Photodynamic therapy with mTHPC and polyethylene glycol-derived mTHPC: a comparative study on human tumour xenografts

The photosensitizing properties of m-tetrahydroxyphenylchlorin (mTHPC) and polyethylene glycol-derivatized mTHPC (pegylated mTHPC) were compared in nude mice bearing human malignant mesothelioma, squamous cell carcinoma and adenocarcinoma xenografts. Laser light (20 J/cm2) at 652 nm was delivered to the tumour (surface irradiance) and to an equal-sized area of the hind leg of the animals after i.p. administration of 0.1 mg/kg body weight mTHPC and an equimolar dose of pegylated mTHPC, respectively. The extent of tumour necrosis and normal tissue injury was assessed by histology. Both mTHPC and pegylated mTHPC catalyse photosensitized necrosis in mesothelioma xenografts at drug-light intervals of 1–4 days. The onset of action of pegylated mTHPC seemed slower but significantly exceeds that of mTHPC by days 3 and 4 with the greatest difference being noted at day 4. Pegylated mTHPC also induced significantly larger photonecrosis than mTHPC in squamous cell xenografts but not in adenocarcinoma at day 4, where mTHPC showed greatest activity. The degree of necrosis induced by pegylated mTHPC was the same for all three xenografts. mTHPC led to necrosis of skin and underlying muscle at a drug-light interval of 1 day but minor histological changes only at drug-light intervals from 2–4 days. In contrast, pegylated mTHPC did not result in histologically detectable changes in normal tissues under the same treatment conditions at any drug-light interval assessed. In this study, pegylated mTHPC had advantages as a photosensitizer compared to mTHPC

Expression of apoptosis regulatory proteins of the Bcl-2 family and p53 in primary resected non-small-cell lung cancer

Proteins of the Bcl-2 family as well as p53 are important regulators of apoptosis. Alterations in the expression of these proteins can contribute to the formation of cancer, as well as influence tumour response to chemo- and radiotherapy. We used antibodies specific for the human Bcl-2, Mcl-1, Bax, Bak and p53 proteins to examine the expression of these apoptosis-regulating genes in 49 archival specimens of patients with radically resected non-small-cell lung cancer (NSCLC). Tumour cells containing immunostaining for the antiapoptotic proteins Bcl-2 and Mcl-1 were present in 31% and 58% of the cases evaluated, respectively, whereas immunopositivity for the proapoptotic proteins Bax and Bak was found in 47% and 58% of the samples. p53 immunopositivity was detected in 61% of the samples. The expression of Bcl-2 and p53 and the expression of Mcl-1 and Bax showed a positive association (P= 0.02 and P= 0.06 respectively), whereas the expression of Bax was inversely related to p53 (P= 0.008). The expression of Bcl-2 had a negative influence on relapse-free survival in this population of primary resected NSCLC patients (P= 0.02). The expression of p53 and Bcl-2 was significantly associated with metastasis-free survival (P< 0.01). Only patients with p53-positive tumours developed metastases during the follow-up period. Our results establish the frequent expression of the Bcl-2 family proteins Bcl-2, Mcl-1, Bax and Bak in NSCLC. It can be expected that Bcl-2 family members have no straightforward impact on clinical outcome in this disease because their interactions in the regulation of apoptosis are complex. © 1999 Cancer Research Campaig

The role of dispersal in river network metacommunities: Patterns, processes, and pathways

1. River networks are hierarchical dendritic habitats embedded within the terrestrial landscape, with varying connectivity between sites depending on their positions along the network. This physical organisation influences the dispersal of organisms, which ultimately affects metacommunity dynamics and biodiversity patterns. 2. We provide a conceptual synthesis of the role of river networks in structuring metacommunities in relation to dispersal processes in riverine ecosystems. We explore where the river network best explains observed metacommunity structure compared to other measurements of physical connectivity. We mostly focus on invertebrates, but also consider other taxonomic groups, including microbes, fishes, plants, and amphibians. 3. Synthesising studies that compared multiple spatial distance metrics, we found that the importance of the river network itself in explaining metacommunity patterns depended on a variety of factors, including dispersal mode (aquatic versus aerial versus terrestrial) and landscape type (arid versus mesic), as well as location-specific factors, such as network connectivity, land use, topographic heterogeneity, and biotic interactions. The river network appears to be less important for strong aerial dispersers and insects in arid systems than for other groups and biomes, but there is considerable variability. Borrowing from other literature, particularly landscape genetics, we developed a conceptual model that predicts that the explanatory power of the river network peaks in mesic systems for obligate aquatic dispersers. 4. We propose directions of future avenues of research, including the use of manipulative field and laboratory experiments that test metacommunity theory in river networks. While field and laboratory experiments have their own benefits and drawbacks (e.g. reality, control, cost), both are powerful approaches for understanding the mechanisms structuring metacommunities, by teasing apart dispersal and niche-related factors. 5. Finally, improving our knowledge of dispersal in river networks will benefit from expanding the breadth of cost-distance modelling to better infer dispersal from observational data; an improved understanding of life-history strategies rather than relying on independent traits; exploring individual-level variation in dispersal through detailed genetic studies; detailed studies on fine-scale environmental (e.g. daily hydrology) and organismal spatiotemporal variability; and synthesising comparative, experimental, and theoretical work. Expanding in these areas will help to push the current state of the science from a largely pattern-detection mode into a new phase of more mechanistically driven research