Significance of cell cycle for wound stratification in clinical trials: analysis of a pressure ulcer clinical trial utilizing cyclin D/cdk4.
During the past 5 years, progress in the treatment of pressure ulcers appears to have reached a plateau. Several factors in the design of recent clinical studies may have contributed to this situation. These factors include the criteria chosen for patient selection, small sample size, and lack of a concisely defined final clinical outcome. Hunt noted that wound stratification according to a patient's physiological characteristics may be a key to quantifying differences among clinical treatments. To address this issue, we examined the expression of cyclin D/cdk4 in pressure ulcer fibroblasts taken from tissues during a recent clinical trial. The treatment groups included patients treated with the following regimens: placebo, granulocyte macrophage-colony stimulating factor alone, basic fibroblast growth factor alone, or granulocyte macrophage-colony stimulating factor and basic fibroblast growth factor given in sequence. Immunocytochemical colocalization of cyclin D and cdk4 showed that, before the initial treatment began, patients were distributed disproportionately among treatment subgroups in regards to the initial expression of these markers. For example, we found that compared with other subgroups, ulcer fibroblasts in the basic fibroblast growth factor treatment group showed a much lower expression of cyclin D/cdk4 at day 0. However, this group exhibited higher levels of expression of this complex after 35 days of treatment. This study shows that measurement of cyclin D/cdk4 expression permits more accurate stratification of patients within treatment subgroups, measurement of a cell's ability to detect the presence of functional cytokines, identification of area(s) of failure within the G1 of the cell cycle, and a basis for critical evaluation of various treatments.
Vande Berg
Jerry S
JS
San Diego Veteran's Administration Medical Center and Division of Plastic Surgery, University of California, San Diego, USA.
Rose
Michael A
MA
Payne
Wyatt G
WG
Haywood-Reid
Patricia L
PL
Robson
Martin C
MC
D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002985:Clinical Protocols; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000032:analysis*; D016222:Fibroblast Growth Factor 2 / Q000627:therapeutic use; D005347:Fibroblasts / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology*; D005500:Follow-Up Studies; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D017063:Outcome Assessment, Health Care; D018579:Patient Selection; D003668:Pressure Ulcer / Q000145:classification* / Q000188:drug therapy / Q000503:physiopathology*; D011518:Proto-Oncogene Proteins; D012720:Severity of Illness Index; D013997:Time Factors
D011518:Proto-Oncogene Proteins; D016222:Fibroblast Growth Factor 2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases