Topotecan

Topotecan is the most reliable chemotherapy regimen for relapsed small-cell lung carcinoma (SCLC). The efficacy and adverse effects of topotecan as reported by previous studies varied greatly. The inclusion criterion was a prospective study that was able to provide data for 6-month over-all survival (OS) rate, 1-year OS rate, objective responses, and/or adverse effects of single agent topotecan as a second line chemotherapy for SCLC, written in English language as a full article. Any topotecan regimen were allowed. Binary data were meta-analyzed with the random-model generic inverse variance method. We included 14 articles consisted of 1347 patients. Pooled values were estimated as follows. Six-month OS rate: 37% (95% CI: 28-46%). One-year OS rate: 9% (95% CI: 5-13%). Response rate: 5% (95% CI: 1-8%). Six-month OS rate: 57% (95% CI: 50-64%). One-year OS rate: 27% (95% CI: 22-32%). Response rate: 17% (95% CI: 11-23%). Grade III/IV neutropenia 69% (95% CI: 58-80%). Grade III/IV thrombopenia 41% (95% CI: 34-48%). Grade III/IV anemia 24% (95% CI: 17-30%). Non-hematorogical events were rare. Chemotherapy-related death 2% (95% CI: 1-3%). In conclusion, Topotecan provided a possibly promising outcome for sensitive-relapse SCLC and poor outcome for refractory relapse SCLC. Adverse events were mainly hematological.

Brain metastases represent an important cause of morbidity in patients with lung cancer and are associated with a mean survival of less than 6 months. Thus, new regimens improving the outcome of these patients are urgently needed. On the basis of promising data raised in a phase I/II trial, we initiated an open, randomised, prospective, multicentric phase III trial, comparing whole brain radiation therapy (WBRT; 20 x 2 Gy) alone with WBRT+topotecan (RCT; 0.4 mg m(-2) day(-1) x 20). A total of 320 patients with CNS-metastases due to SCLC or NSCLC were projected. The primary end point was overall survival, whereas second end points were local response and progression-free survival. However, until the cutoff date of study completion (i.e., a study duration of 34 months), only a total of 96 (RCT:47, WBRT:49) patients had been recruited, and so an analysis was performed at that time point. Although the numbers of grade 3/4 non-haematological toxicities (besides alopecia 115 (RCT/WBRT: 55 out of 60) were evenly distributed, the 25 haematological events occurred mainly in the combined treatment arm (24 out of 1). Local response, evaluated 2 weeks after treatment, was assessable in 44 (RCT/WBRT: 23 out of 21) patients, showing CR in eight (3 out of 5), PR in 17 (11 out of 6), SD in 14 (8 out of 6) and PD in five (1 out of 4) patients (all differences n.s.). Neither OAS (RCT/WBRT: median (days)): 87 out of 95, range 3-752/4-433; HR 1.32; 95% CI (0.83; 2.10)) nor PFS (median (days)): 71 out of 66, range, 3-399/4-228; HR 1.28, 95% CI (0.73; 2.43) differed significantly. On the basis of these results and the slow recruitment, a continuation of the study did not seem reasonable. The available data show no significant advantage for concurrent radiochemotherapy for patients with lung cancer; however, the recruited number of patients is too low to exhibit a small advantage of combined treatment.

Gliomas, the most malignant form of brain tumors, contain a small subpopulation of glioma stem cells (GSCs) that are implicated in therapeutic resistance and tumor recurrence. Topoisomerase I inhibitors, shikonin and topotecan, play a crucial role in anti-cancer therapies. After isolated and identified the GSCs from glioma cells successfully, U251, U87, GSCs-U251 and GSCs-U87 cells were administrated with various concentrations of shikonin or topotecan at different time points to seek for the optimal administration concentration and time point. The cell viability, cell cycle and apoptosis were detected using cell counting kit-8 and flow cytometer to observe the inhibitory effects on glioma cells and GSCs. We demonstrated that shikonin and topotecan obviously inhibited proliferation of not only human glioma cells but also GSCs in a dose- and time-dependent manner. According to the IC50 values at 24 h, 2 μmol/L of shikonin and 3 μmol/L of topotecan were selected as the optimal administration concentration. In addition, shikonin and topotecan induced cell cycle arrest in G0/G1 and S phases and promoted apoptosis. The down-regulation of Bcl-2 expression with the activation of caspase 9/3-dependent pathway was involved in the apoptosis process. Therefore, the above results showed that topoisomerase I inhibitors, shikonin and topotecan, inhibited growth and induced apoptosis of GSCs as well as glioma cells, which suggested that they might be the potential anticancer agents targeting gliomas to provide a novel therapeutic strategy.

Quercetin, a naturally occurring flavonoid, exhibits antiproliferative and pro-apoptotic effects across various cancer models. Topotecan, a topoisomerase I inhibitor, is used in the treatment of retinoblastoma; however, its clinical utility is limited by dose-dependent toxicity. This study aimed to investigate whether quercetin is associated with enhanced topotecan-induced cytotoxicity in retinoblastoma and to explore the underlying mechanisms under both two-dimensional (2D) and three-dimensional (3D) conditions. Cell viability was assessed using the MTT assay, and drug interactions were evaluated using the combination index (CI) based on the Chou-Talalay method. Apoptosis was analyzed by Annexin V-FITC/PI staining and flow cytometry. Reactive oxygen species (ROS) levels and mitochondrial membrane potential were evaluated using fluorometric methods, and N-acetyl-L-cysteine (NAC) was used for functional modulation of oxidative stress. Three-dimensional tumor spheroid models were used to assess treatment effects under conditions that partially recapitulate tumor architecture. Gene expression levels of apoptosis-related markers and PI3K/Akt/mTOR pathway components were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). The combination of quercetin and topotecan was associated with synergistic cytotoxic effects in Y79 cells (CI < 1), accompanied by increased ROS levels, mitochondrial membrane depolarization, and elevated apoptotic cell death. NAC co-treatment partially attenuated ROS levels and restored cell viability. In 3D spheroid models, combination treatment induced structural disruption, reduced viability, and increased cell death, effects that were partially reversed by NAC. Gene expression analysis revealed upregulation of pro-apoptotic genes and downregulation of survival-related genes, along with increased PTEN expression. Quercetin is associated with enhanced topotecan-induced cytotoxicity in retinoblastoma cells under both 2D and 3D conditions. These effects were associated with ROS-associated cellular stress, mitochondrial dysfunction, and modulation of apoptotic and survival-related pathways. The partial rescue by NAC supports a contributory, but not exclusive, role of oxidative stress. These findings should be interpreted within a preclinical context and suggest that quercetin may represent a potential adjunct strategy warranting further validation in translational and in vivo models.