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Cancer Research Communications Jul 2023Prostate cancer is the second leading cause of noncutaneous cancer-related deaths in American men. Androgen deprivation therapy (ADT), radical prostatectomy, and...
UNLABELLED
Prostate cancer is the second leading cause of noncutaneous cancer-related deaths in American men. Androgen deprivation therapy (ADT), radical prostatectomy, and radiotherapy remain the primary treatment for patients with early-stage prostate cancer (castration-sensitive prostate cancer). Following ADT, many patients ultimately develop metastatic castration-resistant prostate cancer (mCRPC). Standard chemotherapy options for CRPC are docetaxel (DTX) and cabazitaxel, which increase median survival, although the development of resistance is common. Cancer stem-like cells possess mesenchymal phenotypes [epithelial-to-mesenchymal transition (EMT)] and play crucial roles in tumor initiation and progression of mCRPC. We have shown that low-dose continuous administration of topotecan (METRO-TOPO) inhibits prostate cancer growth by interfering with key cancer pathway genes. This study utilized bulk and single-cell or whole-transcriptome analysis [(RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq)], and we observed greater expression of several EMT markers, including , , , , , , and in European American and African American aggressive variant prostate cancer (AVPC) subtypes-mCRPC, neuroendocrine variant (NEPC), and taxane-resistant. The taxane-resistant gene was also expressed highly in single-cell subclonal populations in mCRPC. Furthermore, metronomic-topotecan single agent and combinations with DTX downregulated these EMT markers as well as CD44 and CD44/CD133 "stem-like" cell populations. A microfluidic chip-based cell invasion assay revealed that METRO-TOPO treatment as a single agent or in combination with DTX was potentially effective against invasive prostate cancer spread. Our RNA-seq and scRNA-seq analysis were supported by and studies, suggesting METRO-TOPO combined with DTX may inhibit oncogenic progression by reducing cancer stemness in AVPC through the inhibition of EMT markers and multiple oncogenic factors/pathways.
SIGNIFICANCE
The utilization of metronomic-like dosing regimens of topotecan alone and in combination with DTX resulted in the suppression of makers associated with EMT and stem-like cell populations in AVPC models. The identification of molecular signatures and their potential to serve as novel biomarkers for monitoring treatment efficacy and disease progression response to treatment efficacy and disease progression were achieved using bulk RNA-seq and single-cell-omics methodologies.
Topics: Male; Humans; Docetaxel; Topotecan; Prostatic Neoplasms, Castration-Resistant; Administration, Metronomic; Androgen Antagonists; Epithelial-Mesenchymal Transition; Taxoids; Disease Progression; Carrier Proteins; Microfilament Proteins
PubMed: 37476073
DOI: 10.1158/2767-9764.CRC-22-0427 -
Oncotarget Jul 2016Research has exposed cancer to be a heterogeneous disease with a high degree of inter-tumoral and intra-tumoral variability. Individual tumors have unique profiles, and... (Review)
Review
Research has exposed cancer to be a heterogeneous disease with a high degree of inter-tumoral and intra-tumoral variability. Individual tumors have unique profiles, and these molecular signatures make the use of traditional histology-based treatments problematic. The conventional diagnostic categories, while necessary for care, thwart the use of molecular information for treatment as molecular characteristics cross tissue types.This is compounded by the struggle to keep abreast the scientific advances made in all fields of science, and by the enormous challenge to organize, cross-reference, and apply molecular data for patient benefit. In order to supplement the site-specific, histology-driven diagnosis with genomic, proteomic and metabolomics information, a paradigm shift in diagnosis and treatment of patients is required.While most physicians are open and keen to use the emerging data for therapy, even those versed in molecular therapeutics are overwhelmed with the amount of available data. It is not surprising that even though The Human Genome Project was completed thirteen years ago, our patients have not benefited from the information. Physicians cannot, and should not be asked to process the gigabytes of genomic and proteomic information on their own in order to provide patients with safe therapies. The following consensus summary identifies the needed for practice changes, proposes potential solutions to the present crisis of informational overload, suggests ways of providing physicians with the tools necessary for interpreting patient specific molecular profiles, and facilitates the implementation of quantitative precision medicine. It also provides two case studies where this approach has been used.
Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Clinical Trials as Topic; Female; Humans; Male; Medical Oncology; Neoplasms; Precision Medicine; Research Design
PubMed: 27223079
DOI: 10.18632/oncotarget.9488 -
The Korean Journal of Hepatology Mar 2012Low-dose metronomic chemotherapy involves the frequent administration of comparatively low doses of cytotoxic agents with no extended breaks, and it may be as efficient...
BACKGROUND/AIMS
Low-dose metronomic chemotherapy involves the frequent administration of comparatively low doses of cytotoxic agents with no extended breaks, and it may be as efficient as and less toxic than the conventional maximum tolerated dose therapy. This study evaluated the feasibility and therapeutic efficacy of metronomic chemotherapy in patients with advanced hepatocellular carcinoma (HCC) with major portal vein thrombosis (PVT).
METHODS
Thirty consecutive HCC patients with major PVT with or without extrahepatic metastasis were prospectively allocated to metronomic chemotherapy consisting of epirubicin being infused through the correct hepatic artery at a dose of 30 mg/body surface area (BSA) every 4 weeks, and cisplatin (15 mg/BSA) and 5-fluorouracil (50 mg/BSA) every week for 3 weeks, with intervening 1 week breaks. The treatment response was assessed using response evaluation criteria in solid tumors (RECIST).
RESULTS
In total, 116 cycles of metronomic chemotherapy were administered to the 30 patients, with a median of 3 cycles given to individual patients (range, 1-15 cycles). Six patients (20.0%) achieved a partial response and six patients (20.0%) had stable disease. The median time to disease progression and overall survival were 63 days (range, 26-631 days) and 162 days (95% confidence interval; range, 62-262 days), respectively. Overall survival was significantly associated with baseline alpha-fetoprotein level (P=0.001) and tumor response (P=0.005). The baseline alpha-fetoprotein level was significantly associated with the disease control rate (P=0.007). Adverse events were tolerable and managed successfully with conservative treatment.
CONCLUSIONS
Metronomic chemotherapy may be a safe and useful palliative treatment in HCC patients with major PVT.
Topics: Administration, Metronomic; Adult; Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Cisplatin; Epirubicin; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Male; Middle Aged; Portal Vein; Prognosis; Tomography, X-Ray Computed; Venous Thrombosis; alpha-Fetoproteins
PubMed: 22511901
DOI: 10.3350/kjhep.2012.18.1.32 -
Indian Journal of Cancer 2013Metronomics is defined by the combination of metronomic chemotherapy and drug repositioning. Since off-patent chemotherapeutic drugs can be used and given the low... (Clinical Trial)
Clinical Trial
BACKGROUND
Metronomics is defined by the combination of metronomic chemotherapy and drug repositioning. Since off-patent chemotherapeutic drugs can be used and given the low toxicity profile of this approach, metronomics appears to be an invaluable alternative to bring affordable targeted therapies in low-income countries.
OBJECTIVE
The aim of this study was to report on the preliminary efficacy and safety of a metronomic vincristine/cyclophosphamide/methotrexate/valproic acid regimen given to children with refractory cancer of various tumor types or with a very advanced disease.
MATERIALS AND METHODS
This prospective, single-center study evaluated the use of a metronomics protocol, consisting of a first cycle of weekly vincristine 1.5 mg/m2 (days: 1, 8, 15 and 22), daily cyclophosphamide 25 mg/m2 (days: 1-21), twice weekly methotrexate 15 mg/m² (days: 21-42) and daily valproic acid (30 mg/kg/d) followed by a 1-week break. For the following cycles, vincristine was administrated only at week 1 and 5 of the cycle. This treatment was proposed to children with refractory disease and patients who were not eligible for the protocols available in the hospital. Adverse events were determined through laboratory analyses and investigator observations.
RESULTS
From January 2010 to January 2011, 7 children (mean age: 5.4 ± 3 years old) were treated. Most frequent diagnosis was retinoblastoma. Two partial responses were observed in patients with neuroblastoma and retinoblastoma. These two patients are alive with stable disease at last follow-up (6 and 26 months, respectively) after stopping treatment.
CONCLUSION
Metronomics allows treating patients with advanced or refractory or relapsing disease and the introduction of targeted treatments in low-income countries. The potential of metronomics in children and young adults living in middle- and low-income countries warrants further larger studies.
Topics: Administration, Metronomic; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cyclophosphamide; Developing Countries; Female; Humans; Male; Mali; Methotrexate; Neoplasms; Pilot Projects; Poverty; Valproic Acid; Vincristine; Young Adult
PubMed: 24061467
DOI: 10.4103/0019-509X.118741 -
Asian Journal of Surgery May 2023
Topics: Humans; Prednisone; Rituximab; Etoposide; Thalidomide; Procarbazine; Neoplasm Recurrence, Local; Lymphoma, B-Cell; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome
PubMed: 36424265
DOI: 10.1016/j.asjsur.2022.11.012 -
Onkologie Dec 2007
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Clinical Trials as Topic; Drug Therapy; Forecasting; Humans; Neoplasms; Neovascularization, Pathologic; Treatment Outcome
PubMed: 18063872
DOI: 10.1159/000111479 -
BioMed Research International 2018Lung cancer is the leading cause of death worldwide. The treatment choice for advanced stage of lung cancer may depend on histotype, performance status (PS), age, and...
BACKGROUND
Lung cancer is the leading cause of death worldwide. The treatment choice for advanced stage of lung cancer may depend on histotype, performance status (PS), age, and comorbidities. In the present study, we focused on the effect of metronomic vinorelbine treatment in elderly patients with advanced unresectable non-small cell lung cancer (NSCLC).
METHODS
From January 2016 to December 2016, 44 patients affected by non-small cell lung cancer referred to our oncology day hospital were progressively analyzed. The patients were treated with oral vinorelbine 30 mg x 3/wk or 40 mg x 3/wk meaning one day on and one day off. The patients were older than 60, stage IIIB or IV, ECOG PS ≥ 1, and have at least one important comorbidity (renal, hepatic, or cardiovascular disease). The schedule was based on ECOG-PS and comorbidities. The primary endpoint was progression-free survival (PFS). PFS was used to compare patients based on different scheduled dosage (30 or 40 mg x3/weekly) and age (more or less than 75 years old) as exploratory analysis. We also evaluated as secondary endpoint toxicity according to Common Toxicity Criteria Version 2.0.
RESULTS
Vinorelbine showed a good safety profile at different doses taken orally and was effective in controlling cancer progression. The median overall survival (OS) was 12 months. The disease control rate (DCR) achieved 63%. The median PFS was 9 months. A significant difference in PFS was detected comparing patients aged below with those over 75, and the HR value was 0.72 (p<0.05). Not significant was the difference between groups with different schedules.
CONCLUSIONS
This study confirmed the safety profile of metronomic vinorelbine and its applicability for patients unfit for standard chemotherapies and adds the possibility of considering this type of schedule not only for very elderly patients.
Topics: Administration, Metronomic; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Female; Frail Elderly; Humans; Lung Neoplasms; Male; Neoplasm Staging; Retrospective Studies; Treatment Outcome; Vinblastine; Vinorelbine
PubMed: 30225260
DOI: 10.1155/2018/6278403 -
Bulletin Du Cancer Dec 2011Angiogenesis is crucial for the growth and metastasis of many cancers. A series of new inhibitors of angiogenesis are now in intensive development. Recent preclinical... (Review)
Review
Angiogenesis is crucial for the growth and metastasis of many cancers. A series of new inhibitors of angiogenesis are now in intensive development. Recent preclinical studies suggest that frequent administration of certain conventional cytotoxic agents at low doses increases their putative antiangiogenic activity. Moreover, many clinical trials confirm efficacy of this metronomic chemotherapy in terms of clinical benefice and survival prolongation. Combining metronomic chemotherapy with hormonotherapy, angiogenesis inhibitors and radiotherapy increases efficacy. Many biomarkers are used to predict optimal drugs and appropriate use of them. This review describes experimental and clinical studies published and discuss its potential uses and limits.
Topics: Age Factors; Angiogenesis Inhibitors; Antineoplastic Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Resistance, Neoplasm; Drug Therapy, Combination; Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 22146261
DOI: 10.1684/bdc.2011.1493 -
PloS One 2019Metronomic chemotherapy using the 5-FU prodrug uracil-tegafur (UFT) and cyclophosphamide (CTX) was previously shown to only modestly delay primary tumor growth, but...
Metronomic chemotherapy using the 5-FU prodrug uracil-tegafur (UFT) and cyclophosphamide (CTX) was previously shown to only modestly delay primary tumor growth, but nevertheless markedly suppressed the development of micro-metastasis in an orthotopic breast cancer xenograft model, using the metastatic variant of the MDA-MB-231 cell line, 231/LM2-4. Furthermore, a remarkable prolongation of survival, with no toxicity, was observed in a model of postsurgical advanced metastatic disease. A question that has remained unanswered is the seemingly selective anti-metastatic mechanisms of action responsible for this treatment. We assessed the in vivo effect of metronomic UFT, CTX or their combination, on vascular density, collagen deposition and c-Met (cell mediators or modulators of tumor cell invasion or dissemination) via histochemistry/immunohistochemistry of primary tumor sections. We also assessed the effect of continuous exposure to low and non-toxic doses of active drug metabolites 5-fluorouracil (5-FU), 4-hydroperoxycyclophosphamide (4-HC) or their combination, on 231/LM2-4 cell invasiveness in vitro. In the in vivo studies, a significant reduction in vascular density and p-Met[Y1003] levels was associated with UFT+CTX treatment. All treatments reduced intratumoral collagen deposition. In the in vitro studies, a significant reduction of collagen IV invasion by all treatments was observed. The 3D structures formed by 231/LM2-4 on Matrigel showed a predominantly Mass phenotype under treated conditions and Stellate phenotype in untreated cultures. Taken together, the results suggest the low-dose metronomic chemotherapy regimens tested can suppress several mediators of tumor invasiveness highlighting a new perspective for the anti-metastatic efficacy of metronomic chemotherapy.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Line, Tumor; Cyclophosphamide; Female; Fluorouracil; Humans; Mice; Mice, SCID; Neoplasm Invasiveness; Neovascularization, Pathologic; Tegafur; Uracil; Xenograft Model Antitumor Assays
PubMed: 31536574
DOI: 10.1371/journal.pone.0222580 -
Cancer Treatment and Research... 2020Metronomic chemotherapy (MCT) is the continuous administration of low dose chemotherapy. It has significant clinical efficacy with minimal toxicity as compared to...
INTRODUCTION
Metronomic chemotherapy (MCT) is the continuous administration of low dose chemotherapy. It has significant clinical efficacy with minimal toxicity as compared to conventional chemotherapy regimens. Thus represents an attractive treatment modality in selected patients with advanced breast cancer.
METHODS
Patients who received MCT in the form of Capecitabine/Cyclophosphamide for the treatment of advanced breast cancer between May 2014 and October 2018 in Sahlgrenska University Hospital in Sweden and in Cork University Hospital, University Hospital Kerry and the South Infirmary-Victoria University Hospital in Ireland were identified. Medical records were retrospectively reviewed to collect data. All survival analyses were described by Kaplan-Meier curves and analysed with log-rank tests. The primary end-point was time on treatment, used as a surrogate marker for efficacy.
RESULTS
148 patients were identified (84 - Sweden, 64 - Ireland), with a median age of 64.2 (range 31-89). The overall mean time on treatment for all patients in both countries is 9.05 months (range 0.36 - 67.21). In patients with bone only disease the mean time on treatment was 10.1 months (range 0.7 - 67.2), compared to patients with visceral disease of 8.91 months (range 0.36 - 39.77). Treatment was ended in the majority of patients because of progression of disease, representing 108 patients (72.9%).
CONCLUSION
This is an observational, retrospective study demonstrating the real world effectiveness of MCT in the treatment of advanced breast cancer. In this cohort of unselected pre-treated patients, the efficacy of MCT was comparable with the survival outcomes of landmark clinical trials.
Topics: Administration, Metronomic; Adult; Aged; Aged, 80 and over; Breast Neoplasms; Female; Humans; Ireland; Middle Aged; Sweden
PubMed: 33248390
DOI: 10.1016/j.ctarc.2020.100237