Biomedical subjects

Eric P Kaldjian

Publications and source records attributed to Eric P Kaldjian.

5 recordsLinked to original sources

PubMed2005

Multicenter, randomized phase II trial of oral CI-1033 for previously treated advanced ovarian cancer.

PURPOSE: To evaluate the antitumor activity and toxicity of two doses of CI-1033 in patients with platinum-refractory or recurrent ovarian cancer, and to determine baseline expression of epidermal growth factor receptor in tumor cells. PATIENTS AND METHODS: This phase II, open-label clinical trial evaluated CI-1033 in patients with ovarian cancer who failed prior platinum-based therapy. Two oral doses of CI-1033 were evaluated--a 50-mg and a 200--mg oral dose administered daily for 21 days in a 28-day cycle. Patients were evaluated for tumor response and toxicity; in addition, archival baseline tumor samples were analyzed by immunohistochemistry for erbB1 to erbB4 status. RESULTS: One hundred five eligible patients were treated. Baseline demographic characteristics were balanced in this heavily pretreated patient population. The median number of prior chemotherapy regimens received was four. The most commonly encountered drug-related adverse events for both dose arms were gastrointestinal (diarrhea, nausea, stomatitis) toxicity, asthenia, and rash. No responses were observed. Stable disease was confirmed in 34% and 26% of patients in the 200-mg and 50-mg arms, respectively, and 1-year survival rates were 38.5% and 37.7%, respectively. Baseline erbB3 and erbB4 revealed the highest frequencies of expression, while erbB2 was the lowest. CONCLUSION: CI-1033 did not show activity in unscreened patients with advanced ovarian cancer. At 50 mg/d, CI-1033 had a more favorable adverse events profile than at 200 mg/d. erbB3 and erbB4 receptors showed the highest expression in tumor samples while erbB2 revealed the least. There appears to be no association between baseline erbB expression and disease stability.

Administration, Oral↗

PubMed2004

Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer.

PURPOSE: This multicenter, open-label, phase II study was undertaken to assess the antitumor activity and safety of the oral mitogen-activated extracellular signal regulated kinase kinase (MEK) inhibitor, CI-1040, in breast cancer, colon cancer, non-small-cell lung cancer (NSCLC), and pancreatic cancer. PATIENTS AND METHODS: Patients with advanced colorectal, NSCLC, breast, or pancreatic cancer received oral CI-1040 continuously at 800 mg bid. All patients had measurable disease at baseline, a performance status of 2 or less, and adequate bone marrow, liver, and renal function. Expression of pERK, pAkt, and Ki-67 was assessed in archived tumor specimens by quantitative immunohistochemistry. RESULTS: Sixty-seven patients with breast (n = 14), colon (n = 20), NSCLC (n = 18), and pancreatic (n = 15) cancer received a total of 194 courses of treatment (median, 2.0 courses; range, one to 14 courses). No complete or partial responses were observed. Stable disease (SD) lasting a median of 4.4 months (range, 4 to 18 months) was confirmed in eight patients (one breast, two colon, two pancreas, and three NSCLC patients). Treatment was well tolerated, with 81% of patients experiencing toxicities of grade 2 or less severity. Most common toxicities included diarrhea, nausea, asthenia, and rash. A mild association (P < .055) between baseline pERK expression in archived tumor specimens and SD was observed. CONCLUSION: CI-1040 was generally well tolerated but demonstrated insufficient antitumor activity to warrant further development in the four tumors tested. PD 0325901, a second generation MEK inhibitor, has recently entered clinical development and, with significantly improved pharmacologic and pharmaceutical properties compared with CI-1040, it may better test the therapeutic potential of MEK inhibition in cancer.

Administration, Oral↗

PubMed2004

Gender differences in experimental aortic aneurysm formation.

OBJECTIVE: It is hypothesized that a male predominance, similar to that in humans, persists in a rodent model of experimental abdominal aortic aneurysm (AAA) via alterations in matrix metalloproteinases (MMPs). METHODS AND RESULTS: Group I experiments were as follows: elastase perfusion of the infrarenal aorta was performed in male (M) and female (F) rats. At 14 days, aortas were harvested for immunohistochemistry, real-time polymerase chain reaction (PCR), and zymography. Group II experiments were the following: abdominal aorta was transplanted from F or M donors into F or M recipients. At 14 days, rodents that had undergone transplantation underwent elastase perfusion. In group III, male rats were given estradiol or sham 5 days before elastase perfusion. In group I, M rats had larger AAAs with higher frequency than did F rats. M rat aortas had more significant macrophage infiltrates and increased matrix metalloproteinase (MMP)-9 production and activity. In group II, M-to-M aortic transplants uniformly developed aneurysms after elastase perfusion, whereas F-to-F aortic transplants remained resistant to aneurysm formation. F aortas transplanted into M recipients, however, lost aneurysm resistance. In group III, estradiol-treated rats demonstrated smaller aneurysms and less macrophage infiltrate and MMP-9 compared with M controls after elastase. CONCLUSIONS: These data provide evidence of gender-related differences in AAA development, which may reflect an estrogen-mediated reduction in macrophage MMP-9 production.

Animals↗

PubMed2004

The influence of tumor size and environment on gene expression in commonly used human tumor lines.

BACKGROUND: The expression profiles of solid tumor models in rodents have been only minimally studied despite their extensive use to develop anticancer agents. We have applied RNA expression profiling using Affymetrix U95A GeneChips to address fundamental biological questions about human tumor lines. METHODS: To determine whether gene expression changed significantly as a tumor increased in size, we analyzed samples from two human colon carcinoma lines (Colo205 and HCT-116) at three different sizes (200 mg, 500 mg and 1000 mg). To investigate whether gene expression was influenced by the strain of mouse, tumor samples isolated from C.B-17 SCID and Nu/Nu mice were also compared. Finally, the gene expression differences between tissue culture and in vivo samples were investigated by comparing profiles from lines grown in both environments. RESULTS: Multidimensional scaling and analysis of variance demonstrated that the tumor lines were dramatically different from each other and that gene expression remained constant as the tumors increased in size. Statistical analysis revealed that 63 genes were differentially expressed due to the strain of mouse the tumor was grown in but the function of the encoded proteins did not link to any distinct biological pathways. Hierarchical clustering of tissue culture and xenograft samples demonstrated that for each individual tumor line, the in vivo and in vitro profiles were more similar to each other than any other profile. We identified 36 genes with a pattern of high expression in xenograft samples that encoded proteins involved in extracellular matrix, cell surface receptors and transcription factors. An additional 17 genes were identified with a pattern of high expression in tissue culture samples and encoded proteins involved in cell division, cell cycle and RNA production. CONCLUSIONS: The environment a tumor line is grown in can have a significant effect on gene expression but tumor size has little or no effect for subcutaneously grown solid tumors. Furthermore, an individual tumor line has an RNA expression pattern that clearly defines it from other lines even when grown in different environments. This could be used as a quality control tool for preclinical oncology studies.

Analysis of Variance↗

PubMed2002

Expression profiling of human renal carcinomas with functional taxonomic analysis.

BACKGROUND: Molecular characterization has contributed to the understanding of the inception, progression, treatment and prognosis of cancer. Nucleic acid array-based technologies extend molecular characterization of tumors to thousands of gene products. To effectively discriminate between tumor sub-types, reliable laboratory techniques and analytic methods are required. RESULTS: We derived mRNA expression profiles from 21 human tissue samples (eight normal kidneys and 13 kidney tumors) and two pooled samples using the Affymetrix GeneChip platform. A panel of ten clustering algorithms combined with four data pre-processing methods identified a consensus cluster dendrogram in 18 of 40 analyses and of these 16 used a logarithmic transformation. Within the consensus dendrogram the expression profiles of the samples grouped according to tissue type; clear cell and chromophobe carcinomas displayed distinctly different gene expression patterns. By using a rigorous statistical selection based method we identified 355 genes that showed significant (p < 0.001) gene expression changes in clear cell renal carcinomas compared to normal kidney. These genes were classified with a tool to conceptualize expression patterns called "Functional Taxonomy". Each tumor type had a distinct "signature," with a high number of genes in the categories of Metabolism, Signal Transduction, and Cellular and Matrix Organization and Adhesion. CONCLUSIONS: Affymetrix GeneChip profiling differentiated clear cell and chromophobe carcinomas from one another and from normal kidney cortex. Clustering methods that used logarithmic transformation of data sets produced dendrograms consistent with the sample biology. Functional taxonomy provided a practical approach to the interpretation of gene expression data.

Adenocarcinoma, Clear Cell↗