MCF-7 cells to increasing concentrations of R115777 for 24 h resulted in the inhibition of protein farnesylation, as indicated by the appearance of prelamin A at concentrations >1 microM. After continuous exposure to 2 microM R115777, prelamin A levels peaked at 2 h post drug exposure and remained high for up to 72 h. R115777 administered p.o. twice daily for 10 consecutive days to mice bearing established s.c. MCF-7 xenografts induced tumor inhibition at a dose of 25 mg/kg [percentage of treated versus control (% T/C) = 63% at day 21]. Greater inhibition was observed at doses of 50 mg/kg (% T/C at day 21 = 38%) or 100 mg/kg (% T/C at day 21 = 43%). The antitumor effect appeared to be mainly cytostatic with little evidence of tumor shrinkage to less than the starting volume. Tumor response correlated with an increase in the appearance of prelamin A, but no changes in the prenylation of lamin B, heat shock protein 40, or N-Ras were detectable. In addition, significant increases in apoptotic index and p21(WAF1/CIP1) expression were observed, concomitant with a decrease in proliferation as measured by Ki-67 staining. An increase in prelamin A was also observed in peripheral blood lymphocytes in a breast cancer patient who responded to R115777. These data show that R115777 possesses preclinical antitumor activity against human breast cancer and that the appearance of prelamin A may provide a sensitive and convenient pharmacodynamic marker of inhibition of prenylation and/or response.

Alkyl and Aryl Transferases↗
PubMed2001

Endocrine manipulation in advanced breast cancer: recent advances with SERM therapies.

Tamoxifen is one of the most effective treatments for breast cancer through its ability to antagonize estrogen-dependent growth by binding estrogen receptors (ERs) and inhibiting breast epithelial cell proliferation. However, tamoxifen has estrogenic agonist effects in other tissues such as bone and endometrium because of liganded ER-activating target genes in these different cell types. Several novel antiestrogen compounds have been developed that are also selective ER modulators (SERMs) but that have a reduced agonist profile on breast and gynecological tissues. These SERMs offer the potential for enhanced efficacy and reduced toxicity compared with tamoxifen. In advanced breast cancer clinical data exist for three first-generation SERMs (toremifene, droloxifene, idoxifene), which are related to the triphenylethylene structure of tamoxifen. In Phase II trials in a total of 263 patients resistant to tamoxifen, the median objective response rate to these SERMs was only 5% (range, 0-15%), with stable disease for > or =6 months in an additional 18% (range, 9-23%). As first-line therapy for advanced breast cancer, the median response rate was 31% (range, 20-68%) with a median time to progression of 7 months. Randomized Phase III trials for toremifene and idoxifene in more than 1500 patients showed no significant difference compared with tamoxifen. Fewer clinical data exist for the structurally distinct second- and third-generation SERMs (raloxifene, arzoxifene, EM-800, and ERA-923), although a similarly low median response rate of 6% (range, 0-14%) was seen in Phase II trials in tamoxifen-resistant patients. It remains unclear whether any clinical advantage exists for second- and third-generation SERMs over tamoxifen as first-line therapy. With the emergence of potent aromatase inhibitors (AIs) that are superior to tamoxifen, the clinical questions in advanced disease have shifted to which antiestrogen (including SERMs) may be effective following failure of AIs, and whether any merit exists for combined AI/SERM therapy. The main advantage for SERM therapy probably remains in early stage-disease (adjuvant therapy or prevention), in which the estrogenic effects on bone and reduced gynecological side effects may prove more beneficial than either tamoxifen or AI. The issue is whether the current clinical data for SERMs in advanced breast cancer are sufficiently strong to encourage that further development.

Adenocarcinoma↗