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International Journal of Molecular... Jun 2024Monofunctional platinum complexes offer a promising alternative to cisplatin in cancer chemotherapy, showing a unique mechanism of action. Their ability to induce minor...
Monofunctional platinum complexes offer a promising alternative to cisplatin in cancer chemotherapy, showing a unique mechanism of action. Their ability to induce minor helix distortions effectively inhibits DNA transcription. In our study, we synthesized and characterized three monofunctional Pt(II) complexes with the general formula [Pt(en)(L)Cl]NO, where en = ethylenediamine, and L = pyridine (py), 2-methylpyridine (2-mepy), and 2-phenylpyridine (2-phpy). The hydrolysis rates of [Pt(en)(py)Cl]NO () and [Pt(en)(2-mepy)Cl]NO () decrease with the bulkiness of the auxiliary ligand with k() = 2.28 ± 0.15 × 10 s and k() = 8.69 ± 0.98 × 10 s at 298 K. The complex [Pt(en)(2-phpy)Cl]Cl () demonstrated distinct behavior. Upon hydrolysis, an equilibrium (K = 0.385 mM) between the complexes [Pt(en)(2-phpy)Cl] and [Pt(en)(2-phpy-H)] was observed with no evidence (NMR or HR-ESI-MS) for the presence of the aquated complex [Pt(en)(2-phpy)(HO)]. Despite the kinetic similarities between phenanthriplatin and (), complexes () and () exhibit minimal activity against A549 lung cancer cell line (IC > 100 μΜ), whereas complex () exhibits notable cytotoxicity (IC = 41.11 ± 2.1 μΜ). In examining the DNA binding of () and () to the DNA model guanosine (guo), we validated their binding through guoN7, which led to an increased population of the C3'- sugar conformation, as expected. However, we observed that the rapid transition E (C2') ↔ E (C3'), in the case of [Pt(en)(py)(guo)](NO) ([-guo]), slows down in the case of [Pt(en)(2-mepy)(guo)](NO) ([-guo]), resulting in separate signals for the two conformers in the H NMR spectra. This phenomenon arises from the steric hindrance between the methyl group of pyridine and the sugar moiety of guanosine. Notably, this hindrance is absent in [-(9-MeG)] (9-MeG = 9-methylguanine), probably due to the absence of a bulky sugar unit in 9-MeG. In the case of (), where the bulkiness of the substitution on the pyridine is further increased by a phenyl group, we observed a notable proximity between 9-MeGH8 and the phenyl ring of 2-phpy. Considering that only () exhibited good cytotoxicity against the A549 cancer cell line, it is suggested that auxiliary ligands, L, with an extended aromatic system and proper orientation in complexes of the type cis-[Pt(en)(L)Cl]NO, may enhance the cytotoxic activity of such complexes.
Topics: Antineoplastic Agents; DNA; Humans; Ligands; Organoplatinum Compounds; Cell Line, Tumor; Hydrolysis; Platinum; A549 Cells
PubMed: 38928230
DOI: 10.3390/ijms25126526 -
Cancers Jun 2024Lazertinib is a third-generation tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR-TKI) that selectively inhibit common EGFR mutation and T790M...
Lazertinib versus Platinum-Based Chemotherapy with Epidermal Growth Factor Receptor (EGFR)-Positive Non-Small-Cell Lung Cancer after Failing EGFR-Tyrosine Kinase Inhibitor: A Real-World External Comparator Study.
BACKGROUND
Lazertinib is a third-generation tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR-TKI) that selectively inhibit common EGFR mutation and T790M mutation in non-small-cell lung cancer (NSCLC) patients. No previous studies have compared lazertinib to platinum-based chemotherapy. We have compared lazertinib with platinum-based chemotherapy in EGFR-mutated NSCLC patients after previous EGFR-TKI therapy.
METHODS
We retrospectively compared 200 patients from LASER201, LASER301, and LASER-PMS studies to 334 patients who were treated with platinum-based chemotherapy after previous EGFR-TKI from the Samsung Medical Center. After propensity score matching (PSM), we selected 156 patients from each group. The primary outcome was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), and time to treatment discontinuation (TTD) as secondary outcomes.
RESULTS
The median follow-up of PFS was 15.61 months in the lazertinib group and 21.67 months in the external control group. The PFS was significantly longer in patients who were treated with lazertinib than those treated with platinum-based chemotherapy (10.97 months vs. 5.10 months; adjusted hazard ratio (HR) 0.40; 95% confidence interval (CI), 0.29-0.55; < 0.01) after PSM. Lazertinib showed superior OS (32.23 months vs. 18.73 months; adjusted HR 0.45; 95% CI, 0.29-0.69; < 0.001), ORR (64.1% vs. 47.4%), and TTD (11.66 months vs. 6.73 months; adjusted HR 0.54; 95% CI, 0.39-0.75; < 0.001) compared to platinum-based chemotherapy.
CONCLUSION
Based on this retrospective, external control study, lazertinib has demonstrated significantly better efficacy compared with platinum-based chemotherapy. The external controls provide important context to evaluate efficacy in single-arm studies.
PubMed: 38927875
DOI: 10.3390/cancers16122169 -
Bioengineering (Basel, Switzerland) Jun 2024(1) Background: Medical devices, especially neuromodulation devices, are often explanted for a variety of reasons. The removal process imparts significant forces on...
(1) Background: Medical devices, especially neuromodulation devices, are often explanted for a variety of reasons. The removal process imparts significant forces on these devices, which may result in device fracture and tissue trauma. We hypothesized that a device's form factor interfacing with tissue is a major driver of the force required to remove a device, and we isolated helical and linear electrode structures as a means to study atraumatic removal. (2) Methods: Ductile linear and helical microwire structure electrodes were fabricated from either Gold (Au) or Platinum-Iridium (Pt-Ir, 90-10). Removal forces were captured from synthetic gel models and following chronic implantation in rodent and porcine models. Devices were fully implanted in the animal models, requiring a small incision (<10 mm) and removal via tissue forceps. (3) Results: Helical devices were shown to result in significantly lower maximal removal forces in both synthetic gel and rodent studies compared to their linear counterparts. Chronically (1 yr.), the maximal removal force of helical devices remained under 7.30 N, for which the Platinum-Iridium device's tensile failure force was 32.90 ± 2.09 N, resulting in a safety factor of 4.50. (4) Conclusions: An open-core helical structure that can freely elongate was shown to result in reduced removal forces both acutely and chronically.
PubMed: 38927847
DOI: 10.3390/bioengineering11060611 -
Genes May 2024Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma accounting for 15% of lung cancers with dismal survival outcomes. Minimal changes in therapy and... (Review)
Review
Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma accounting for 15% of lung cancers with dismal survival outcomes. Minimal changes in therapy and prognosis have occurred in SCLC for the past four decades. Recent progress in the treatment of extensive-stage disease (ES-SCLC) has been marked by incorporating immune checkpoint inhibitors (ICIs) into platinum-based chemotherapy, leading to modest improvements. Moreover, few second-line-and-beyond treatment options are currently available. The main limitation for the molecular study of SCLC has been the scarcity of samples, because only very early diseases are treated with surgery and biopsies are not performed when the disease progresses. Despite all these difficulties, in recent years we have come to understand that SCLC is not a homogeneous disease. At the molecular level, in addition to the universal loss of retinoblastoma (RB) and TP53 genes, a recent large molecular study has identified other mutations that could serve as targets for therapy development or patient selection. In recent years, there has also been the identification of new genetic subtypes which have shown us how intertumor heterogeneity exists. Moreover, SCLC can also develop intratumoral heterogeneity linked mainly to the concept of cellular plasticity, mostly due to the development of resistance to therapies. The aim of this review is to quickly present the current standard of care of ES-SCLC, to focus on the molecular landscapes and subtypes of SCLC, subsequently present the most promising therapeutic strategies under investigation, and finally recap the future directions of ongoing clinical trials for this aggressive disease which still remains a challenge.
Topics: Humans; Small Cell Lung Carcinoma; Lung Neoplasms; Immune Checkpoint Inhibitors; Mutation
PubMed: 38927637
DOI: 10.3390/genes15060701 -
Biomedicines May 2024Large cell neuroendocrine carcinoma (LCNEC) presents significant treatment challenges due to its rarity and limited therapeutic options. The LANCE study was designed to...
BACKGROUND
Large cell neuroendocrine carcinoma (LCNEC) presents significant treatment challenges due to its rarity and limited therapeutic options. The LANCE study was designed to explore the survival benefits of incorporating atezolizumab in chemotherapy for metastatic LCNEC.
METHODS
In this non-randomized study, patients with metastatic LCNEC were prospectively enrolled and assigned to receive either standard chemotherapy plus atezolizumab followed by maintenance with atezolizumab or standard chemotherapy alone. The primary outcomes measured were 12- and 24-month survival rates, progression-free survival (PFS), and overall survival (OS) between the two groups.
RESULTS
Of the 22 patients screened, 17 met the inclusion criteria and received either atezolizumab plus platinum-based chemotherapy ( = 10) or chemotherapy alone ( = 7). After a median follow-up of 23.3 months, the 12-month survival rate was 57.1% (95% CI: 32.6-100%) and 14.3% (95% CI: 2.33-87.7%) for the atezolizumab and the chemotherapy-only groups, respectively. The survival benefit for the atezolizumab group was sustained at 24 months (45.7% vs. 14.3%). Overall survival was significantly higher for the atezolizumab group, and PFS was non-significantly associated with the addition of atezolizumab (log-rank = 0.04 and 0.05, respectively).
CONCLUSIONS
This pilot study suggests that the addition of atezolizumab to standard platinum-based chemotherapy may provide a substantial survival benefit compared with chemotherapy alone in the first-line treatment of metastatic LCNEC.
PubMed: 38927367
DOI: 10.3390/biomedicines12061161 -
Biomedicines May 2024Polyamines are small polycationic alkylamines that are absolutely required for the continual growth and proliferation of cancer cells. The polyamine analogue ivospemin,...
Polyamines are small polycationic alkylamines that are absolutely required for the continual growth and proliferation of cancer cells. The polyamine analogue ivospemin, also known as SBP-101, has shown efficacy in slowing pancreatic and ovarian tumor progression in vitro and in vivo and has demonstrated encouraging results in early pancreatic cancer clinical trials. We sought to determine if ivospemin was a viable treatment option for the under-served platinum-resistant ovarian cancer patient population by testing its efficacy in combination with commonly used chemotherapeutics. We treated four ovarian adenocarcinoma cell lines in vitro and found that each was sensitive to ivospemin regardless of cisplatin sensitivity. Next, we treated patients with ivospemin in combination with four commonly used chemotherapeutics and found that ivospemin increased the toxicity of each; however, only gemcitabine and topotecan combination treatments were more effective than ivospemin alone. Using the VDID8 murine ovarian cancer model, we found that the addition of ivospemin to either topotecan or gemcitabine increased median survival over untreated animals alone, delayed tumor progression, and decreased the overall tumor burden. Our results indicate that the combination of ivospemin and chemotherapy is a worthwhile treatment option to further explore clinically in ovarian cancer.
PubMed: 38927364
DOI: 10.3390/biomedicines12061157 -
Biomolecules May 2024BUB1 is overexpressed in most human solid cancers, including breast cancer. Higher BUB1 levels are associated with a poor prognosis, especially in patients with...
BUB1 is overexpressed in most human solid cancers, including breast cancer. Higher BUB1 levels are associated with a poor prognosis, especially in patients with triple-negative breast cancer (TNBC). Women with TNBC often develop resistance to chemotherapy and radiotherapy, which are still the mainstay of treatment for TNBC. Our previous studies demonstrated that a BUB1 kinase inhibitor (BAY1816032) reduced tumor cell proliferation and significantly enhanced radiotherapy efficacy in TNBC. In this study, we evaluated the effectiveness of BAY1816032 with a PARP inhibitor (olaparib), platinum agent (cisplatin), and microtubule poison (paclitaxel) alone or in combination with radiotherapy using cytotoxicity and clonogenic survival assays. BUB1 inhibitors sensitized BRCA1/2 wild-type SUM159 and MDA-MB-231 cells to olaparib, cisplatin, and paclitaxel synergistically (combination index; CI < 1). BAY1816032 significantly increased the radiation sensitization of SUM159 and MDA-MB-231 by olaparib, cisplatin, or paclitaxel at non-toxic concentrations (doses well below the IC concentrations). Importantly, the small molecular inhibitor of BUB1 synergistically (CI < 1) sensitized the BRCA mutant TNBC cell line HCC1937 to olaparib. Furthermore, the BUB1 inhibitor significantly increased the radiation enhancement ratio (rER) in HCC1937 cells (rER 1.34) compared to either agent alone (BUB1i rER 1.19; PARPi rER 1.04). The data presented here are significant as they provide proof that inhibition of BUB1 kinase activity sensitizes TNBC cell lines to a PARP inhibitor and radiation, irrespective of BRCA1/2 mutation status. Due to the ability of the BUB1 inhibitor to sensitize TNBC to different classes of drugs (platinum, PARPi, microtubule depolarization inhibitors), this work strongly supports the role of BUB1 as a novel molecular target to improve chemoradiation efficacy in TNBC and provides a rationale for the clinical evaluation of BAY1816032 as a chemosensitizer and chemoradiosensitizer in TNBC.
Topics: Humans; Triple Negative Breast Neoplasms; Cell Line, Tumor; Phthalazines; Cisplatin; Piperazines; Paclitaxel; Protein Serine-Threonine Kinases; Female; Antineoplastic Agents; Cell Proliferation; Poly(ADP-ribose) Polymerase Inhibitors; Protein Kinase Inhibitors; BRCA1 Protein
PubMed: 38927028
DOI: 10.3390/biom14060625 -
Anticancer Research Jul 2024Irinotecan monotherapy was the most widely used third-line chemotherapy for unresectable advanced or recurrent gastric cancer in Japan until the approval of nivolumab in...
BACKGROUND/AIM
Irinotecan monotherapy was the most widely used third-line chemotherapy for unresectable advanced or recurrent gastric cancer in Japan until the approval of nivolumab in September 2017 and trifluridine/tipiracil in August 2019. The benefit of continuing ramucirumab with irinotecan, an anti-VEGFR-2 monoclonal antibody, after the failure of paclitaxel plus ramucirumab (PTX+RAM) as second-line chemotherapy, has been under debate.
PATIENTS AND METHODS
A single-center phase II study was conducted in patients with unresectable advanced or recurrent gastric cancer previously treated with fluoropyrimidines and platinum, who received PTX+RAM as second-line therapy and irinotecan plus ramucirumab (IRI+RAM) as third-line therapy after treatment failure (UMIN000022956).
RESULTS
Eleven patients were enrolled from July 2016 to July 2018. Enrolment was discontinued due to difficulties in case ascertainment because of expanded third-line treatment options (originally planned for 53 patients). The median progression-free survival (the primary endpoint) of the IRI+RAM was 3.98 months [95% confidence interval (CI)=1.78-NA]. Among secondary endpoints, the transition rate to IRI+RAM was 45%, the rate of 8-week treatment continuation for IRI+RAM was 100%, the response rate for IRI+RAM was 0%, the median overall survival (OS) for PTX+RAM was 13.53 months (95%CI=1.61-24.36), and the median OS for IRI+RAM was 9.99 months (95CI=4.5-NA).
CONCLUSION
The transition rate from PTX+RAM to IRI+RAM was reasonable. Ramucirumab beyond progressive disease may be beneficial for patients who are able to transition to IRI+RAM.
Topics: Humans; Ramucirumab; Stomach Neoplasms; Antibodies, Monoclonal, Humanized; Male; Female; Paclitaxel; Aged; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Adult; Progression-Free Survival
PubMed: 38925825
DOI: 10.21873/anticanres.17126 -
Anticancer Research Jul 2024The combination of programmed cell death ligand 1 inhibitors and platinum-based chemotherapy has become the standard treatment for first-line therapy in extensive-stage... (Comparative Study)
Comparative Study
Comparison of Real-world Efficacy and Safety of Atezolizumab and Durvalumab in Combination With Chemotherapy for First-line Treatment of Extensive-stage Small-cell Lung Cancer.
BACKGROUND/AIM
The combination of programmed cell death ligand 1 inhibitors and platinum-based chemotherapy has become the standard treatment for first-line therapy in extensive-stage small-cell lung cancer (ES-SCLC). This study compared the efficacy and safety of atezolizumab plus chemotherapy and durvalumab plus chemotherapy in the treatment of ES-SCLC in clinical practice.
PATIENTS AND METHODS
We retrospectively analyzed 40 patients with ES-SCLC treated with atezolizumab plus chemotherapy or durvalumab plus platinum-based chemotherapy at the Fukuoka University Hospital between October 2019 and November 2022.
RESULTS
Among the 40 patients, 20 were treated with atezolizumab and 20 were treated with durvalumab. There was no significant difference in patient characteristics between the two groups; five patients who received atezolizumab and one who received durvalumab showed a performance status of 2 or higher. The median progression-free survival of patients who received atezolizumab or durvalumab was 5.6 and 5.4 months, respectively (p=0.881). The median overall survival of patients who received atezolizumab or durvalumab was 10.0 and 17.1 months, respectively (p=0.163). The objective response rate of the patients who received atezolizumab or durvalumab was 80.0% and 85.0%, respectively. There was no significant difference in the incidence of immune-related adverse events between the groups.
CONCLUSION
This retrospective study was the first to compare the efficacy and safety of PD-L1 antibody, atezolizumab or durvalumab, in combination with carboplatin and etoposide in treatment-naïve ES-SCLC Japanese patients in a real-world setting. Both regimens, atezolizumab or durvalumab with carboplatin and etoposide, were effective and well-tolerated in Japanese ES-SCLC patients, in line with clinical trial findings.
Topics: Humans; Male; Antibodies, Monoclonal, Humanized; Small Cell Lung Carcinoma; Female; Lung Neoplasms; Aged; Antineoplastic Combined Chemotherapy Protocols; Middle Aged; Retrospective Studies; Antibodies, Monoclonal; Aged, 80 and over; Treatment Outcome; Adult; Neoplasm Staging
PubMed: 38925816
DOI: 10.21873/anticanres.17132 -
Anticancer Research Jul 2024Nivolumab and ipilimumab combination therapy has been extensively explored for the treatment of advanced non-small-cell lung cancer (NSCLC) through the pivotal phase III...
Clinical Association Between Immune-related Adverse Events and Treatment Efficacy in Patients With Non-small-cell Lung Cancer Treated With Nivolumab-Ipilimumab-based Therapy.
BACKGROUND/AIM
Nivolumab and ipilimumab combination therapy has been extensively explored for the treatment of advanced non-small-cell lung cancer (NSCLC) through the pivotal phase III trials CheckMate 227 and CheckMate 9LA. However, the relationship between immune-related adverse events (irAEs) and the effectiveness of nivolumab plus ipilimumab-based therapy in a real-world clinical setting remains uncertain.
PATIENTS AND METHODS
We performed a retrospective analysis of 28 patients with advanced or recurrent NSCLC who underwent treatment with nivolumab plus ipilimumab, with or without platinum-doublet chemotherapy, from February 2021 to January 2023. The primary objective was to elucidate the clinical association between irAEs and treatment efficacy associated with nivolumab plus ipilimumab-based therapy.
RESULTS
Among the 28 patients, 22 (78.6%) experienced irAEs. The median progression-free survival (PFS) was significantly longer for patients with irAEs than for those without (p=0.0158), as was overall survival (OS) (p=0.000394). The severity of irAEs had no significant influence on PFS or OS. The objective response rate tended to be higher in patients with irAEs than in those without (50.0% versus 0.0%, respectively; p=0.0549). Multivariate analysis indicated that irAE occurrence was an independent factor for improved PFS (hazard ratio=0.2084, p=0.01383) and OS (hazard ratio=0.0857, p=0.001588). Interstitial lung disease was inferior to other irAE profiles for both PFS and OS.
CONCLUSION
Patients with advanced NSCLC experiencing irAEs demonstrated superior clinical outcomes when treated with nivolumab plus ipilimumab-based therapy compared with those without irAEs. However, immune-related interstitial lung disease may be less linked with PFS and OS than other irAE profiles.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Nivolumab; Ipilimumab; Male; Lung Neoplasms; Female; Aged; Middle Aged; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Aged, 80 and over; Treatment Outcome; Progression-Free Survival; Adult
PubMed: 38925810
DOI: 10.21873/anticanres.17122