Chemotherapy Regimens For Cancer Research Articles

Efficacy and safety of multi-day antiemetic treatment for patients undergoing multi-day chemotherapy: a systematic review of Clinical Practice Guidelines for Antiemesis 2023 from Japan Society of Clinical Oncology.

A standardized multi-day antiemetic regimen for multi-day chemotherapy remains elusive. This systematic review evaluated the efficacy and safety of multi-day antiemetic regimens in patients undergoing multi-day intravenous chemotherapy. We conducted a comprehensive search of PubMed, Cochrane Library, and Ichushi-Web databases for relevant studies published from January 1990 to December 2020. We included studies comparing multi-day and single-day antiemetic regimens for preventing chemotherapy-induced nausea and vomiting. No studies directly comparing multi-day versus single-day antiemetic regimens were found. Despite expanding control group criteria beyond "single-day antiemetic therapy" limited high-quality studies and variations in cancer types, chemotherapy regimens, and antiemetic treatments precluded meta-analysis. Among the included studies, some randomized controlled trials (RCTs) focused on complete response and vomiting rates. Two studies comparing two- and three-drug combinations reported higher complete response and no-vomiting rates with the three-drug regimen. Limited RCTs explored "nausea control" and "cost," and assessing "adverse events" proved challenging due to inconsistent reporting. The research on multi-day antiemetic therapy is limited, necessitating further investigation. Nonetheless, our findings suggest that three-drug combination therapy, including aprepitant, may offer superior antiemetic efficacy compared to two-drug regimens. Multi-day antiemetic therapy is strongly recommended during multi-day intravenous administration of cytotoxic anticancer drugs.

Administration sequences in single-day chemotherapy regimens for breast cancer: a comprehensive review from a practical perspective.

Breast cancer is one of the most prevalent malignant tumors globally, posing a severe threat to human life and health. Chemotherapy, a cornerstone in the treatment of breast cancer, often overlooks the sequence of drug administration within single-day regimens. This study aims to explore the impact of drug administration order on the efficacy and toxicity of combination chemotherapy protocols for breast cancer. Through a comprehensive review and analysis based on current evidence from evidence-based medicine, we delved into how the order of drug administration affects both efficacy and toxicity. We systematically classified and analyzed commonly used combination drug regimens, providing graded recommendations and a reasoned analysis to offer valuable references for clinical decision-making. Our findings indicate that the sequence of drug administration in complex combination chemotherapy protocols is not arbitrary but necessitates multifaceted considerations. Rational drug sequencing can maximize synergistic effects between drugs, thereby augmenting therapeutic efficacy while effectively mitigating drug-related adverse effects. Additionally, some drug labels and clinical trials have explicitly highlighted the therapeutic benefits of specific drug sequences. This study underscores the importance of considering the sequence of drug administration in clinical practice. It is recommended to prioritize the sequential drug administration according to official drug product labeling, while also considering factors such as the administration sequence from large randomized controlled trials, cell proliferation kinetics specific to cancer types, drug interactions, chronopharmacology, drug irritability, clinical experiences, and patient preferences. By taking these factors into account, the goal is to maximize treatment efficacy and minimize the occurrence of adverse reactions.

Melatonin mitigates chemotherapy-induced small intestinal atrophy in rats and reduces cytotoxicity in murine intestinal organoids.

Cancer continues to pose a significant global health challenge, with gastrointestinal (GI) cancers among the most prevalent and deadly forms. These cancers often lead to high mortality rates and demand the use of potent cytotoxic chemotherapeutics. For example, 5-fluorouracil (5-FU) forms the backbone of chemotherapy regimens for various GI cancers, including colorectal cancer. While these chemotherapeutics efficiently kill cancer cells, they frequently cause off-target effects such as chemotherapy-induced mucositis (CIM), characterized by debilitating symptoms like pain, nausea, and diarrhoea, necessitating medical intervention. In this study, we elucidated the potential of melatonin and misoprostol to reduce 5-FU-induced small intestinal mucositis. Morphological and cellular changes in the jejunum, along with colonic faecal water content were quantified in rats as markers for CIM. Additionally, the effects of melatonin were investigated in vitro on 5-FU treated murine intestinal organoids. The results showed that melatonin prevented villus atrophy in the rat jejunal mucosa and upheld cell viability in murine intestinal organoids. In contrast, misoprostol alone or in combination with melatonin did not significantly affect CIM caused by 5-FU. These in vivo and in vitro experiments provided promising insights that melatonin may be used as a preventive and/or adjuvant combination therapy to prevent and reduce CIM, holding the potential to enhance cancer treatment outcomes and improve patient quality-of-life.

Exploring Genetic Variants and Platinum Chemotherapy Response in Indonesian Non-Small Cell Lung Cancer Patients: Insights from ERCC2 rs13181.

Individual responses to platinum-based treatment for Non-Small Cell Lung Cancer (NSCLC) are influenced by genetic polymorphisms, including Single Nucleotide Polymorphisms (SNPs). This study aimed to explore the role of ERCC2 in the Nucleotide Excision Repair (NER) pathway for platinum-based chemotherapy in NSCLC. While ERCC2 is widely studied, data for Southeast Asian populations are lacking. Addressing this gap could improve personalized treatment strategies for NSCLC in this demographic. This study recruited 82 NSCLC patients with wildtype mutations of EGFR at Dr. H.A. Rotinsulu Lung Hospital, Bandung, and Dharmais Cancer Hospital, Jakarta. Data were collected prospectively from whole blood samples and medical records, while the effectiveness of chemotherapy was assessed by evaluating the response using RECIST 1.1 criteria on fourth cycle of chemotherapy. The results of this study showed the presence of genotype variation among the subjects, with frequency distribution as follows: AA genotype (82.9%), AC genotype (15.9%), and CC genotype (1.2%). The analysis of the association between ERCC2 rs13181 CC + AC versus AA with RECIST 1.1 yielded an odds ratio (OR) of 1.042 (95% CI: 0.292-3.715; p=0.950). A multivariate analysis that included cancer stage and chemotherapy regimen as additional variables produced an adjusted odds ratio (aOR) of 0.970 (95% CI: 0.263-3.568; p=0.963). This study did not find statistically significant associations between ERCC2 rs13181 polymorphisms and chemotherapy responses. However, this research highlights the presence of genetic variation within the Indonesian population, with the AA genotype being the most prevalent, which may influence chemotherapy responses. The results provided preliminary data and lay the foundation for future comprehensive cohort observational investigations.

Paclitaxel in colon cancer management: from conventional chemotherapy to advanced nanocarrier delivery systems.

Paclitaxel, a potent chemotherapeutic agent derived from the bark of the Pacific yew tree, has demonstrated significant efficacy in the treatment of various cancers, including colon cancer. This comprehensive review delves into the conventional treatments for colon cancer, emphasizing the crucial role of paclitaxel in contemporary management strategies. It explores the intricate process of sourcing and synthesizing paclitaxel, highlighting the importance of its structural properties in its anticancer activity. The review further elucidates the mechanism of action of paclitaxel, its pharmacological effects, and its integration into chemotherapy regimens for colon cancer. Additionally, novel drug delivery systems, such as nanocarriers, liposomes, nanoparticles, microspheres, micelles, microemulsions, and niosomes, are examined for their potential to enhance the therapeutic efficacy of paclitaxel. The discussion extends to recent clinical trials and patents, showcasing advancements in paclitaxel formulations aimed at improving treatment outcomes. The review concludes with prospects in the field underscoring the ongoing innovation and potential breakthroughs in colon cancer therapy.

A Cyclometalated Ruthenium(II) Complex Induces Oncosis for Synergistic Activation of Innate and Adaptive Immunity

AbstractAn optimal cancer chemotherapy regimen should effectively address the drug resistance of tumors while eliciting antitumor‐immune responses. Research has shown that non‐apoptotic cell death, such as pyroptosis and ferroptosis, can enhance the immune response. Despite this, there has been limited investigation and reporting on the mechanisms of oncosis and its correlation with immune response. Herein, we designed and synthesized a Ru(II) complex that targeted the nucleus and mitochondria to induce cell oncosis. Briefly, the Ru(II) complex disrupts the nucleus and mitochondria DNA, which active polyADP‐ribose polymerase 1, accompanied by ATP consumption and porimin activation. Concurrently, mitochondrial damage and endoplasmic reticulum stress result in the release of Ca2+ ions and increased expression of Calpain 1. Subsequently, specific pore proteins porimin and Calpain 1 promote cristae destruction or vacuolation, ultimately leading to cell membrane rupture. The analysis of RNA sequencing demonstrates that the Ru(II) complex can initiate the oncosis‐associated pathway and activate both innate and adaptive immunity. In vivo experiments have confirmed that oncosis promotes dendritic cell maturation and awakens adaptive cytotoxic T lymphocytes but also activates the innate immune by inducing the polarization of macrophages towards an M1 phenotype.

A Cyclometalated Ruthenium(II) Complex Induces Oncosis for Synergistic Activation of Innate and Adaptive Immunity.

An optimal cancer chemotherapy regimen should effectively address the drug resistance of tumors while eliciting antitumor-immune responses. Research has shown that non-apoptotic cell death, such as pyroptosis and ferroptosis, can enhance the immune response. Despite this, there has been limited investigation and reporting on the mechanisms of oncosis and its correlation with immune response. Herein, we designed and synthesized a Ru(II) complex that targeted the nucleus and mitochondria to induce cell oncosis. Briefly, the Ru(II) complex disrupts the nucleus and mitochondria DNA, which active polyADP-ribose polymerase 1, accompanied by ATP consumption and porimin activation. Concurrently, mitochondrial damage and endoplasmic reticulum stress result in the release of Ca2+ ions and increased expression of Calpain 1. Subsequently, specific pore proteins porimin and Calpain 1 promote cristae destruction or vacuolation, ultimately leading to cell membrane rupture. The analysis of RNA sequencing demonstrates that the Ru(II) complex can initiate the oncosis-associated pathway and activate both innate and adaptive immunity. In vivo experiments have confirmed that oncosis promotes dendritic cell maturation and awakens adaptive cytotoxic T lymphocytes but also activates the innate immune by inducing the polarization of macrophages towards an M1 phenotype.

Survival Analysis of Lung Cancer Patients at Dr. Saiful Anwar Hospital

Background: Comprising 14% of all cancer, lung cancer is the main cause of cancer-related mortality worldwide. Previous studies showed various findings regarding the survival rate of lung cancer, and factors significantly correlated with survival rate in lung cancer patients. Aim: This research aims to identify the profile and survival rate of lung cancer patients receiving chemotherapy in Saiful Anwar General Hospital from 2018 to 2020. Methods: This cohort retrospective study used medical records of patients diagnosed with lung cancer who underwent chemotherapy from 2018 to 2020. Data analysis was done using the Mantel Cox log rank test. Survival data shown as progression free survival (PFS) and overall survival (OS) were shown using Kaplan-Meier curves. Results: Subjects were largely male (73,2%). Adenocarcinoma is the most often type of lung cancer found (59,8%) with wild type EGFR mutation being the most prevalent (20,6%). Carboplatin – Paclitaxel is the most widely used chemotherapy regimen (54,6%). Survival analysis showed a significant correlation between age, OS, and PFS (p < 0,05) Conclusion: Various factors such as gender, cancer cell type, EGFR mutation, and chemotherapy regimen were not found to be related to survival rate in lung cancer patients. A significant correlation between age and survival rate showed potential in utilizing age as a predictor of survival rate in lung cancer patients.

3D stem-like spheroids-on-a-chip for personalized combinatorial drug testing in oral cancer

BackgroundFunctional drug testing (FDT) with patient-derived tumor cells in microfluidic devices is gaining popularity. However, the majority of previously reported microfluidic devices for FDT were limited by at least one of these factors: lengthy fabrication procedures, absence of tumor progenitor cells, lack of clinical correlation, and mono-drug therapy testing. Furthermore, personalized microfluidic models based on spheroids derived from oral cancer patients remain to be thoroughly validated. Overcoming the limitations, we develop 3D printed mold-based, dynamic, and personalized oral stem-like spheroids-on-a-chip, featuring unique serpentine loops and flat-bottom microwells arrangement.ResultsThis unique arrangement enables the screening of seven combinations of three drugs on chemoresistive cancer stem-like cells. Oral cancer patients-derived stem-like spheroids (CD 44+) remains highly viable (> 90%) for 5 days. Treatment with a well-known oral cancer chemotherapy regimen (paclitaxel, 5 fluorouracil, and cisplatin) at clinically relevant dosages results in heterogeneous drug responses in spheroids. These spheroids are derived from three oral cancer patients, each diagnosed with either well-differentiated or moderately-differentiated squamous cell carcinoma. Oral spheroids exhibit dissimilar morphology, size, and oral tumor-relevant oxygen levels (< 5% O2). These features correlate with the drug responses and clinical diagnosis from each patient’s histopathological report.ConclusionsOverall, we demonstrate the influence of tumor differentiation status on treatment responses, which has been rarely carried out in the previous reports. To the best of our knowledge, this is the first report demonstrating extensive work on development of microfluidic based oral cancer spheroid model for personalized combinatorial drug screening. Furthermore, the obtained clinical correlation of drug screening data represents a significant advancement over previously reported personalized spheroid-based microfluidic devices. Finally, the maintenance of patient-derived spheroids with high viability under oral cancer relevant oxygen levels of less than 5% O2 is a more realistic representation of solid tumor microenvironment in our developed device.Graphical

Patient characteristics associated with primary prophylactic granulocyte colony-stimulating factor (G-CSF) use among women treated for early-stage breast cancer.

e12605 Background: The National Comprehensive Cancer Network (NCCN) recommends several chemotherapy regimens for early-stage breast cancer that have elevated risk of neutropenia (&gt;20%). In these regimens, primary prophylactic use of granulocyte colony-stimulating factor (G-CSF) is recommended. Little is known about how patient-level factors relate to receipt of prophylactic G-CSF among women receiving these regimens. Methods: In the Optimal Breast Cancer Chemotherapy Dosing (OBCD) Study, we examined use of G-CSF among women with stage I-IIIA breast cancer between 2005-2019 in Kaiser Permanente Northern California (KPNC) and Kaiser Permanente Washington (KPWA). We evaluated the patient-level factors associated with primary prophylactic G-CSF use (≤7 days before to ≤3 days after first day of chemotherapy) among women receiving chemotherapy regimens with high risk of neutropenia, for which the NCCN guidelines recommend prophylactic G-CSF use. Multivariable-adjusted prevalence ratios (PR) and their corresponding 95% Confidence Intervals (95% CI) were calculated using generalized linear models of the Poisson family with a log link-function and robust standard errors. Results: Overall, while all 3,083 women receiving these regimens ultimately received G-CSF, 2412 (79%) received primary prophylactic G-CSF within the period 7 days prior to 3 days post first cycle. Younger women had higher prevalence of prophylactic G-CSF receipt (82.7% in ages 18-39 years vs. 58.1% in 70+ years). Black women had higher prevalence of receipt compared to white women (82.7% in non-Hispanic Black women vs 76.1% in White women). Women with a higher body mass index (BMI) had lower prevalence of receipt compared to normal weight women (73.3% in 35+ kg/m2 group vs 81.5% in 18.5-&lt;25 kg/m2 group). In multivariable models, older women were less likely to receive prophylactic G-CSF (PR70+ vs 18-39: 0.69; 95% CI: 0.57-0.84; p-trend&lt;0.001), as were those with a higher BMI (PRBMI 35+ vs 18.5-&lt;25: 0.92; 95% CI: 0.85, 0.97; p-trend=0.006), and a later year of diagnosis (PR2016-19 vs 2005-07: 0.81; 95% CI: 0.77, 0.85; p-trend&lt;0.001). Although race/ethnicity was not significantly associated with receipt of prophylactic G-CSF use overall in multivariable models, we observed Non-Hispanic Black women to experience slightly higher likelihood of G-CSF receipt than Non-Hispanic White women (PR: 1.08; 95% CI: 1.02, 1.15). Conclusions: Women of older age and those with higher BMI were less likely to receive primary prophylactic G-CSF, as were women treated in later years. Further research looking at timing of G-CSF use is warranted, as are studies examining provider/facility-level factors in relation to patterns of G-CSF use, G-CSF’s impact on survival outcomes, and the real-world impact of decisions around G-CSF use across age, BMI, and racial/ethnic groups.

Prevalence, Attributes, and Risk Factors of QT-Interval-Prolonging Drugs and Potential Drug-Drug Interactions in Cancer Patients: A Prospective Study in a Tertiary Care Hospital.

Introduction Cancer chemotherapy regimens include multiple classes of adjuvant drugs as supportive therapy. Because of the concurrent intake of other drugs (like antiemetics, antidepressants, analgesics, and antimicrobials), there is a heightened risk for possible QT interval prolongation. There is a dearth of evidence in the literature regarding the usage of QT-prolonging anticancer drugs and associated risk factors that have the propensity to prolong QT interval. The purpose was to explore the extent of the use of QT-interval-prolonging drugs and potential QT-prolonging drug-drug interactions (QT-DDIs) in cancer patients attending OPD in a tertiary-care hospital. Methods This was a hospital-based, cross-sectional, observational study. Risk stratification of QT-prolonging drugs for torsades de pointes (TdP) was done by the Arizona Center for Education and Research on Therapeutics (AzCERT)/CredibleMeds-lists, and potential QT-DDIs were determined with four online DDI-checker-software. Results In 1331 cancer patients, the overall prevalence of potential QT-prolonging drug utilization was 97.3%. Ondansetron, pantoprazole, domperidone, and olanzapine were the most frequent QT-prolonging drugs in cancer patients. The top six antineoplastics with potential QT-prolongingand torsadogenic actions were capecitabine, oxaliplatin, imatinib, bortezomib, 5-fluorouracil, and bendamustine. Evidence-based pragmatic QTc interval prolongation risk assessment tools are imperative for cancer patients. Conclusion This study revealed a high prevalence of QT-prolonging drugs and QT-DDIs among cancer patients who are treated with anticancer and non-anticancer drugs. As a result, it's critical to take precautions, stay vigilant, and avoid QT-prolongingin clinical situations. Evidence-based pragmatic QTc interval prolongation risk assessment tools are needed for cancer patients.

Ketogenesis attenuated KLF5 disrupts iron homeostasis via LIF to confer oxaliplatin vulnerability in colorectal cancer

Oxaliplatin has been included as a basal drug in various chemotherapy regimens for colorectal cancer (CRC), a global health concern. However, acquired resistance to oxaliplatin affects the prognosis. This study aimed to determine whether the consumption of a KD increases the sensitivity of CRC cells to oxaliplatin via the inhibition of a classical stem cell marker, Krupple-like factor 5 (KLF5). KLF5 functions as a transcription factor for the leukemia inhibitory factor (LIF) and directly binds to its promoter region. LIF upregulation induces dephosphorylation of metal regulatory transcription factor 1 (MTF1), which is recruited to the promoter area of Ferroportin (FPN1), the only cellular iron exporter. FPN1 upregulation reduces the labile iron pool (LIP) and ferroptosis in CRC cells. KLF5 knockdown inhibits the LIF/MTF1/FPN1 axis and induces iron overload, thereby conferring sensitivity to oxaliplatin to CRC cells. KD mimicked KLF5 silencing and sensitized CRC cells to oxaliplatin via a similar mechanism. Thus, potential correlations were observed among ketogenesis, stemness, and iron homeostasis. This finding can be used to formulate a new strategy for overcoming oxaliplatin resistance in patients with CRC.

Abstract PO2-12-12: REaCT 5G: A randomized study comparing bone pain after 5 days of filgrastim or one day of pegfilgrastim for primary febrile neutropenia prophylaxis during neo-/adjuvant chemotherapy for early breast cancer

Abstract Background: Granulocyte colony stimulating factor (G-CSF) such as filgrastim (FIL) or pegfilgrastim (PEG) significantly reduces the risk of febrile neutropenia (FN) and treatment-related hospitalization in patients with early breast cancer receiving chemotherapy. However, patients receiving G-CSF can experience clinically significant bone pain. Previous studies examining post-GCSF bone pain were mostly based on physician pain assessment and compared mixed doses (30/60/100 μg/kg) of PEG vs. FIL (5μg/kg/day or 300 μg/day) given for 7 to 14 days. Based on a randomized non-inferiority study, 5 days of FIL is considered non-inferior to 10 days of FIL to prevent FN and hospitalizations and is frequently used in patients receiving chemotherapy for breast cancer. Patient-reported bone pain after 5 days of FIL vs. single dose of PEG has never been compared in a prospective randomized study and has important implications for patient and physician treatment preferences. Methods: In this multicenter, open-label trial, patients receiving neo-/adjuvant chemotherapy for early-stage breast cancer requiring primary FN prophylaxis with G-CSF were randomized 1:1 to either 5 days of FIL (300 μg or 480μg if ≥ 90 kg) or 1 day of PEG (6 mg) with each cycle of chemotherapy. The primary endpoint was bone pain using area under the curve (AUC) of the daily pain score from days 1-5 (AUC score 0 to 40) during cycle 1. We used linear regression adjusting for stratification factors [cancer center (2 centers) and chemotherapy regimen (taxane (TAX) or anthracycline (ANTH)-based during cycle 1] and prespecified baseline covariates: age, pain, and use of pain medications pre-chemotherapy. Supportive analysis of bone pain across cycles 1 to 4 was conducted using repeated linear regression. Key secondary endpoints included incidence of FN, hospitalizations, chemotherapy delay, dose-reduction or discontinuation, and chemotherapy-related deaths. Results: From June 2021 to March 2023, 233 patients were enrolled, with 217 patients (108 FIL/109 PEG) in the intention-to-treat analysis; 16 (7.4%) patients were excluded because of incomplete follow-up. Participants were mean age 55.6 years; almost exclusively female (99.1%), on chemotherapy regimen TAX 57% vs. ANTH 43%, had mean baseline pain score 1.12, and prevalence of pain medication use pre-chemotherapy was acetaminophen 14.7%, non-steroidal anti-inflammatory drugs (NSAIDs) 6.0% and opioids 3.2%. Characteristics were balanced between arms (Table 1). After repeated measures linear regression adjusted for age, chemotherapy regimen, baseline pain, and use of pain medications pre-chemotherapy, mean AUC for bone pain at cycle 1 was 10.94 for FIL and 10.12 for PEG (mean difference 0.82; 95% CI: -1.59, 3.23; p = 0.516). There was no significant difference between arms across treatment cycles (interaction p = 0.785; mean time-averaged difference 0.28; 95% CI: -1.75, 2.32). Across cycles 1 to 4, mean peak pain over 5 days post-GCSF was 3.27 vs. 3.41 (p=0.700); frequency of bone pain during first 8 days (pain score &amp;gt; 0) was 52.5% vs. 51.3%; p=0.358, and mean frequency of severe pain (pain score ≥ 5) was 17.5% vs. 15.2%; p=0.014 for FIL vs. PEG, respectively. The incidence of FN [4.6% vs. 0%, absolute difference 4.6% (95% CI: -0.3%, 9.5%; p=0.069)] and hospitalization [FN and non-FN related: 10.2% vs. 1.8%, absolute difference of 8.4% (95% CI: 1.2%, 15.5%; p=0.021)] was higher in the FIL group. There were no significant differences in chemotherapy delay (13% vs. 11%; p=0.815), dose reduction (14.8% vs. 14.7%; p=0.999), early discontinuation (8.3% vs. 5.5%; p=0.580), or chemotherapy-related death (0.9% vs. 0%; p=0.996) in the FIL vs. PEG groups, respectively. Conclusion: There was no difference in patient-reported bone pain after 5 days of FIL or PEG, even after controlling for important clinical factors. Importantly, the study observed higher rates of FN and hospitalizations in patients receiving FIL for 5 days only. Table 1 Baseline Characteristics Citation Format: Terry Ng, Yuxin Zhang, Carol Stober, Jennifer Shamess, Natalie Mills, Stuart Nicholls, Mohammed Ibrahim, Daniel Davoudpour, Christopher Armiento, Marie-France Savard, Moira Rushton, Arif Awan, Sandeep Sehdev, John Hilton, Xinni Song, Rakesh Goel, Fiona Macdonald, Kelly Daigle, Lisa Vandermeer, Monica Taljaard, Mark Clemons. REaCT 5G: A randomized study comparing bone pain after 5 days of filgrastim or one day of pegfilgrastim for primary febrile neutropenia prophylaxis during neo-/adjuvant chemotherapy for early breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-12-12.

Circadian rhythms in CYP2A5 expression underlie the time-dependent effect of tegafur on breast cancer

The chemotherapeutic agent tegafur, a prodrug that prolongs the half-life of fluorouracil (5-FU), exerts antitumor effects against various cancers. Since tegafur is metabolized to 5-FU by CYP2A6 in the liver, the expression of CYP2A6 determines the effect of tegafur. Here, we report that the expression rhythm of Cyp2a5, a homolog of human CYP2A6, in female mice causes dosing time-dependent differences in tegafur metabolism. In the livers of female mice, CYP2A5 expression showed a circadian rhythm, peaking during the dark period. This rhythm is regulated by RORA, a core clock component, and abrogation of the CYP2A5 activity abolished the time-dependent difference in the rate of tegafur metabolism in female mice. Furthermore, administration of tegafur to mice transplanted with 4T1 breast cancer cells during the dark period suppressed increases in tumor size compared to female mice treated during the light period. Our findings reveal a novel relationship between 5-FU prodrugs and circadian clock machinery, potentially influencing antitumor effects, and contributing to the development of time-aware chemotherapy regimens for breast cancer.

Exploring the vast potentials and probable limitations of novel and nanostructured implantable drug delivery systems for cancer treatment.

Conventional cancer chemotherapy regimens, albeit successful to some extent, suffer from some significant drawbacks, such as high-dose requirements, limited bioavailability, low therapeutic indices, emergence of multiple drug resistance, off-target distribution, and adverse effects. The main goal of developing implantable drug delivery systems (IDDS) is to address these challenges and maintain anti-cancer drugs directly at the intended sites of therapeutic action while minimizing inevitable side effects. IDDS possess numerous advantages over conventional drug delivery, including controlled drug release patterns, one-time drug administration, as well as loading and stabilizing poorly water-soluble chemotherapy drugs. Here, we summarized conventional and novel (three-dimensional (3D) printing and microfluidic) preparation techniques of different IDDS, including nanofibers, films, hydrogels, wafers, sponges, and osmotic pumps. These systems could be designed with high biocompatibility and biodegradability features using a wide variety of natural and synthetic polymers. We also reviewed the published data on these systems in cancer therapy with a particular focus on their release behavior. Various release profiles could be attained in IDDS, which enable predictable, adjustable, and sustained drug releases. Furthermore, multi-step or stimuli-responsive drug release could be obtained in these systems. The studies mentioned in this article have proven the effectiveness of IDDS for treating different cancer types with high prevalence, including breast cancer, and aggressive cancer types, such as glioblastoma and liver cancer. Additionally, the challenges in applying IDDS for efficacious cancer therapy and their potential future developments are also discussed. Considering the high potential of IDDS for further advancements, such as programmable release and degradation features, further clinical trials are needed to ensure their efficiency. The overall goal of this review is to expand our understanding of the behavior of commonly investigated IDDS and to identify the barriers that should be addressed in the pursuit of more efficient therapies for cancer. See also the graphical abstract(Fig. 1).

Dose-Dense Chemotherapy Regimen for Breast Cancer Associated with Significant Decline in Ovarian Reserve.

Purpose: To determine the impact of dose-dense chemotherapy administration on ovarian reserve in women undergoing treatment for breast cancer. Patients and Methods: We conducted a retrospective cohort study of reproductive age women who underwent dose-dense chemotherapy regimens with doxorubicin hydrochloride and cyclophosphamide with or without paclitaxel for a new diagnosis of breast cancer. We compared pre- and post-treatment serum antimullerian hormone (AMH) levels and assessed changes in AMH over time. Results: Fifty-seven patients met inclusion criteria. Median pre-treatment AMH was 2.9 ng/mL, whereas post-treatment AMH was 0.1 ng/mL, demonstrating a dramatic reduction in AMH levels after treatment with a dose-dense regimen. This change was independent of age and was sustained over 12 months from treatment completion. Conclusions: Dose-dense chemotherapy regimens for breast cancer lead to marked and sustained decreases in AMH irrespective of patient age.

ABC/VEN – ANALYSIS OF DRUG PROVISION OF SMALL CELL LUNG CANCER CHEMOTHERAPY REGIMENS

This work is aimed at conducting a pharmacoeconomical analysis of chemotherapy for small cell lung cancer using ABC/ VEN analysis to identify the most expensive chemotherapy regimens. A retrospective evaluation of chemotherapy regimens for small cell lung cancer at various stages of the disease was carried out, presented in 408 case histories of patients who were treated from January 2021 to December 2021 in oncological dispensaries of the Voronezh and Lipetsk regions. During the study, the main regimens used in chemotherapy were identified and the most expensive treatment regimen for small cell lung cancer was determined, for which 50-70% of the budget is spent this is the scheme: etoposide + carboplatin and the least expensive group of drugs, for which 5-10% of the budget is spent this is scheme 3: cyclophosphamide 1000 mg/m2 in the 1st day + doxorubicin 50 mg/m2 on day 1 + vincristine 1.5 mg/m2 on day 1.

Role and efficacy of capecitabine in the anthracycline-free regimen in breast cancer patients: a systematic review and meta-analysis.

Capecitabine has extensive utilization in the treatment of diverse solid tumors, and its efficacy has been substantiated. Its oral administration and minimal toxicity in clinical practice render it advantageous. Nevertheless, uncertainty remains regarding whether capecitabine can substitute anthracycline drugs in chemotherapy regimens to achieve a lower risk of anthracycline-induced degradation. Consequently, we conducted a meta-analysis of randomized controlled trials (RCTs) to assess the potential of capecitabine as a replacement for anthracycline drugs in chemotherapy regimens for breast cancer. We systematically searched PubMed, Embase, Web of Science, and the Cochrane Controlled Trials Register (CENTRAL) to retrieve eligible studies published before July 18, 2023. Two independent reviewers extracted relevant data from the included studies using a pre-established data extraction form. The primary endpoints of interest encompassed overall survival (OS) and progression-free survival (PFS)for postoperative adjuvant therapy, as well as pathological complete response (PCR) following neoadjuvant therapy. Adverse events were considered as secondary outcomes. The statistical analysis was performed using Revman 5.4.1. A total of six studies involving 2348 breast cancer patients were deemed eligible according to the selection criteria. The pooled meta-analysis revealed that there were no statistically significant differences observed in the primary outcomes of overall survival (OS) (HR 1.06, 95% CI 0.88-1.28) and progression-free survival (PFS) (HR 1.10, 95% CI 0.90-1.34) across the four postoperative adjuvant chemotherapy trials, as well as in the two neoadjuvant chemotherapy trials with respect to the primary outcome of pathological complete response (PCR) (OR 1.65, 95% CI 0.93-2.95) when comparing regimens containing anthracycline drugs to those without. In terms of adverse events, the probability of experiencing diarrhea (OR 3.94, P = 0.004) and hand-foot syndrome (OR 10.89, P = 0.004) was significantly higher in the capecitabine group, attributable to the drug characteristics. Conversely, the likelihood of developing neutropenia (OR 0.50, P = 0.03) was higher in the anthracycline group. According to the current evidence, there was no statistically significant difference in the primary outcomes when capecitabine was substituted for anthracycline drugs. Thus, capecitabine can be regarded as a feasible alternative in the subset of patients who necessitate the exclusion of anthracyclines.

Particularities of arterial stiffness dynamics on the background of breast cancer chemotherapy

Modern breast cancer chemotherapy regimens (BC) consider individual patient parameters and ranges of cardiotoxic doses. However, clinicians often record clinical and laboratory-instrumental signs of cardio- and vasculotoxicity in patients, which emphasizes the high importance of searching for markers of early toxic response. To study the characteristics of the response of arterial stiffness on the background of anthracycline-containing chemotherapy to determine potential markers of vasculotoxicity in BC patients. 20 women with a BC were included. The patients received 4 cycles of chemotherapy in the doxorubicin + cyclophosphane (AC) regimen with an interval of 2-3 weeks, then they were injected with paclitaxel weekly for 12 injections, or docetaxel once every 3 weeks. All patients underwent TTE, arterial stiffness determination by the "gold standard" method and using volumetric sphygmography before the start of treatment, after the completion of the anthracycline component and after the end of taxanes. The average age of the patients was 45.5±5.31 years. After completing the course of anthracyclines, there was a significant increase in heart rate (from 65.6±9.3 to 73.3±10.1 beats/min.), a decrease in SBP (from 122.6±9.9 to 116.5±12.3 mmHg) and DBP (from 78.9±8.5 to 76.2±8.6 mmHg), a decrease in carotid femoral pulse wave velocity (cfPWV) (from 9.32±1.41 to 7.85±1.57 m/s), CAVI index on the left (from 6.78±0.81 to 6.5±0.88), the velocity of the cardio-ankle pulse wave on the right and left (from 6.7±0.6 to 6.5±0.7 m/s; from 7.0±0.6 to 6.3±0.8 m/sc, respectively). After the completion of the taxane, there was a tendency to increase these indicators, however, they remained significantly lower compared to the values before the start of treatment. A comparative analysis of arterial stiffness indicators at different stages of chemotherapy showed a more pronounced reaction of cfPWV, CAVI, cardio-ankle pulse wave to the administration of anthracyclines, which presumably may be associated with concomitant hemodynamic restructuring.

Deep learning-assisted high-content screening identifies isoliquiritigenin as an inhibitor of DNA double-strand breaks for preventing doxorubicin-induced cardiotoxicity

BackgroundAnthracyclines including doxorubicin are essential components of many cancer chemotherapy regimens, but their cardiotoxicity severely limits their use. New strategies for treating anthracycline-induced cardiotoxicity (AIC) are still needed. Anthracycline-induced DNA double-strand break (DSB) is the major cause of its cardiotoxicity. However, DSB-based drug screening for AIC has not been performed possibly due to the limited throughput of common assays for detecting DSB. To discover new therapeutic candidates for AIC, here we established a method to rapidly visualize and accurately evaluate the intranuclear anthracycline-induced DSB, and performed a screening for DSB inhibitors.ResultsFirst, we constructed a cardiomyocyte cell line stably expressing EGFP-53BP1, in which the formation of EGFP-53BP1 foci faithfully marked the doxorubicin-induced DSB, providing a faster and visible approach to detecting DSB. To quantify the DSB, we used a deep learning-based image analysis method, which showed the better ability to distinguish different cell populations undergoing different treatments of doxorubicin or reference compounds, compared with the traditional threshold-based method. Subsequently, we applied the deep learning-assisted high-content screening method to 315 compounds and found three compounds (kaempferol, kaempferide, and isoliquiritigenin) that exert cardioprotective effects in vitro. Among them, the protective effect of isoliquiritigenin is accompanied by the up-regulation of HO-1, down-regulation of peroxynitrite and topo II, and the alleviation of doxorubicin-induced DSB and apoptosis. The results of animal experiments also showed that isoliquiritigenin maintained the myocardial tissue structure and cardiac function in vivo. Moreover, isoliquiritigenin did not affect the killing of HeLa and MDA-MB-436 cancer cells by doxorubicin and thus has the potential to be a lead compound to exert cardioprotective effects without affecting the antitumor effect of doxorubicin.ConclusionsOur findings provided a new method for the drug discovery for AIC, which combines phenotypic screening with artificial intelligence. The results suggested that isoliquiritigenin as an inhibitor of DSB may be a promising drug candidate for AIC.