Spotlight

Authors

  • Caroline Seydel


Phorbol Esters Fight Pancreatic Cancer and Disulfide Bonds Improve Drug Delivery

Bond et al., pp. 1445–1454

Leamon et al., pp. 1585–1592

In a surprising twist, phorbol esters – generally known for their potent tumor promotion – were recently discovered to kill thyroid cancer cells expressing mutant RAS, yet leave normal cells alone. Seizing on the obvious therapeutic potential for the many tumors that express mutant RAS, Bond et al. have now pitted phorbol esters against pancreatic cancer cells and found that the chemicals killed these tumors, as well.

In addition to thyroid tumors, phorbol esters have been reported to act against prostate and gastric tumors, and now Bond et al., simultaneously with another, independently reported study, add pancreas to the list. The current work demonstrated that a single in vivo administration of phorbol ester causes widespread tumor cell death and prolonged cessation of tumor growth. In most of the 9 cell lines tested, the phorbol ester induced nonapoptotic cell death, apparently acting independently of protein kinase C – its “classic” target. Given the high incidence and mortality of pancreatic cancer, further investigation of phorbol ester activity as a therapeutic agent seems desirable.

The ability of folic acid to deliver covalently attached drugs to folate receptor (FR)-positive cells makes it an attractive courier for anticancer drugs. Many cancers, but few normal tissues, express very high levels of FR. Following up a recently reported folate-drug conjugate, EC140, Leamon et al. report a disulfide bond-containing counterpart to EC140, called EC145. The new conjugate appears more active and better tolerated than EC140 and will be further developed for clinical use.

The authors evaluated EC145 for specific antineoplastic activity both in cell culture and animal models. Like EC140, EC145 retained high affinity for FR-positive cells, and reduced tumor volume in both syngeneic and xenograft animal models. EC145 did not act against a FR-negative tumor model and appears to be a superior agent, possibly because the disulfide bond-containing linkers and more efficiently cleaved inside cells.

Three-Dimensional Model of Ovarian Cancer

Kenny et al., pp. 1463–1472

By developing a unique 3-D culture model, Kenny et al. have allowed a new look at the beginnings of ovarian cancer metastasis. They observed that mesothelial cells inhibit the attachment and invasion of ovarian cancer cells, while fibroblasts and ECM encourage their growth. The results could enhance understanding of the early stages of ovarian cancer metastasis.

Ovarian cancer preferentially metastasizes to the omentum, a fold of the peritoneum. Why this is so remains a mystery. Recent studies, though informative, have been limited by the types of cell cultures employed. For instance, most published studies have investigated metastasis to the abdominal peritoneum, assuming that the mechanisms involved in metastasis to the omentum are similar, yet this may not be the case. Kenny et al. created a 3-D model comprising primary human fibroblasts extracted from the omentum, mixed with extracellular matrix and covered by a layer of omental mesothelial cells. This model, they report, better reproduces a physiologically relevant microenvironment than earlier, two-dimensional monolayer cultures containing only one-type of cell.

By adding ovarian cancer cells to the 3D omental culture, the authors evaluated the contribution of various cell types and ECMs to the spread of ovarian cancer. The behavior of mesothelial cells, which fend off the cancer cells, remained consistent regardless of demographic factors or preparation. Once mesothelial cells are removed, ovarian tumor cells exhibit strong attachment to the ECM.

Sensitivity to Radiation in BRCA1 and BRCA2 Carriers

Barwell et al., pp. 1631–1636

Carriers of BRCA1 and BRCA2 mutations appear to be more sensitive to ionizing radiation than controls, according to new work by Barwell et al. Although the study evaluated women who had not yet been diagnosed with breast cancer, the findings could have implications for how BRCA1 and BRCA2 mutation carriers might go on to develop cancer.

The authors obtained peripheral blood lymphocytes from 26 BRCA1 and 18 BRCA2 mutation carriers and 38 controls matched for age and ethnicity. They exposed the blood cells to radiation and then looked for chromosome breaks and gaps. Women carrying BRCA1 and BRCA2 mutations developed significantly more breaks and gaps per cell than their matched controls. Mutation carriers did not differ from controls in their cell cycle kinetics or apoptotic responses of PBL after irradiation, which suggests that the increased radiosensitivity is likely the result of a defect in DNA repair. Previous studies, which have employed different assays for radiosensitivity, have suggested that BRCA1 mutations reduce the fidelity of DNA repair rather than induction and repair of DNA damage. Cells with two mutant copies of BRCA1 or BRCA2 lose the ability to repair DNA by homologous recombination, perhaps driving the cell to more frequent use of error-prone repair methods (such as nonhomologous end joining).

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