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International Journal of Oncology Feb 2024Metronomic chemotherapy (MCT) regimens may be associated with risks to the patient due to the ambiguity surrounding low dosages and schedules. In the present study,...
Metronomic chemotherapy (MCT) regimens may be associated with risks to the patient due to the ambiguity surrounding low dosages and schedules. In the present study, metronomic regimens of vinorelbine (NVB) combined with cisplatin (CDDP) or fluorouracil (5‑FU) were chosen to study the dose‑response associations with tumor growth and metastasis, along with the underlying mechanisms in angiogenesis, apoptosis and tumor immunity, using experimental techniques such as immunofluorescence, immunohistochemistry, western blotting and flow cytometry. The results demonstrated a dual‑directional pharmacological action of promoting and suppressing tumor growth or metastasis in BALB/c mice bearing a 4T1 tumor at certain low and high doses of the drugs. Low doses of NVB combined with CDDP or 5‑FU accelerated tumor growth by enhancing angiogenesis, increasing the expression of angiogenic proteins, NF‑κB and osteopontin in tumor tissues, and inducing the accumulation of myeloid‑derived suppressor cells and macrophages. By contrast, higher doses inhibited tumor growth by suppressing these effects. Notably, the upregulation of apoptotic proteins was observed after low‑ and high‑dose treatments. Furthermore, at low concentrations, NVB combined with CDDP or 5‑FU stimulated certain functions of endothelial and tumor cells, including migration and invasion, whereas at higher concentrations they suppressed proliferation and induced apoptosis. Therefore, the results of the present study suggested the potential risks of metronomic combination chemotherapy by demonstrating that, at certain low doses, tumor growth or metastasis was promoted, and emphasized the existence of an effective dose interval that changes with different drug combinations. However, further studies are needed before a specific metronomic combination regimen can be administered clinically for cancer treatment.
Topics: Mice; Animals; Humans; Female; Vinorelbine; Breast Neoplasms; Fluorouracil; Cisplatin; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Administration, Metronomic
PubMed: 38063236
DOI: 10.3892/ijo.2023.5601 -
BMC Immunology May 2024Metronomic capecitabine used as an adjuvant therapy improves survival in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). This therapeutic...
INTRODUCTION
Metronomic capecitabine used as an adjuvant therapy improves survival in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). This therapeutic approach may also contribute to improving immune function, consequently enhancing overall therapeutic efficacy.
AIM
We aimed to evaluate the effect of metronomic capecitabine as adjuvant therapy on immune function and survival in cases of LA-NPC.
SUBJECTS AND METHODS
28 patients with LA-NPC were enrolled in the study and equally assigned to two groups of 14 each: experimental and control group. The experimental group received induction chemotherapy + concurrent chemotherapy + adjuvant chemotherapy as well as oral capecitabine at a dose of 650 mg/m² of body surface area twice daily for 1 year, with the option to discontinue in case of intolerance. The control group did not receive additional chemotherapy or targeted drugs after the induction chemotherapy + concurrent chemoradiotherapy; however, they were followed up regularly. Changes in immune function and survival were compared between the two groups.
RESULTS
The median follow-up time was 43.5 months. One year after adjuvant chemotherapy, the experimental group showed higher levels of CD8 + cells, CD28 + CD8 + cells, and activated CD8 + cells compared to the control group (P < 0.05). The CD4/CD8 ratio and proportion of monocyte-derived dendritic cells were also higher in the experimental group than in the control group, but the difference was not statistically significant (P ≥ 0.05). Comparisons of 3-year overall survival, local-regional recurrence-free survival, progression-free survival, and distant metastasis-free survival between the two groups showed percentages of 92.9% vs. 78.6%, 92.9% vs. 92.9%, 78.6% vs. 71.4%, and 85.7% vs. 0.78 0.6% respectively, but these differences were not significant (P > 0 0.05 ).
CONCLUSION
Metronomic capecitabine chemotherapy was observed to induce an immunomodulatory effect in LA-NPC.
TRIAL REGISTRATION
NCT02958111, date of registration 04-11-2016.
Topics: Humans; Capecitabine; Male; Nasopharyngeal Carcinoma; Female; Middle Aged; Administration, Metronomic; Adult; Chemotherapy, Adjuvant; Nasopharyngeal Neoplasms; CD8-Positive T-Lymphocytes; Aged; Neoplasm Staging; Treatment Outcome; Antimetabolites, Antineoplastic; Follow-Up Studies
PubMed: 38710996
DOI: 10.1186/s12865-024-00621-3 -
Breast (Edinburgh, Scotland) Jun 2024Optimizing chemotherapy to achieve disease and symptoms control is a noteworthy purpose in advanced breast cancer (ABC). We reported the activity and quality of life of... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Phase II randomized trial comparing metronomic anthracycline-containing chemotherapy versus standard schedule in untreated HER2 negative advanced breast cancer: activity and quality of life results of the GOIM 21003 trial.
BACKGROUND
Optimizing chemotherapy to achieve disease and symptoms control is a noteworthy purpose in advanced breast cancer (ABC). We reported the activity and quality of life of a phase II study, comparing metronomic regimen with standard schedule as first line chemotherapy for ABC.
METHODS
Patients with HER2 negative ABC were randomized to non-pegylated liposomal doxorubicin (NPLD, 60 mg/m2 every 3 weeks) and cyclophosphamide (CTX, 600 mg/m2 every 3 weeks) (Arm A) or NPLD (20 mg/m2 day, on day 1, 8 and 15 every 4 weeks) and metronomic daily oral CTX 50 mg (ARM B). Primary end-points were overall response rate (ORR) and quality of life, secondary progression-free survival (PFS), overall survival (OS) and toxicity.
RESULTS
From August 2012 to December 2017, 121 patients were enrolled, 105 evaluable. Median follow-up was 21.3 months. Most patients had hormone receptor positive. ORR was 43 % in arm A and 50 % in arm B. Median PFS was 8.9 months in arm A and 6,4 months in arm B. There was no difference in OS. Total score was not clinically different between the two arms. Grade 4 neutropenia was observed in 12 patients and 16 patients respectively; alopecia G2 in 41 % (77 %) vs 14 (27 %) in arm A and in arm B respectively. One cardiac toxicity was observed (arm A).
CONCLUSIONS
First line metronomic chemotherapy for HER2 negative ABC had similar clinical activity and quite better tolerability than standard schedule and could be considered a further treatment option when chemotherapy is indicated.
Topics: Humans; Female; Breast Neoplasms; Middle Aged; Quality of Life; Administration, Metronomic; Cyclophosphamide; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Receptor, ErbB-2; Progression-Free Survival; Drug Administration Schedule; Treatment Outcome; Anthracyclines; Polyethylene Glycols
PubMed: 38615483
DOI: 10.1016/j.breast.2024.103725 -
BMC Research Notes Jan 2024Metformin is a widely used antidiabetic biguanide. Retrospective data demonstrated the association of metformin use with survival benefit in multiple tumor types....
Metformin is a widely used antidiabetic biguanide. Retrospective data demonstrated the association of metformin use with survival benefit in multiple tumor types. Interest in repurposing metformin to treat cancer has not been translated into encouraging clinical benefit. In animal models, metformin activated cytotoxic T cells and exerted an immune-mediated anticancer effect. The current research was conducted to investigate the possible therapeutic benefit of metformin in combination with metronomic cyclophosphamide in an experimental cancer model. Ehrlich ascites carcinoma was injected into the subcutaneous tissue to induce solid tumors in syngeneic mice. Exponential solid tumor growth ensued and was effectively arrested with the administration of a cytotoxic dose of parenteral cyclophosphamide. Alternatively, oral metformin and continuous, low-dose cyclophosphamide significantly inhibited tumor growth relative to untreated mice. The drug combination was well tolerated. Histopathological examination of the tumor showed an increased number of tumor-infiltrating lymphocytes and enhanced expression of granzyme B by this drug combination. The current data suggests a potential role of metformin and metronomic chemotherapy that warrants further investigation.
Topics: Mice; Animals; Lymphocytes, Tumor-Infiltrating; Metformin; Retrospective Studies; Administration, Metronomic; Cyclophosphamide; Carcinoma; Drug Combinations; Cell Line, Tumor
PubMed: 38167322
DOI: 10.1186/s13104-023-06651-1 -
International Immunopharmacology Nov 2023Liver transplantation is one of the most effective treatments for hepatocellular carcinoma (HCC). The balance between inhibiting immune rejection and preventing tumor...
Liver transplantation is one of the most effective treatments for hepatocellular carcinoma (HCC). The balance between inhibiting immune rejection and preventing tumor recurrence after liver transplantation is the key to determining the long-term prognosis of patients with HCC after liver transplantation. In our previous study, we found that capecitabine (CAP), an effective drug for the treatment of HCC, could exert an immunosuppressive effect after liver transplantation by inducing T cell ferroptosis. Recent studies have shown that ferroptosis is highly associated with autophagy. In this study, we confirmed that the autophagy inducer rapamycin (RAPA) combined with metronomic capecitabine (mCAP) inhibits glutathione peroxidase 4 (GPX4) and promotes ferroptosis in CD4 T cells to exert immunosuppressive effects after rat liver transplantation. Compared with RAPA or mCAP alone, the combination of RAPA and mCAP could adequately reduce liver injury in rats with acute rejection after transplantation. The CD4 T cell counts in peripheral blood, spleen, and transplanted liver of recipient rats significantly decreased, and the oxidative stress level and ferrous ion concentration of CD4 T cells significantly increased in the combination group. In vitro, the combination of drugs significantly promoted autophagy, decreased GPX4 protein expression, and induced ferroptosis in CD4 T cells. In conclusion, the autophagy inducer RAPA improved the mCAP-induced ferroptosis in CD4 T cells. Our results support the concept of ferroptosis as an autophagy-dependent cell death and suggest that the combination of ferroptosis inducers and autophagy inducers is a new research direction for improving immunosuppressive regimens after liver transplantation.
Topics: Humans; Rats; Animals; Sirolimus; T-Lymphocytes; Capecitabine; Liver Transplantation; Ferroptosis; Carcinoma, Hepatocellular; Liver Neoplasms; Neoplasm Recurrence, Local; CD4-Positive T-Lymphocytes
PubMed: 37625370
DOI: 10.1016/j.intimp.2023.110810 -
Journal of Controlled Release :... May 2024Local and long-lasting administration of potent chemotherapeutics is a promising therapeutic intervention to increase the efficiency of chemotherapy of hard-to-treat...
Local and long-lasting administration of potent chemotherapeutics is a promising therapeutic intervention to increase the efficiency of chemotherapy of hard-to-treat tumors such as the most lethal brain tumors, glioblastomas (GBM). However, despite high toxicity for GBM cells, potent chemotherapeutics such as gemcitabine (Gem) cannot be widely implemented as they do not efficiently cross the blood brain barrier (BBB). As an alternative method for continuous administration of Gem, we here operate freestanding iontronic pumps - "GemIPs" - equipped with a custom-synthesized ion exchange membrane (IEM) to treat a GBM tumor in an avian embryonic in vivo system. We compare GemIP treatment effects with a topical metronomic treatment and observe that a remarkable growth inhibition was only achieved with steady dosing via GemIPs. Daily topical drug administration (at the maximum dosage that was not lethal for the embryonic host organism) did not decrease tumor sizes, while both treatment regimes caused S-phase cell cycle arrest and apoptosis. We hypothesize that the pharmacodynamic effects generate different intratumoral drug concentration profiles for each technique, which causes this difference in outcome. We created a digital model of the experiment, which proposes a fast decay in the local drug concentration for the topical daily treatment, but a long-lasting high local concentration of Gem close to the tumor area with GemIPs. Continuous chemotherapy with iontronic devices opens new possibilities in cancer treatment: the long-lasting and highly local dosing of clinically available, potent chemotherapeutics to greatly enhance treatment efficiency without systemic side-effects. SIGNIFICANCE STATEMENT: Iontronic pumps (GemIPs) provide continuous and localized administration of the chemotherapeutic gemcitabine (Gem) for treating glioblastoma in vivo. By generating high and constant drug concentrations near the vascularized growing tumor, GemIPs offer an efficient and less harmful alternative to systemic administration. Continuous GemIP dosing resulted in remarkable growth inhibition, superior to daily topical Gem application at higher doses. Our digital modelling shows the advantages of iontronic chemotherapy in overcoming limitations of burst release and transient concentration profiles, and providing precise control over dosing profiles and local distribution. This technology holds promise for future implants, could revolutionize treatment strategies, and offers a new platform for studying the influence of timing and dosing dependencies of already-established drugs in the fight against hard-to-treat tumors.
Topics: Animals; Gemcitabine; Deoxycytidine; Brain Neoplasms; Glioblastoma; Chick Embryo; Apoptosis; Cell Line, Tumor; Humans; Antineoplastic Agents; Administration, Metronomic
PubMed: 38548064
DOI: 10.1016/j.jconrel.2024.03.044 -
Frontiers in Oncology 2023A series of seven clinical trials on relapsed or refractory (r/r) metastatic neoplasias followed the question: Are networks of ligand-receptor cross-talks that support... (Review)
Review
A series of seven clinical trials on relapsed or refractory (r/r) metastatic neoplasias followed the question: Are networks of ligand-receptor cross-talks that support tumor-specific cancer hallmarks, druggable with tumor tissue editing approaches therapeutically exploiting tumor plasticity? Differential recombinations of pioglitazone, a dual peroxisome-proliferator activated receptor (PPARα/γ) agonist, with transcriptional modulators, i.e., all-trans retinoic acid, interferon-α, or dexamethasone plus metronomic low-dose chemotherapy (MCT) or epigenetic modeling with azacitidine plus/minus cyclooxygenase-2 inhibition initiated tumor-specific reprogramming of cancer hallmarks, as exemplified by inflammation control in r/r melanoma, renal clear cell carcinoma (RCCC), Hodgkin's lymphoma (HL) and multisystem Langerhans cell histiocytosis (mLCH) or differentiation induction in non-promyelocytic acute myeloid leukemia (non-PML AML). Pioglitazone, integrated in differentially designed editing schedules, facilitated induction of tumor cell death as indicated by complete remission (CR) in r/r non-PML AML, continuous CR in r/r RCCC, mLCH, and in HL by addition of everolimus, or long-term disease control in melanoma by efficaciously controlling metastasis, post-therapy cancer repopulation and acquired cell-resistance and genetic/molecular-genetic tumor cell heterogeneity (M-CRAC). PPARα/γ agonists provided tumor-type agnostic biomodulatory efficacy across different histologic neoplasias. Tissue editing techniques disclose that wide-ranging functions of PPARα/γ agonists may be on-topic focused for differentially unlocking tumor phenotypes. Low-dose MCT facilitates targeted reprogramming of cancer hallmarks with transcriptional modulators, induction of tumor cell death, M-CRAC control and editing of non-oncogene addiction. Thus, pioglitazone, integrated in tumor tissue editing protocols, is an important biomodulatory drug for addressing urgent therapeutic problems, such as M-CRAC in relapsed or refractory tumor disease.
PubMed: 38273846
DOI: 10.3389/fonc.2023.1289222 -
Biomedicines Jan 2024A group of 27 patients diagnosed with metastatic triple-negative breast cancer (mTNBC) was randomly distributed into two groups and underwent different lines of...
Differential Expression of NOTCH-1 and Its Molecular Targets in Response to Metronomic Followed by Conventional Therapy in a Patient with Advanced Triple-Negative Breast Cancer.
A group of 27 patients diagnosed with metastatic triple-negative breast cancer (mTNBC) was randomly distributed into two groups and underwent different lines of metronomic treatment (mCHT). The former group (N 14) received first-line mCHT and showed a higher overall survival rate than the second group (N 13), which underwent second-line mCHT. Analysis of one patient still alive from the first group, diagnosed with mTNBC in 2019, showed a complete metabolic response (CMR) after a composite approach implicating first-line mCHT followed by second-line epirubicin and third-line nab-paclitaxel, and was chosen for subsequent molecular characterization. We found altered expression in the cancer stemness-associated gene and its corresponding protein. Additionally, we found changes in the expression of oncogenes, such as and , along with their respective proteins. Overall, our data suggest that a first-line treatment with mCHT followed by MTD might be effective by negatively regulating stemness traits usually associated with the emergence of drug resistance.
PubMed: 38397874
DOI: 10.3390/biomedicines12020272 -
Journal of Clinical Medicine Nov 2023In the original publication [...].
Correction: Bocci et al. Remarkable Remission Rate and Long-Term Efficacy of Upfront Metronomic Chemotherapy in Elderly and Frail Patients, with Diffuse Large B-Cell Lymphoma. 2022, , 7162.
In the original publication [...].
PubMed: 38002810
DOI: 10.3390/jcm12227053 -
British Journal of Cancer May 2024Glioblastoma represents a brain tumor with a notoriously poor prognosis. First-line therapy may include adjunctive Tumor Treating Fields (TTFields) which are electric...
BACKGROUND
Glioblastoma represents a brain tumor with a notoriously poor prognosis. First-line therapy may include adjunctive Tumor Treating Fields (TTFields) which are electric fields that are continuously delivered to the brain through non-invasive arrays. On a different note, CUSP9v3 represents a drug repurposing strategy that includes 9 repurposed drugs plus metronomic temozolomide. Here, we examined whether TTFields enhance the antineoplastic activity of CUSP9v3 against this disease.
METHODS
We performed preclinical testing of a multimodal approach of TTFields and CUSP9v3 in different glioblastoma models.
RESULTS
TTFields had predominantly synergistic inhibitory effects on the cell viability of glioblastoma cells and non-directed movement was significantly impaired when combined with CUSP9v3. TTFields plus CUSP9v3 significantly enhanced apoptosis, which was associated with a decreased mitochondrial outer membrane potential (MOMP), enhanced cleavage of effector caspase 3 and reduced expression of Bcl-2 and Mcl-1. Moreover, oxidative phosphorylation and expression of respiratory chain complexes I, III and IV was markedly reduced.
CONCLUSION
TTFields strongly enhance the CUSP9v3-mediated anti-glioblastoma activity. TTFields are currently widely used for the treatment of glioblastoma patients and CUSP9v3 was shown to have a favorable safety profile in a phase Ib/IIa trial (NCT02770378) which facilitates transition of this multimodal approach to the clinical setting.
Topics: Humans; Glioblastoma; Drug Repositioning; Metabolic Reprogramming; Temozolomide; Antineoplastic Agents; Brain Neoplasms; Electric Stimulation Therapy; Combined Modality Therapy
PubMed: 38396172
DOI: 10.1038/s41416-024-02608-8