Biomedical subjects

Malcolm Mason

Publications and source records attributed to Malcolm Mason.

9 recordsLinked to original sources

PubMed2005

Anti-cancer ProTides: tuning the activity of BVDU phosphoramidates related to thymectacin.

Based on our wide ranging knowledge of phosphoramidate ProTides as anti-viral agents we have tuned the lead anti-cancer agent thymectacin in the ester and amino acid regions and revealed a substantial enhancement in in vitro potency versus colon and prostate cancer cell lines. Twelve analogues have been reported, with yields of 29-78%. The compounds are fully characterised and data clearly reveal the presence of two phosphate diastereoisomers, as expected, in roughly equi-molar proportions. The compounds were evaluated in tissue culture versus three different tumour cell lines, using thymectacin as the control. It is notable that minor structural modification of the parent phenyl methoxyalaninyl structure of thymectacin leads to significant enhancements in potency. In particular, replacement of the methyl ester moiety in the lead by a benzyl ester gave a 175-fold boost in potency versus colon cancer HT115. This derivative emerges as a low micromolar inhibitor of HT115 cells and a new lead for further optimisation.

Amides↗

PubMed2005

Assessment of immunological competence and SV40 specific recall immunity in malignant pleural mesothelioma.

Diffuse malignant pleural mesothelioma (MPM) is the third most common lung malignancy showing rising incidence with 250,000 deaths expected from it in Western Europe over the next 35 year. The tumour is generally resistant to conventional treatment and there is urgent need for novel preventative and therapeutic measures to combat this growing public threat. Finding of SV40 DNA sequences in a high proportion (40-90%) of several series of MPM cases, and suggestion of its potential co-carcinogen role provide a rationale for the development of novel anti-MPM vaccines incorporating SV40 gene sequences or antigenic determinants. As a prelude to adopting this approach, general T cell function was examined in relatively early cases of MPM presenting for biopsy or debulking surgery. CD8+ T cell responses were studied using antigenic epitopes of common viral antigens covering a broad range of haplotypes. 74.1% (20/27) of MPM patients and 80% (8/10) of the control subjects showed T cell responsiveness to the viral peptides mix, whilst a small proportion showed SV40 specific recall immunity.

Amino Acid Sequence↗

PubMed2004

A randomised trial of accelerated radiotherapy for localised invasive bladder cancer.

BACKGROUND AND PURPOSE: To evaluate the efficacy and toxicity of an accelerated fractionation regimen to treat localised muscle invasive bladder cancer. PATIENTS AND METHODS: A prospective randomised trial was undertaken in 229 patients randomised between 1988 and 1998 comparing accelerated fractionation (AF) to a dose of 60.8 Gy in 32 fractions over 26 days with conventional fractionation (CF) treating to 64 Gy in 32 fractions over 45 days. Accelerated fractionation was delivered using two fractions per day with a 6h gap between fractions and with the first daily fraction size being 1.8 Gy and the second daily fraction size being 2.0 Gy. There was a 1 week treatment gap after the first 12 fractions. Conventional fractionation was one fraction per day, 5 days per week. Eligible patients had clinical stage T2 or T3, N0 or N1, M0 transitional cell carcinoma. The primary endpoint of the trial was local control and the trial was powered to detect a 20% difference (alpha 0.05, power 90%). Secondary endpoints were toxicity and survival. RESULTS: In the initial phase of the trial, randomisation was unequal such that in total 129 patients were randomised to accelerated fractionation and 100 to conventional fractionation. Acute toxicity was evaluable in 121 patients treated with AF and 96 patients treated with CF. RTOG grade 2 or 3 bowel toxicity was noted in 44% of AF patients compared to 26% of CF patients (P trend =0.001). Acute grade 2 or 3 bladder toxicity was seen in 35% of AF patients compared to 36% of CF patients (P=0.99). Late radiation toxicity was evaluated in patients surviving free from local recurrence at 2 years post treatment. Late radiation toxicity equivalent to RTOG grade 2 or more had occurred in 44% (95% CI 34-55%) of AF patients and in 38% (95% CI 26-49%) of CF patients (logrank over 5 years follow-up P=0.23). There was no significant difference in analysis of time to loss of local tumour control comparing the two treatment arms; local recurrence was recorded in 29 of the 100 patients treated with CF and in 41 of 129 patients treated with AF (logrank P=0.86). There was also no significant difference between the treatment arms comparing disease-free survival and overall survival. The overall survival figures at 3 years were for AF 54% (95% CI 45-63%) and for CF 47% (95% CI 36-57%). By 5 years the overall survival was 37% for AF and 40% for CF. There were two treatment related deaths, both on the AF arm of the trial. CONCLUSIONS: This accelerated fractionation schedule did not improve on the efficacy of conventional fractionation for patients with T2 and T3 bladder cancer and accelerated fractionation was associated with increased acute bowel reactions.

Adult↗

PubMed2004

Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy - a systematic review of the randomised trials.

BACKGROUND: Recent randomised studies reported that single fraction radiotherapy was as effective as multifraction radiotherapy in relieving pain due to bone metastasis. However, there are concerns about the higher re-treatment rates and the efficacy of preventing future complications such as pathological fracture and spinal cord compression by single fraction radiotherapy. OBJECTIVES: To undertake a systematic review and meta-analysis of single fraction radiotherapy versus multifraction radiotherapy for metastatic bone pain relief and prevention of bone complications. SEARCH STRATEGY: Trials were identified through MEDLINE, EMBASE, Cancerlit, reference lists of relevant articles and conference proceedings. Relevant data was extracted. SELECTION CRITERIA: Randomised studies comparing single fraction radiotherapy with multifraction radiotherapy on metastatic bone pain DATA COLLECTION AND ANALYSIS: The analyses were performed using intention-to-treat principle. The results were pooled using meta-analysis to estimate the effect of treatment on pain response, re-treatment rate, pathological fracture rate and spinal cord compression rate. MAIN RESULTS: Eleven trials that involved 3435 patients were identified. Of 3435 patients, 52 patients were randomised more than once for different painful bone metastasis sites. Altogether, 3487 painful sites were randomised. The trials included patients with painful bone metastases of any primary sites, but were mainly prostate, breast and lung. The overall pain response rates for single fraction radiotherapy and multifraction radiotherapy were 60% (1059/1779) and 59% (1038/1769) respectively, giving an odds ratio of 1.03 (95% confidence interval [CI], 0.89 - 1.19) indicating no difference between the two radiotherapy schedules. There was also no difference in complete pain response rates for single fraction radiotherapy (34% [497/1441]) and multifraction radiotherapy (32% [463/1435]) with an odds ratio of 1.11 (95%CI 0.94-1.30). Patients treated by single fraction radiotherapy had a higher re-treatment rate with 21.5% (267/1240) requiring re-treatment compared to 7.4% (91/1236) of patients in the multifraction radiotherapy arm (odds ratio 3.44 [95%CI 2.67-4.43]). The pathological fracture rate was also higher in single fraction radiotherapy arm patients. Three percent (37/1240) of patients treated by single fraction radiotherapy developed pathological fracture compared to 1.6% (20/1236) for those treated by multifraction radiotherapy (odds ratio 1.82 [95%CI 1.06-3.11]). The spinal cord compression rates were similar for both arms (odds ratio 1.41 [95%CI 0.72-2.75]). Repeated analyses excluding dropout patients gave similar results. REVIEWERS' CONCLUSIONS: Single fraction radiotherapy was as effective as multifraction radiotherapy in relieving metastatic bone pain. However, the re-treatment rate and pathological fracture rates were higher after single fraction radiotherapy. Studies with quality of life and health economic end points are warranted to find out the optimal treatment option.

Bone Neoplasms↗

PubMed2004