Novel molecular and immunotherapeutic strategies for lung cancer

Lung cancer therapy in the future will be guided by specific characteristics of the individual tumor specimens. The molecular cancer phenotyping will allow for targeted approaches based on the amplification of oncogenes, lack of tumor suppressor genes, dysregulation of growth factors, and angiogenesis or matrix metalloproteinases. Specific immunotherapeutic approaches based on.     

Breast and cervical cancer survival: making sense of ‘league tables’

During 1998, the Department of Health proposed to use survival rates of cervical and breast cancer in the 1989/90 incidence cohort as indicators of care. Valid interpretation was of concern within Trent and the Trent Cancer Registry responded by performing additional analyses. Trent Cancer Registry registrations for 1989/90 were re-analysed and the stability of districts' ranks for that cohort was investigated using random simulation techniques. Stability of ranks across more recent cohorts was investigated and attempts made to use all available information.The Department of Health's analyses were confirmed by our re-analysis of the 1989/90 cohort: Rotherham residents appeared to have the "worst" survival for cervical cancer, and Sheffield residents for breast cancer, although not statistically significantly so. Random simulations indicated that ranks based on a single cohort are not stable: for example Sheffield (ranked tenth for 1-y breast cancer survival) was ranked third or better in 6% of randomisations. Ranks were also unstable across cohorts: for example Rotherham 1-y cervical cancer survival was ranked tenth for 1989/90, fifth for 1991/92 and tenth for 1993/94. Analysis of 3-y running averages provided better information than the league table approach. Most districts improved over time, to different degrees, and similar sized gaps remained between the "best" and the "worst" districts. This analysis illustrates the need to be circumspect when interpreting "league tables" based on a single year or cohort analysis. League tables are based on ranks: clearly a large difference in rank may reflect only trivial (ie medically unimportant) differences in actual outcome. Lack of a statistically significant difference in survival between two districts does not mean their survival is equivalent. Even for a common cancer, like breast cancer, rankings were unstable from cohort to cohort. At the Registry we propose to perform these trend analyses routinely in future, adjusting, when possible, for the effects of deprivation and stage at diagnosis.     

Preliminary screening of some traditional zulu medicinal plants for anti-inflammatory and anti-microbial activities

Aqueous and methanolic extracts from different parts of nine traditional Zulu medicinal plants, of the Vitaceae from KwaZulu-Natal, South Africa were evaluated for therapeutic potential as anti-inflammatory and anti-microbial agents. Of the twenty-nine crude extracts assayed for prostaglandin synthesis inhibitors, only five methanolic extracts of Cyphostemma natalitium-root, Rhoicissus digitata-leaf, R. rhomboidea-root, R. tomentosa-leaf/stem and R. tridentata-root showed significant inhibition of cyclo-oxygenase (COX-1). The extracts of R. digitata-leaf and of R. rhomboidea-root exhibited the highest inhibition of prostaglandin synthesis with 53 and 56%, respectively. The results suggest that Rhoicissus digitata leaves and of Rhoicissus rhomboidea roots may have the potential to be used as anti-inflammatory agents. All the screened plant extracts showed some degrees of anti-microbial activity against gram-positive and gram-negative microorganisms. The methanolic extracts of C. natalitium-stem and root, R. rhomboidea-root, and R. tomentosa-leaf/stem, showed different anti-microbial activities against almost all micro-organisms tested. Generally, these plant extracts inhibited the gram-positive micro-organisms more than the gram-negative ones. Several plant extracts inhibited the growth of Candida albicans while only one plant extract showed inhibitory activity against Saccharomyces cerevisiae. All the plant extracts which demonstrated good anti-inflammatory activities also showed better inhibitory activity against Candida albicans.     

The NCI Digital Divide Pilot Projects: Implications for cancer education

The National Cancer Institute (NCI) supported four innovative demonstration research projects, “The Digital Divide Pilot Projects”, to test new strategies for disseminating health information via computer to vulnerable consumers. These projects involved active research collaborations between the NCI’s Cancer Information Service (CIS) and regional cancer control researchers to field test new approaches for enhancing cancer communication in vulnerable communities. The projects were able to use computers to successfully disseminate relevant cancer information to vulnerable populations. These demonstration research projects suggested effective new strategies for using communication technologies to educate underserved populations about cancer prevention, control, and care.     

A double-blind placebo-controlled study of the effect of inhaled beclomethasone dipropionate for 2 years in patients with nonasthmatic chronic obstructive pulmonary disease

Treatment of chronic obstructive pulmonary disease (COPD) with inhaled and oral corticosteroids is common, although their exact role is unclear. Previous studies suggest these drugs may reduce decline in lung function in this group of patients. We report a study investigating the effect of inhaled beclomethasone diproprionate (BDP) on lung function and symptoms in a group of patients with COPD. Treatment was given for 2 years, and the decline in FEV₁ in individual patients calculated over this period. Ninety-eight patients were randomized for the study, 59 completing 2 years of treatment. Patients withdrawn had more severe airflow obstruction. Decline in FEV₁, measured both prior to and after bronchodilator, was less in patients receiving inhaled BDP, although the differences failed to reach statistical significance except in a subgroup of patients with more severe airflow obstruction. Exacerbation rates were also reduced by inhaled BDP, but again the differences failed to reach conventional levels of statistical significance. The results of this study are consistent with previous published work, but further insight into the long-term role of corticosteroids in COPD await the publication of large studies which have recently been completed. Although the changes seen in this study and others are numerically small, the rate of decline in FEV₁ returned to normal levels expected from age-related decline, and hence such treatment combined with other strategies may well have a significant role in the long-term treatment of this condition.     

Palliation of malignant dysphagia with laser therapy: predictability of results.

This study reports the results of 189 patients treated by laser therapy for malignant dysphagia. Ninety-one per cent of patients derived benefit from treatment, but the long-term survival rate was poor, with only 12 per cent of patients surviving for 6 months. Survival was not influenced by either tumour length, site or histological type. Patients with adenocarcinomas initially showed improved swallowing after laser treatment compared with those with squamous tumours, but this difference had disappeared by 2 months. The results of laser treatment were not influenced by either tumour length or site.     

Water-soluble, core-modified porphyrins as novel, longer-wavelength-absorbing sensitizers for photodynamic therapy. II. Effects of core heteroatoms and meso-substituents on biological activity.

Water-soluble, core-modified porphyrins were prepared and evaluated as sensitizers for photodynamic therapy (PDT). The addition of an aromatic aldehyde to 2,5-dilithiothiophene or -selenophene gave diol 3 as a nearly equimolar mixture of meso and d,l diastereomers, which gave a single diastereomer following careful recrystallization. The condensation of pyrrole with a diol 3 using catalytic BF(3)-etherate gave bispyrrolochalcogenophenes (4). Condensation of a diol 3 with 4 in the presence BF(3)-etherate gave 21,23-dichalcogenaporphyrins (5). 21-Thiaporphyrins (6) were prepared by condensation of a diol 3 with excess pyrrole and benzaldehyde in the presence of tetrachlorobenzoquinone and catalytic BF(3)-etherate. Sulfonation of 5 and 6 with concentrated sulfuric acid at 100 degrees C gave sulfonated derivatives 7-15. Bis-4-methoxy-21,23-dithiaporphyrins 5h and 5l were demethylated with BBr(3), and the resulting phenols were alkylated with ethyl bromoacetate. Saponification gave 21,23-dithiaporphyrin dicarboxylate salts 16 and 17. The 21,23-core-modified porphyrins gave band I absorption maxima (lambda(max) of 689-717 nm) at longer wavelengths than band I for the corresponding 21-core-modified porphyrins, but both classes had band I maxima at longer wavelengths than either TPPS(4) or Photofrin (lambda(max) of 630 nm for both). The core heteroatoms had little effect on either absorption maxima or quantum yields of singlet oxygen generation in 7-17. The meso substituents had a greater impact on absorption maxima. Compounds 7-17 were evaluated for phototoxicity against Colo-26 cells in culture using 4 J cm(-2) of 570-800 nm light. Compounds 8-12, 14, 16, and 17 gave a 50% cell kill in vitro at a lower concentration than Photofrin [5.7 mg (9 micromol)/kg]. Compounds 14, 16, and 17 gave a 50% cell kill with 4 J cm(-2) of light and submicromolar concentrations of sensitizer. Sensitizers 8 and 11 showed no toxicity or side effects in BALB/c mice observed for 90 days following a single intravenous injection of 10 mg/kg of sensitizer. Distribution studies show that sensitizer 8 accumulates in the tumors of BALB/c mice. PDT with 8 at 0.125 mg (0.13 micromol)/kg or 11 at 2.5 mg (2.5 micromol)/kg and 135 J cm(-2) of 694 nm light was comparable to PDT with Photofrin at 2.5 mg (4 micromol)/kg and 135 J cm(-2) of 630 nm light against Colo-26 tumors in BALB/c mice.     

Cardioactive neuropeptide Phe-Met-Arg-Phe-NH2 (FMRFamide) and novel related peptides are encoded in multiple copies by a single gene in the snail Lymnaea stagnalis

The neuropeptide Phe-Met-Arg-Phe-NH2 (FMRFamide) is a potent cardioactive neuropeptide in Lymnaea stagnalis. Isolation and sequencing of 2 cDNAs and a genomic clone shows that a single gene encodes a precursor protein which contains 9 copies of the FMRFamide peptide, 2 copies of the related peptide Phe-Leu-Arg-Phe-NH2 (FLRFamide), and single copies of the putative pentapeptides Gln-Phe-Tyr-Arg-lle-NH2 (posttranslationally modified to pQFYRlamide) and Glu-Phe-Leu-Arg-lle-NH2 (EFLRlamide). The gene is transcribed in the CNS and gives rise to a single RNA of 1.7 kb in size. The organization of the Lymnaea gene is significant with respect to the evolution of FMRFamide and related peptides in other organisms.