In vivo chemoresistance of prostate cancer in metronomic cyclophosphamide therapy

Thoenes, Lilja; Hoehn, Miriam; Kashirin, Roman; Ogris, Manfred; Arnold, Georg J.; Wagner, Ernst; Guenther, Michael

doi:10.1016/j.jprot.2010.02.019

Cited by 32 publications

(22 citation statements)

References 46 publications

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“…Until now, however, few studies have investigated the association of annexin A3 expression and chemoresistance in ovarian cancer patients. Thoenes et al showed that annexin A3 was up-regulated in chemo-resistant prostatic cancer following metronomic cyclophosphamide therapy, both in vitro and in vivo 23, in keeping with our previous study in ovarian cancer9,10.…”

Section: Discussionsupporting

confidence: 91%

Annexin A3 Is a Potential Predictor of Platinum Resistance in Epithelial Ovarian Cancer Patients in a Prospective Cohort

Jin

Feng²,

Jiang³

et al. 2015

J. Cancer

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Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies and is rarely cured in the recurrent setting, mainly because of progressive chemoresistance, especially platinum resistance. In our previous studies, the platinum-resistance-related protein, annexin A3, was selected by comparative proteomics. In this study, we detected serum annexin A3 levels using a self-developed chemiluminescence immunoassay kit in a prospective EOC patient cohort. We also evaluated the capacity of serum annexin A3 levels to predict platinum resistance. Serum annexin A3 levels in healthy women exhibited a similar normal distribution (Z=0.723, P=0.673), allowing determination of a normal cutoff level of 0.11-1.45 ng/mL. Of the 89 EOC patients, 21 were platinum resistant and 68 were platinum sensitive. Residual disease after primary surgery (p=0.004) and serum annexin A3 levels (p=0.036) were both independent factors associated with platinum resistance. The AUC was 0.733 (95% confidence interval (CI), 0.627-0.823). The optimal cutoff value for serum annexin A3 levels was 2.05 ng/mL. Multivariate logistic analysis showed that expression of annexin A3 as assessed by immunohistochemistry (P=0.005) and residual tumor size (P=0.000) had a significant influence on platinum resistance. The AUC of ROC curve of annexin A3 expression by immunohistochemistry was 0.664 (95% CI, 0.554-0.763) and the cut off value was “>=moderate scores”. In conclusion, we demonstrate that annexin A3 is a secreted protein that may be measured in the peripheral blood using a self-developed, chemiluminescence immunoassay kit. Serum annexin A3 levels may be a potential predictor of platinum resistance in epithelial ovarian cancer patients.

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Section: Discussionsupporting

confidence: 91%

Annexin A3 Is a Potential Predictor of Platinum Resistance in Epithelial Ovarian Cancer Patients in a Prospective Cohort

Jin

Feng²,

Jiang³

et al. 2015

J. Cancer

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“…Reduced NK cell recruitment was also seen in CPA(210)/9d-treated tumors, where the elevated CPA dose was able to compensate for the reduced innate immune response. Resistance to metronomic CPA has been associated with dormant stem-cell foci in hepatocellular carcinoma [51], ischemia-dependent K-ras mutations in colorectal carcinoma [52] and increased annexin A3 expression in prostate cancer [53; 54]. Different resistance mechanisms may be activated in different tumor models and by different CPA doses and schedules [55; 56]; these mechanisms could include immune-based resistance, as well as repopulation of quiescent tumor cells that are distal of blood vessel and deprived of oxygen and nutrients, selection of tumor cell populations with increased drug efflux and detoxification ability, increased DNA damage repair between metronomic CPA treatments, metabolic adaptation, and emergence of resistance to apoptosis [57; 58].…”

Section: Discussionmentioning

confidence: 99%

Metronomic cyclophosphamide schedule-dependence of innate immune cell recruitment and tumor regression in an implanted glioma model

Waxman

2014

Cancer Letters

107

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Metronomic cyclophosphamide (CPA) treatment activates robust innate anti-tumor immunity and induces major regression of large, implanted brain tumor xenografts when administered on an intermittent, every 6-day schedule, but not on a daily low-dose or a maximum-tolerated dose CPA schedule. Here, we used an implanted GL261 glioma model to compare five intermittent metronomic CPA schedules to elucidate the kinetics and schedule dependence of innate immune cell recruitment and tumor regression. Tumor-recruited natural killer cells induced by two every 6-day treatment cycles were significantly ablated one day after a third CPA treatment, but largely recovered several days later. Natural killer and other tumor-infiltrating innate immune cells peaked 12 days after the last CPA treatment on the every 6-day schedule, suggesting that drug-free intervals longer than 6 days may show increased efficacy. Metronomic CPA treatments spaced 9 or 12 days apart, or on an alternating 6 and 9 day schedule, induced extensive tumor regression, similar to the 6-day schedule, however, the tumor-infiltrating natural killer cell responses were not sustained, leading to rapid resumption of tumor regrowth after day 24, despite ongoing metronomic CPA treatment. Increasing the CPA dose prolonged the period of tumor regression on the every 9-day schedule, but natural killer cell activation was markedly decreased. Thus, while several intermittent metronomic CPA treatment schedules can activate innate immune cell recruitment leading to major tumor regression, sustained immune and anti-tumor responses are only achieved on the 6-day schedule. However, even with this schedule, some tumors eventually relapse, indicating a need for further improvements in immunogenic metronomic therapies.

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“…A comparative proteome analysis of cyclophosphamide (CPA) resistant prostate cancer cell PC3 sublines derived from tumor xenografts with acquired in vivo resistance to CPA treatment versus the nonresistant parental PC3 cell line revealed a total of 25 differently expressed proteins. Association of three differentially expressed proteins (thioredoxin containing protein 5, cathepsin B, and annexin A3) with CPA resistance was validated both in vitro and in xenografts [28]. In order to elucidate the mechanisms of MDR of vincristine-resistant human gastric carcinoma cell line SGC7901/VCR, we used proteomics to identify the differential proteins in SGC7901/VCR and its parental cell line SGC7901.…”

Section: 1mentioning

confidence: 99%

“…Eleven mitochondrial proteins were found with abundances altered such as cofilin and coproporphyrinogen III oxidase in the drug-resistant MCF-7 cells, and implications of the changes were considered with respect to drug resistance[34]. A proteomic study of cyclophosphamide (CPA) resistant prostate cancer cells revealed that a truncated version of cathepsin B translocated into mitochondria in the drug-resistant clones whereas it stayed cytoplasmic in corresponding parental PC3 cells, indicating that its translocation into mitochondria was related to drug resistance[28]. As drug resistance is often associated with membrane-associated drug-efflux systems and cross-talk between different membrane receptors, a membrane proteomic analysis is valuable in search for novel proteins related to drug resistant phenotypes.…”

mentioning

confidence: 99%

Proteomics for identifying mechanisms and biomarkers of drug resistance in cancer

Li¹,

Cui²,

Xiao³

2011

Journal of Proteomics

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In vivo chemoresistance of prostate cancer in metronomic cyclophosphamide therapy

Cited by 32 publications

References 46 publications

Annexin A3 Is a Potential Predictor of Platinum Resistance in Epithelial Ovarian Cancer Patients in a Prospective Cohort

Annexin A3 Is a Potential Predictor of Platinum Resistance in Epithelial Ovarian Cancer Patients in a Prospective Cohort

Metronomic cyclophosphamide schedule-dependence of innate immune cell recruitment and tumor regression in an implanted glioma model

Proteomics for identifying mechanisms and biomarkers of drug resistance in cancer

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