UNASSIGNED: Pre-clinical studies showed the anti-tumor mechanisms of PARP inhibitors (PARPi) and platinum have some crossover and overlap in the DNA damage repair pathway, patients who respond to platinum-based chemotherapy are also more likely to be sensitive to PARPi. This real-world study mainly aimed to evaluate whether TRAE (treatment-related adverse event) between platinum based chemotherapy (PBC) and niraparib are also associated.
UNASSIGNED: Patients received niraparib as maintenance treatment or salvage therapy for advanced ovarian cancer at the First Affiliated Hospital of Gannan Medical University from January 2020 to August 2023 were included. Survival data of niraparib treatment and adverse events occurred during the last platinum-based chemotherapy cycle before starting niraparib treatment and during niraparib treatment are documented. Fisher\'s exact test were used for correlation analysis.
UNASSIGNED: 1. 40 patients treated with niraparib were included in the analysis, including 31 patients treated with niraparib for 1st-line maintenance therapy, 6 patients for PSR (platinum-sensitive recurrence) maintenance therapy, and 3 patients for salvage therapy. The overall median follow-up time was 15.0 months (ranged from 2.2 months to 32.1 months). 2. Overall grade≥3 TRAE (40% vs 70%, p=0.012) including anemia (20% vs 45%, p=0.041) and neutrophil count decreased (17.5% vs 57.5%, p<0.001) was significantly lower during niraparib treatment compared to during chemotherapy. 3. Any grade TRAE (75% vs 100%, p=0.002) including white blood cell count decreased (47.5% vs 87.5%, p<0.001), red blood cell count decreased (57.5% vs 92.5%, p<0.001), anemia (55% vs 87.5%, p<0.001) and neutrophil count decreased (35% vs 85%, p<0.001) were also significantly lower in niraparib treatment group compared with chemotherapy group. No new safety signals were identified.
UNASSIGNED: 1. In this real-world practice, we observed that patients with advanced ovarian cancer who experienced any grade and grade ≥3 TRAE during chemotherapy were well tolerated when treated with niraparib, particularly the incidence of any grade and grade ≥3 anemia, and neutrophil count decreased during niraparib treatment were significantly lower compared with that during chemotherapy. 2. For patients with ovarian cancer who have experienced grade ≥3 hematological adverse reactions during prior platinum-based chemotherapy, greater attention should be paid to the monitoring and management of hematological adverse reactions during subsequent treatment with niraparib.

The search for better chemotherapeutic drugs to alleviate the deficiencies of existing platinum (Pt) drugs has picked up the pace in the millennium. There has been a disparate effort to design better and safer Pt drugs to deal with the problems of deactivation, Pt resistance and toxic side effects of clinical Pt drugs. In this review, we have discussed the potential of kinetically inert Pt complexes as an emerging class of next-generation Pt drugs. The introduction gives an overview about the development, use, mechanism of action and side effects of clinical Pt drugs as well as the various approaches to improve some of their pharmacological properties. We then describe the impact of kinetic lability on the pharmacology of functional Pt drugs including deactivation, antitumor efficacy, toxicity and resistance. Following a brief overview of numerous pharmacological advantages that a non-functional kinetically inert Pt complex can offer; we discussed structurally different classes of kinetically inert Pt (II) complexes highlighting their unique pharmacological features.

Research into cancer therapeutics has uncovered various potential medications based on metal-containing scaffolds after the discovery and clinical applications of cisplatin as an anti-cancer agent. This has resulted in many metallodrugs that can be put into medical applications. These metallodrugs have a wider variety of functions and mechanisms of action than pure organic molecules. Although platinum-based medicines are very efficient anti-cancer agents, they are often accompanied by significant side effects and toxicity and are limited by resistance. Some of the most studied and developed alternatives to platinum-based anti-cancer medications include metallodrugs based on ruthenium, gold, copper, iridium, and osmium, which showed effectiveness against many cancer cell lines. These metal-based medicines represent an exciting new category of potential cancer treatments and sparked a renewed interest in the search for effective anti-cancer therapies. Despite the widespread development of metal complexes touted as powerful and promising in vitro anti-cancer therapeutics, only a small percentage of these compounds have shown their worth in vivo models. Metallodrugs, which are more effective and less toxic than platinum-based drugs and can treat drug-resistant cancer cells, are the focus of this review. Here, we highlighted some of the most recently developed Pt, Ru, Au, Cu, Ir, and Os complexes that have shown significant in vivo antitumor properties between 2017 and 2023.

OBJECTIVE: Platinum-based drugs are cytotoxic drugs commonly used in cancer treatment. They cause DNA damage, effects of which on chromatin and cellular responses are relatively well described. Yet, the nuclear stress responses related to RNA processing are incompletely known and may be relevant for the heterogeneity with which cancer cells respond to these drugs. Here, we determine the type and extent of nuclear stress responses of prostate cancer cells to clinically relevant platinum drugs.
METHODS: We study nucleolar and Cajal body (CB) responses to cisplatin, carboplatin, and oxaliplatin with immunofluorescence-based methods in prostate cancer cells. We utilize organelle-specific markers NPM, Fibrillarin, Coilin, and SMN1, and study CB-regulatory proteins FUS and TDP-43 using siRNA-mediated downregulation.
RESULTS: Different types of prostate cancer cells have different sensitivities to platinum drugs. With equally cytotoxic doses, cisplatin, and oxaliplatin induce prominent nucleolar and CB stress responses while the nuclear stress phenotypes to carboplatin are milder. We find that Coilin is a stress-specific marker for platinum drug response heterogeneity. We also find that CB-associated, stress-responsive RNA binding proteins FUS and TDP-43 control Coilin and CB biology in prostate cancer cells and, further, that TDP-43 is associated with stress-responsive CBs in prostate cancer cells.
CONCLUSIONS: Our findings provide insight into the heterologous responses of prostate cancer cells to different platinum drug treatments and indicate Coilin and TDP-43 as stress mediators in the varied outcomes. These results help understand cancer drug responses at a cellular level and have implications in tackling heterogeneity in cancer treatment outcomes.

Breast cancer is the most common malignant tumor in women around the world, and it is also a common cause of death in female patients with malignant tumors in China, which seriously harms women\'s health. At present, with the application of comprehensive treatment approaches, breast cancer has become one of the most effective solid tumors. Platinum drugs are widely used in malignant tumors, and they are also commonly used as effective chemotherapeutic drugs for breast cancer. To regulate the application of platinum drugs in breast cancer, the experts from Breast Cancer Group, Branch of Oncologist, Chinese Medical Doctor Association, discuss and approve the \"Guidelines for clinical application of platinum drugs in breast cancer (2023 edition)\" . This guideline is developed from the \"Expert consensus on the clinical application of platinums in advanced breast cancer (2020 version)\" , which is updated from the latest evidence based on breast cancer at home and abroad, for platinum drugs in breast cancer clinical use, application scheme, efficacy analysis and treatment of adverse effects. This guideline aims to guide clinicians to use drugs rationally, and to further standardize the diagnosis and treatment.
乳腺癌是全球女性最常见的恶性肿瘤，也是我国女性恶性肿瘤患者死亡的常见原因，严重危害女性的健康。目前，通过综合治疗手段的应用，乳腺癌已成为疗效较好的实体肿瘤之一。铂类药物在恶性肿瘤中应用广泛，是乳腺癌常用且有效的化疗药物之一。为规范铂类药物在乳腺癌治疗中的应用，中国医师协会肿瘤医师分会乳腺癌学组组织相关专家，在《铂类药物晚期乳腺癌应用专家共识(2020版)》基础上，根据国内外乳腺癌最新循证医学证据，对铂类药物在乳腺癌临床使用的适宜范围、应用方案、疗效分析及不良反应处理等方面进行充分讨论和更新，增加了铂类药物在早期乳腺癌临床使用的适宜范围、应用方案、疗效分析及不良反应处理等方面内容，制定《乳腺癌铂类药物临床应用专家共识(2023版)》，以指导临床医师合理用药，进一步规范诊疗行为。.

The impact of kinetic lability or reactivity on in vitro cytotoxicity, stability in plasma, in vivo tumor and tissue accumulation, and antitumor efficacy of functional platinum(II) (Pt) anticancer agents containing a O˄O β-diketonate leaving ligand remain largely unexplored. To investigate this, we synthesized Pt complexes [(NH3 )2 Pt(L1-H)]NO3 and [(DACH)Pt(L1-H)]NO3 (L1=4,4,4-trifluoro-1-ferrocenylbutane-1,3-dione, DACH=1R,2R-cyclohexane-1,2-diamine) containing an electron deficient [L1-H]- O˄O leaving ligand and [(NH3 )2 Pt(L2-H)]NO3 and [(DACH)Pt(L2-H)]NO3 (L2=1-ferrocenylbutane-1,3-dione) containing an electron-rich [L2-H]- O˄O leaving ligand. While all four complexes have comparable lipophilicity, the presence of the electron-withdrawing CF3 group was found to dramatically enhance the reactivity of these complexes toward nucleophilic biomolecules. In vitro cellular assays revealed that the more reactive complexes have higher cellular uptake and higher anticancer potency as compared to their less reactive analogs. But the scenario is opposite in vivo, where the less reactive complex showed improved tissue and tumor accumulation and better anticancer efficacy in mice bearing ovarian xenograft when compared to its more reactive analog. Finally, in addition to demonstrating the profound but contrasting impact of kinetic lability on in vitro and in vivo antitumor potencies, we also described the impact of kinetic lability on the mechanism of action of this class of promising antitumor agents.

The therapeutic advantages of some platinum complexes as major anticancer chemotherapeutic agents and of nucleoside analogue-based compounds as essential antiviral/antitumor drugs are widely recognized. Red blood cells (RBCs) offer a potential new strategy for the targeted release of therapeutic agents due to their biocompatibility, which can protect loaded drugs from inactivation in the blood, thus improving biodistribution. In this study, we evaluated the feasibility of loading model nucleobase-containing Pt(II) complexes into human RBCs that were highly stabilized by four N-donors and susceptible to further modification for possible antitumor/antiviral applications. Specifically, platinum-based nucleoside derivatives [PtII(dien)(N7-Guo)]2+, [PtII(dien)(N7-dGuo)]2+, and [PtII(dien)(N7-dGTP)] (dien = diethylenetriamine; Guo = guanosine; dGuo = 2\'-deoxy-guanosine; dGTP = 5\'-(2\'-deoxy)-guanosine-triphosphate) were investigated. These Pt(II) complexes were demonstrated to be stable species suitable for incorporation into RBCs. This result opens avenues for the possible incorporation of other metalated nucleobases analogues, with potential antitumor and/or antiviral activity, into RBCs.

High mobility group box 1 (HMGB1) is secreted from activated immune cells, necrotic cells, and certain cancers. Previous studies have reported that different patterns of post-translational modification, particularly acetylation and oxidation, mediate HMGB1 release and confer distinct extracellular HMGB1 signaling activity. Here we report that cisplatin but not carboplatin induces secretion of HMGB1 from human A549 non-small cell lung cancer (NSCLC) cells. Cisplatin-mediated HMGB1 secretion was dose-dependent and was regulated by nuclear exportin 1 (XPO1) also known as chromosomal maintenance 1 (CRM1) rather than adenosine diphosphate (ADP)-ribosylation, acetylation, or oxidation. HMGB1, as well as lysine acetylation and cysteine disulfide oxidation of secreted HMGB1, were monitored by sensitive and specific assays using immunoprecipitation, stable isotope dilution, differential alkylation, and nano liquid chromatography parallel reaction monitoring/high-resolution mass spectrometry (nano-LC-PRM/HRMS). A major fraction of the HMGB1 secreted by low-dose cisplatin treatment of A549 NSCLC cells was found to be in the fully reduced form. In contrast, mainly oxidized forms of HMGB1 were secreted by dimethyl sulfoxide (DMSO)-mediated apoptosis. These findings suggest that inhibition of XPO1 could potentiate the anti-tumor activity of cisplatin by increasing the nuclear accumulation of HMGB1 protein, an inhibitor of cisplatin DNA-adduct repair. Furthermore, low-dose cisplatin therapy could modulate the immune response in NSCLC through the established chemokine activity of extracellular reduced HMGB1. This could potentially enhance the efficacy of subsequent immunotherapy treatment.

Challenges and pitfalls in the application of diethyldithiocarbamate derivatization for LC analysis of cisplatin and oxaliplatin, as well as the suitability of this method for different biological matrices with implications for use in routine practice have been identified. The LC of platinum drugs presents a significant challenge. They are polar compounds with poor retention on reverse phase packings. Cisplatin also exhibits poor absorption in UV and ionization in mass spectrometry. Therefore, we developed and optimized a derivatization approach for the LC analysis of total platinum in plasma, plasma ultrafiltrate, peritoneal fluid, and urine. Derivatization in urine proved to be difficult due to the complexity of the matrix, and extended testing was required. Our results highlight the important issues affecting the efficiency, reliability, and suitability of platinum drug derivatization. Although precolumn derivatization is less selective than its postcolumn counterpart, the application of precolumn derivatization is a simple, rapid, and universal approach for the determination of platinum drugs by HPLC. One of its major advantages is that it allows a more affordable analysis using UV detection without the need for additional high-end instrumentation such as a MS detector.

Chemoinduced polyneuropathy (CIPNP) is a common side-effect of chemotherapy, significantly impairing quality of life in patients treated for cancer. Platinum preparations are the most commonly used chemotherapeutic agents used in the treatment of ovarian, testicular, breast, lung and colon cancers. Clinical examination reveals restrictions on the motor, sensory and autonomic functions of the upper and lower extremities, which occur at different stages of antitumor treatment, seriously complicating the treatment of the underlying disease. Pain and sensory disturbances may persist for months or even years after chemotherapy is completed. Thus, CIPNP is a major problem because it is impossible to predict which patients will develop neurological symptoms, to estimate their timing of manifestation, which can occur at any time during the course of chemotherapy, there is no early indication to reduce the dose of the cytotoxic drug, and there are no drugs that effectively prevent or alleviate the course of neuropathy. This review focuses on neurotoxicity with the use of platinum drugs, including the frequency of occurrence, risk factors, cumulative doses, various pathogenetic mechanisms for the development of CIPNP, clinical features and variants of the neurophysiological picture.
Химиоиндуцированная полинейропатия (ХИПНП) является частым побочным эффектом химиотерапии, значительно ухудшающим качество жизни у пациентов, получающих лечение по поводу злокачественного новообразования. Препараты платины являются наиболее часто используемыми химиотерапевтическими средствами, применяемыми при лечении рака яичников, яичка, молочной железы, легких и толстой кишки. При клиническом осмотре выявляются ограничения двигательных, чувствительных и вегетативных функций верхних и нижних конечностей, которые возникают на разных этапах противоопухолевого лечения, серьезно затрудняющие лечение основного заболевания. Боль и чувствительные нарушения могут сохраняться в течение нескольких месяцев и даже лет после завершения химиотерапии. Таким образом, ХИПНП представляет серьезную проблему, так как невозможно предсказать, у каких пациентов возникнут неврологические симптомы, оценить их сроки проявления, нет ранних показаний для снижения дозы цитостатического препарата, нет лекарственных средств, эффективно предотвращающих или облегчающих течение нейропатии. В данном обзоре особое внимание уделяется нейротоксичности при использовании препаратов платины, включая частоту встречаемости, факторы риска, кумулятивные дозы, различные патогенетические механизмы развития ХИПНП, клинические особенности и варианты нейрофизиологической картины.