© 2004 by Oxford University Press
© 2004 Oxford University Press
IN THIS ISSUE |
In This Issue
Fruits and Vegetables and Chronic Disease RiskDietary recommendations call for the consumption of at least five servings of fruits and vegetables a day to reduce the risk of cancer and cardiovascular disease. However, the data supporting these recommendations have come mainly from case-control studies. Hung et al. (p. 1577) investigated the association between fruit and vegetable consumption and risk of major chronic disease by analyzing data from two large prospective cohorts with more than a decade of follow up. For men and women combined, participants in the highest quintile of total fruit and vegetable intake had a modest and statistically non-significant reduction in the risk of major chronic disease. Increased fruit and vegetable consumption was associated with a reduced risk of cardiovascular disease but not with a reduction in risk of cancer. The authors note that their results support the dietary recommendations but suggest that the cancer-protective effect of fruits and vegetables may have been overestimated.
In an editorial, Schatzkin and Kipnis (p. 1564) discuss the possibility that error in assessing diet and other potential confounding factors may have attenuated, especially in multivariate analysis, a true association between fruit and vegetable intake and cancer risk, if such an association exists. They discuss several approaches to addressing potential exposure assessment problems.
Cytochrome P450 3A4 Phenotyping and Irinotecan
Irinotecan has been approved for treatment of colorectal cancer, but the response to irinotecan is variable. Because inter-individual variation in enzymes that metabolize irinotecan, such as cytochrome P450 3A4 (CYP3A4) and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), may account for this variability, Mathijssen et al. (p. 1585) explored the relationships between the CYP3A4 phenotype, as assessed by erythromycin metabolism and midazolam clearance, and irinotecan metabolism. They found that erythromycin metabolism varied sevenfold among patients and was not associated with irinotecan metabolism but that midazolam clearance varied fourfold and was highly correlated with irinotecan metabolism. They also found that increased metabolism of irinotecan was associated with a UGT1A1 variant, UGT1A1*28. They conclude that CYP3A4 phenotype assessed by midazolam clearance is associated with irinotecan metabolism and that combining midazolam clearance with UGT1A1*28 genotyping may assist with optimization of irinotecan chemotherapy.
Mesenchymal Stem Cell Targeting and Interferon Beta
Bone marrow-derived mesenchymal stem cells (MSC) contribute to the tumor
microenvironment when intravenously injected into tumor-bearing mice. Studeny
et al. (p. 1593)
examined whether human bone marrow-derived MSC engineered to express the human
interferon beta gene (MSC-IFN-
cells) could be used to target IFN-
to tumors, thereby reducing toxicity. They found that MSC-IFN- cells
co-cultured with human MDA 231 breast carcinoma cells or A375SM melanoma cells
inhibited tumor cell proliferation compared with tumor cells cultured alone.
MSC-IFN- cells intravenously injected into tumor-bearing mice were
incorporated in the tumor architecture and prolonged mouse survival compared
with untreated control mice. Intravenously administered IFN- did not
prolong survival in the same mouse model. The authors conclude that MSC may be
an effective platform for the targeted delivery of therapeutic proteins to
cancer sites.
Isolated Limb Perfusion With Melphalan and Histamine
Isolated limb perfusion is a treatment method in which a chemotherapy drug is administered to the circulation of the affected limb rather than to the entire body. To enhance the uptake of and hence the antitumor effects of melphalan, a drug commonly used in isolated limb perfusion, Brunstein et al. (p. 1603) combined melphalan with histamine, a vasodilator. Using a rat model of metastatic sarcoma, the authors monitored tumor growth after isolated limb perfusion with melphalan alone or in combination with histamine. The drug combination was synergistic, and tumor uptake of melphalan increased upon histamine treatment. Tumor regression was observed in 66% of the rats treated with histamine and melphalan, compared with 17% with melphalan alone. The authors conclude that histamine and melphalan act through direct and indirect mechanisms.
Targeting a Photosensitizer to Rat Bladder Carcinoma Cells
Tumor-selective accumulation of a photosensitizer in superficial bladder cancer would allow photodiagnosis and fluorescence-guided transurethral resection of lesions. Derycke et al. (p. 1620) examined whether targeting the photosensitizer aluminum phthalocyanine tetrasulfonate (AlPcS4) by encapsulating it in transferrin-conjugated liposomes (Tf-Lip-AlPcS4) is an effective strategy to achieve AlPcS4 accumulation in bladder tumors, which overexpress the transferrin receptor. They found that bladder carcinoma cells exposed to Tf-Lip-AlPcS4 took up more of this compound than cells exposed to nontargeted liposomes containing AlPcS4. In a rat tumor model, intravesical treatment with Tf-Lip-AlPcS4 resulted in selective accumulation of AlPcS4 in tumor tissue, whereas treatment with free AlPcS4 resulted in nonselective accumulation throughout the whole bladder wall. Transferrin targeting also increased the in vitro photocytotoxicity of the encapsulated photosensitizer. The authors conclude that transferrin-mediated liposomal targeting of photosensitizers is a promising tool for photodynamic therapy of superficial bladder tumors.
Combined Immunotherapy for Epithelial Tumors
To determine the mechanisms associated with effective immunotherapy of human epithelial cancers, Matsumoto et al. (p. 1611) measured skin graft rejection in mice treated with immunotherapy. Skin grafts expressing a cervical cancer-associated tumor antigen, human papilloma-virus 16 (HPV16) E7, were rejected after the mice were immunized with the HPV16 E7 protein only if the mice were also treated by adoptive transfer of antigen-specific CD8+ T cells. Mice immunized and treated by adoptive transfer developed gamma interferon-secreting memory CD8+ cells but could not reject a second HPV16 E7-expressing skin graft placed at a later time unless they had been given a second immunization. The authors conclude that effective cancer immunotherapy in humans may require combined immunization and adoptive transfer of antigen-specific T cells and may require additional immunization, even if antigen-specific memory T cells are already present.
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