Aspirin and other nonsteroidal anti-inflammatory drugs prevent some cases of colon cancer by inhibiting prostaglandin (PG) synthesis. PGE 2 promotes colon neoplasia, as shown by knockout mouse studies on enzymes and receptors in the PG cascade. A few experiments 20 to 30 years ago suggested that PGD 2 may suppress tumors, but a role for biosynthetic enzymes for PGD 2 in tumor development has not been studied. We report here that disruption of the gene for hematopoietic PGD synthase in Apc Min/+ mice led to f50% more intestinal adenomas compared with controls. Tumor size was not affected. By immunohistochemistry, we detected hematopoietic PGD synthase mainly in macrophages and monocytes of the gut mucosa. The mean number of tumors did not increase with knockout of the gene for the lipocalin type of the enzyme, which is not produced in the intestine. On the other hand, ApcMin/+ mice with transgenic human hematopoietic PGD synthase tended to have 80% fewer intestinal adenomas. The transgene produced high mRNA levels (375-fold over endogenous). There was a suggestion of higher urinary excretion of 11B-PGF 2A and a lower excretion of a PGE 2 metabolite in transgenic mice, but differences (30-40%) were not statistically significant. The results support an interpretation that hematopoietic PGD synthase controls an inhibitory effect on intestinal tumors. Further studies will be needed to prove possible mechanisms, such as routing of PG production away from protumorigenic PGE 2 or inhibition of the nuclear factor-KB cascade by PGD 2 metabolites. [Cancer Res 2007;67(3):881-9]
Intestinal tumors in ApcMin/+ mice are suppressed by over-production of HPGDS, which is a glutathione transferase that forms prostaglandin D2 (PGD2). We characterized naturally occurring HPGDS isoenzymes, to see if HPGDS variation is associated with human colorectal cancer risk. We used DNA heteroduplex analysis and sequencing to identify HPGDS variants among healthy individuals. HPGDS isoenzymes were produced in bacteria, and their catalytic activities were tested. To determine in vivo effects, we conducted pooled case-control analyses to assess whether there is an association of the isoenzyme with colorectal cancer. Roughly 8% of African Americans and 2% of Caucasians had a highly stable Val187lle isoenzyme (with isoleucine instead of valine at position 187). At 37 °C, the wild-type enzyme lost 15% of its activity in one hour, whereas the Val187Ile form remained >95% active. At 50 °C, the half life of native HPGDS was 9 minutes, compared to 42 minutes for Val187Ile. The odds ratio for colorectal cancer among African Americans with Val187Ile was 1.10 (95% CI, 0.75–1.62; 533 cases, 795 controls). Thus, the Val187Ile HPGDS isoenzyme common among African Americans is not associated with colorectal cancer risk. Other approaches will be needed to establish a role for HPGDS in occurrence of human intestinal tumors, as indicated by a mouse model.
The dispersion of single‐walled carbon nanotubes (SWNTs) in a non‐polar solvent is controlled with a series of polystyrene‐block‐polybutadiene‐block‐polystyrene (PSBS) block copolymers that contain cholesteryl chloroformate (CC) in side‐chains. Esterification of CC with the partially hydroxylated polybutadiene (PB) blocks allows one to tune the polarity of the block copolymers, which decreases with the amount of CC attached. An excellent dispersion of weak polar SWNTs is observed with PSBS that contains a partially hydroxylated PB block. The dispersion is then significantly deteriorated when the amount of non‐polar CC moieties increases in the block copolymers. A good dispersion is achieved with a polymer that gives rise to strong SWNT–polymer interactions, which ensures contact of the polymer molecules with the nanotube surface, rather than a good solubility of the polymer dispersant in solvent. The stability of the SWNTs in solution arises from unique needle‐like nanowires of the block copolymer aligned perpendicular to the nanotube axis.
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