Phase II study of FOLFIRI regimen in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin.

PURPOSE: To evaluate the efficacy and safety of FOLFIRI regimen in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin. METHODS: The FOLFIRI regimen consisted of intravenous infusion of irinotecan 180 mg/m(2) on day 1 plus leucovorin (LV) 400 mg/m(2) on day 1 plus 5-fluorouracil (5-FU) 400 mg/m(2) bolus on day 1 plus 46-hour intravenous infusion of 5-FU 2,400 mg/m(2), every 2 weeks as one cycle. The main selection criterion for this study was the advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin. RESULTS: Of the 57 evaluable patients for efficacy, 4 (7.5%) had a partial response, 36 (67.9%) had stable disease, and 13 (24.5%) had progressive disease. Median progression-free survival was 4.8 months (95% CI 3.9-5.7 months), and median overall survival was 7.8 months (95% CI 13.1-16.5 months). Safety analysis was based on the data of 57 evaluable patients. The most frequently observed grade 3 or 4 toxicities were neutropenia 16 (27.8%), nausea/vomiting 7 (12.3%), and diarrhea 1 (1.8%). CONCLUSION: FOLFIRI regimen is effective and well tolerated in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin in Chinese population.

[TLR4 signals are involved in multiple myeloma cell proliferation and apoptosis].

OBJECTIVE: To investigate the TLR4 signaling in multiple myeloma cell proliferation and apoptosis. METHODS: TLR4 gene transcription and protein expression were detected by RT-PCR and PE flow cytometry staining; the cells proliferation were detected by MTT assay; doxorubicin-induced apoptosis of cells was detected by AnnexinV-PI double staining flow cytometry. RESULT: TLR4 gene transcription and protein expression was detected in the myeloma cell lines. Under the lipopolysaccharides (LPS) stimulation, MM1-s cells TLR4 positive proliferation significantly increased (P<0.05), but not found in U266 cells TLR4 negative; MM1-s cells showed the resistance to doxorubisin-induced apoptosis, but LPS did not protect doxorubicin-induced U266 cell apoptosis. CONCLUSION: TLR4 signaling may play an important role both in multiple myeloma proliferation and survival.

A Phase II trial of oxaliplatin, folinic acid, and 5-fluorouracil (FOLFOX4) as first-line chemotherapy in advanced colorectal cancer: a China single-center experience.

PURPOSE: To evaluate the efficacy and toxicity of leucovorin (LV) plus 5-fluorouracil (5-FU) combined with oxaliplatin every 2 weeks on previously untreated advanced colorectal cancer patients in Chinese population. PATIENTS AND METHODS: Forty-nine patients were enrolled to receive, entirely as inpatients, 2-weekly cycles of oxaliplatin 85 mg/m2 i.v. over 2 hours on Day 1, together with leucovorin 200 mg/m2 over 2 hours, 5-FU 400 mg/m2, bolus, followed by a 22-hours infusion of 5-FU at 600 mg/m2 Days 1-2 (FOLFOX4) every 2 weeks. Treatment was given until progression or unmanageable toxicity. In all, 49 patients received ≥ 1 oxaliplatin dose and a median of 7 treatment cycles (range 1∼27 cycles). RESULTS: Of the 45 eligible patients, 1 complete response (CR) and 18 partial responses (PRs) were observed for an overall response rate of 42.2 percent (95 percent confidence interval 26∼56 percent). Median progression-free survival was 7.2 months (6.4∼8.0) and median overall survival was 14.8 months (13.1∼16.5). Six patients (12.2 percent) reported Grade 3∼4 neutropenia. Thirty-one patients (62.3 percent) experienced Grade 1∼3 neurotoxicity and only 5 patients (10.2 percent) experienced Grade 3 neurotoxicity. CONCLUSION: In our experience, FOLFOX4 regimen is active and well tolerated in patients with previously untreated advanced colorectal cancer in Chinese population.

[Polymorphisms of UGT1A gene and irinotecan toxicity in Chinese colorectal cancer patients].

OBJECTIVE: To assess the polymorphism of UGT1A gene in Chinese, and to investigate the correlation between UGT1A polymorphism and irinotecan toxicity in colorectal cancer patients. METHODS: 70 patients with advanced colorectal cancer were treated with irinotecan and 5-fluorouracil. Polymorphism analysis was performed in all those patients and 100 healthy subjects. Genomic DNA was extracted from peripheral blood and genotyped using polymerase chain reaction and direct sequencing. RESULTS: 14 patients exhibiting grade 3 - 4 neutropenia (20.0%), 16 patients experienced grade 2 - 4 diarrhea (22.9%), including only 4 patients with grade 3 - 4 diarrhea (5.7%). Compared with TA6/7 and TA7/7, UGT1 A1 * 28 wild genotype TA6/6 was significantly associated with reduced toxicity (42.1% vs. 15.7%, P = 0.027). There was no significant difference in the distribution of UGT1A genotypes between colorectal cancer patients and healthy subjects. CONCLUSION: Chinese patients exhibit less irinotecan-related diarrhea due to higher frequence of UGT1A A1 * 28 wild genotype TA6/6.

[Expression of survivin mRNA in HHT-induced cell apoptosis of hematological malignancy cell lines].

OBJECTIVE: To investigate the expression of survivin mRNA in hematological malignancy cells and its correlation with HHT-induced cell apoptosis. METHODS: Hematological malignancy cell lines MUTZ-1, K562, Jurkat, RPMI and HL60 were treated with HHT in vitro. Cell apoptosis was observed by flow cytometry (FCM) and the expression of surviving and XIAP mRNA was evaluated with semi-quantitative RT-PCR. RESULT: The expression of survivin mRNA on cell lines was negatively correlated to HHT-induced cell apoptotic rate (r=-0.980, P=0.003). There were no significant differences in XIAP expression among these 5 cell lines. CONCLUSION: Survivin could be used as a new marker for drug-sensitivity and a new target for treatment of hematological malignancies.

Correlation between survivin mRNA expression and homoharringtonine induced apoptosis of malignant hematopoietic cells.

BACKGROUND: The inhibitor of apoptosis (IAP) gene family is involved in the suppression of apoptotic cell death as well as an increasing number of seemingly unrelated cellular functions. It is not known, however, whether IAP expression in malignant hematopoietic cells is affected by chemotherapeutic agents such as homoharringtonine (HHT). In this study, we investigated mRNA expression levels of IAPs, especially survivin, in various hematopoietic cell lines in relation with apoptosis induced by HHT. METHODS: Semiquantitative reverse transcriptase polymerase chain reaction was used to determine survivin mRNA levels. Cell apoptosis was examined by flow cytometry. Cell viability and proliferation assay was evaluated by MTT. The experiments were performed on the malignant hematopoietic cell lines MUTZ-1, K562, Jurkat, RMPI and HL60, with or without survivin antisense-oligodeoxynucleotides (AS-ODN) and HHT. RESULTS: The expression levels of survivin mRNA were variable in the cell lines and negatively correlated to HHT induced cell apoptosis. Survivin AS-ODN significantly decreased mRNA level of survivin, but not those of bax and bcl-2. Survivin also inhibited MUTZ-1 cell growth and induced apoptosis in a dose dependent manner. AS-ODN and HHT showed synergistic effect on MUTZ-1 cell growth. CONCLUSION: The apoptotic effect of HHT on the hematopoietic cell lines is associated with decreased level of survivin expression. Survivin could be a new marker for drug sensitivity and a new target for cancer treatment.

[Expression and significance of apoptosis protein inhibitor survivin and XIAP, in patients with myelodysplastic syndromes and in the cell line MUTZ-1].

OBJECTIVE: To investigate the expression of apoptotic protein inhibitors, survivin and XIAP, in patients with myelodysplastic syndromes (MDS) and in the cell line MUTZ-1, as well as to explore the possible mechanisms of homoharringtonine (HHT) in the treatment of MDS. METHODS: Bone marrow samples from 47 patients with de novo MDS at diagnosis were examined and bone marrow samples from 15 normal donors were used as control. A MDS-RAEB cell line MUTZ-1 was used as in vitro model. Detection of apoptotic cells and cell cycle analysis were performed with flow cytometry (FACS). The expression of apoptotic protein inhibitor survivin and XIAP in the MDS cells were detected by RT-PCR technique. MUTZ-1 were treated with antisense oligodeoxynucleotide (AS-ODNs) of survivin and or HHT, the effects were evaluated by cell viability and cell apoptosis. RESULTS: Survivin mRNA positive rate in MDS were significantly higher than that in normal controls (38.3% and 0, respectively, P < 0.01), and the positive rate in high risk group (RAEB, RAEBT and CMML) was significantly higher than that in RA/RAS group (53.6% and 16.7%, respectively, P < 0.05). XIAP was expressed in all untreated MDS and healthy controls. XIAP mRNA expression in high risk group was significantly higher than that in RA/RAS subtypes and healthy controls (1.55 +/- 0.34, 0.74 +/- 0.24, and 1.01 +/- 0.28, respectively, P < 0.01). However, XIAP mRNA expression was significantly lower in RA/RAS subtypes than in healthy control (0.74 +/- 0.24 and 1.01 +/- 0.28, P < 0.054). Apoptosis peak detected by FACS analysis and positive Annexin V FITC staining on cell membrane indicated that HHT could induce MUTZ-1 cell undergoing apoptosis in dose- and time-dependent manners. Treatment of MUTZ-1 cells with HHT revealed that HHT could significantly down-regulate survivinexpression but had no significant effect on XIAP expression in the cells. AS-ODNs of survivin could inhibit MUTZ-1 cells growth, induce them to apoptosis and sensitize them to HHT. CONCLUSION: The expression levels of survivin; Institute of Hematology, Oncology and Tumor Immunology, Robert Roessle Clinic, Humboldt University, Berlin, Germany (Wolf Dieter Ludwig, Christian Wuchter) and XIAP vary in different subtypes of MDS patients, suggesting that the proteins may play an important role in the pathogenesis of the disease. Down-regulation of survivin in MUTZ-1 cells may be one of the mechanisms that HHT induces apoptosis of MDS cells.