Schedule-dependent cytotoxicity of 5-fluorouracil and irinotecan in p53 mutant human colon cancer.

IFL [irinotecan (CPT-11), 5-fluorouracil (5-FU), and folinic acid] is one of the treatments for metastatic colorectal cancer. We evaluated cytotoxic effects of a sequentially administered a combination of 5-FU with CPT-11 in human p53 mutant colon cancer. Sequential combination of 5-FU and CPT-11 in human colon cancer SW480 cells using a WST-8 colorimetric assay was studied. Cytotoxicity and cell cycle distribution for each drug were evaluated using an apoptosis assay and flow cytometry. Potential mechanisms of sequence-dependent cytotoxic effects were investigated using microarrays. Cytotoxicity of 5-FU (10, 100, 1000 microM) combined with subsequent use of CPT-11 (1 microM) was significantly greater than the reverse sequence of CPT-11 followed by 5-FU (p < 0.05). Following 24 hrs treatment with 5-FU (0.1-100 microM), no significant apoptosis was observed. In contrast, apoptosis was significantly induced after 24 hrs treatment with CPT-11 (1 and 10 microM). Flow cytometric analysis showed no significant difference in cell cycle distribution between different drug concentrations. We demonstrated up-regulation of 85 genes and down-regulation of 21 genes correlating with sequence-dependent cytotoxicities of 5-FU and CPT-11. The superiority of 5-FU-CPT-11 sequence was proven for p53 mutant colon cancer, SW480. Treatment with 5-FU followed by CPT-11 administration may be the optimal sequence for IFL treatment of metastatic colon cancers.

Naturally acquired regulatory mechanism of perioperative cytokine response in neonates.

The inflammatory reaction is known to be controlled in neonates. We clarified the characteristics of cytokine profile in neonatal patients and assess its clinical significance. Serum levels of interleukin (IL)-6 and IL-1 receptor antagonist (ra) were determined in 152 pediatric patients and 33 each of maternal and cord bloods. Supernatant IL-1ra levels of cultured monocytes and granulocytes stimulated with IL-1beta or LPS, and IL-1ra mRNA expression of granulocytes were assayed in 15 each of cord and healthy adult bloods. Although surgical stress in neonates was heavier than that in infants, there was no difference in the occurrence of postoperative morbidity and mortality. In neonates, the perioperative serum level of IL-1ra was significantly raised, and the postoperative IL-6 response was well controlled. The serum concentration of IL-1ra in cord blood was not different from that in maternal blood, whereas, the serum concentration of IL-6 in cord blood was significantly reduced than that in maternal blood. In granulocytes, significantly more IL-1ra was produced from cord than from adult blood. An IL-1ra predominant immune status in neonates may be a naturally acquired adaptation system and play a crucial role in attenuating acute inflammatory reaction in a vulnerable host defense.