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Objective: Separation and identification of the process impurities in the manufacture of temsirolimus drug viz., rapamycin, temsirolimus regioisomer (monoester) (TS monoester), and temsirolimus diester (TS diester). Methods: During the process development of temsirolimus (TS), three process impurities-rapamycin, temsirolimus regioisomer (monoester) and temsirolimus diester-were detected by high-performance liquid chromatography (HPLC). Impurities were isolated by medium pressure liquid Chromatography (MPLC) and characterized by ESI-MS/MS, 1H NMR, FT-IR spectral data. Results: These impurities are characterised with the help of ESI MS/MS, 1H NMR, and FT-IR data. The impurities are identified and characterised as the process impurities. One of them is the starting material i.e. rapamycin and the other two are formed during the manufacture of the drug. This method offers advantages over using photodiode-array UV detection (LC-PDA) for the determination of peak purity, viz. components with similar UV spectra can be distinguished. Conclusion: The structures of these impurities were characterized as rapamycin, TS Monoester, and TS Diester. Out of these process impurities, rapamycin has been previously identified while the other two are previously unreported.
ABSTRACT
PURPOSE: Temsirolimus is effective in the treatment for metastatic non-clear cell renal cell carcinoma (nccRCC) with poor prognosis. We aim to investigate the efficacy and tolerability of temsirolimus in treatment of naïve Asian patients with metastatic/recurrent nccRCC. MATERIALS AND METHODS: From January 2008 to July 2017, data of treatment-naïve, metastatic/recurrent nccRCC patients, who were treated with temsirolimus according to the standard protocol, were collected. The primary end-point was progression-free survival (PFS). Secondary end points were overall survival (OS), objective response rate (ORR), and tolerability of temsirolimus. RESULTS: Forty-four metastatic/recurrent nccRCC patients, 10 from prospective and 34 from retrospective groups, were enrolled; 24 patients (54%) were papillary type, and other histology subtypes included 11 chromophobes (25%), two collecting ducts (5%), one Xp11.2 translocation (2%), and six others (14%). The median PFS and OS were 7.6 months and 17.6 months, res-pectively. ORR was 11% and disease control rate was 83%. Patients with prior nephrectomy had longer PFS (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.06 to 0.42; p < 0.001) and OS (HR, 0.15; 95% CI, 0.05 to 0.45; p < 0.001). Compared to favorable/intermediate prognosis group, poor prognosis group had shorter median PFS (4.7 months vs. 7.6 months [HR, 2.91; 95% CI, 1.39 to 6.12; p=0.005]) and median OS (9.2 months vs. 17.6 months [HR, 2.84; 95% CI, 1.23 to 6.56; p=0.015]). CONCLUSION: Temsirolimus not only benefits poor-risk nccRCC patients, but it is also effective in favorable or intermediate-risk group in Asians. Temsirolimus was well-tolerated with manageable adverse events.
Subject(s)
Humans , Asian People , Carcinoma, Renal Cell , Disease-Free Survival , Nephrectomy , Prognosis , Prospective Studies , Retrospective StudiesABSTRACT
Notwithstanding the noteworthy advances in its treatment,malignant tumor remains one of the main diseases threat?ening human health. Therefore,it is urgent to search and develop novel anticancer drugs with high curative effect and less side effect. In this review,we focus on summarizing the physio-chemical properties,preparation processes,anti-tumor activity mechanisms,clini?cal effects,side effects,and main isomers,especially the research progress of temsirolimus,with the hope to provide some reference for the further research.
ABSTRACT
Notwithstanding the noteworthy advances in its treatment, malignant tumor remains one of the main diseases threatening human health. Therefore, it is urgent to search and develop novel anticancer drugs with high curative effect and less side effect. In this review, we focus on summarizing the physio-chemical properties, preparation processes, anti-tumor activity mechanisms, clinical effects, side effects, and main isomers, especially the research progress of temsirolimus, with the hope to provide some reference for the further research.
ABSTRACT
Mantal cell lymphoma (MCL) is a rare and special type of non-Hodgkin lymphoma.MCL is classified as an aggressive variety of lymphoma and yet it sometimes behaves as an indolent lymphoma.Although the first-line therapy of MCL is highly effective,but it is incurable through conventional chemotherapy.Patients with MCL have a poor prognosis.This review focus on a new therapeutic approach,mammalian target of rapamycin (mTOR) inhibitor.Temsirolimus,a derivation of rapamycin,in MCL cell lines inhibited mTOR.Temsirolimus could inhibits tumor cell proliferation through cell cycle arrest and able to down-regulation of cyclin D1 and Ki-67 in lymphomacell.Clinical trials showed that temsirolimus induced patients with MCL response rate and a prolong progression-free survival.In addition,preclinical studies demonstrated the use of a combination of temsirolimus with monoclonal antibodies or conventional chemotherapy to improve the efficacy of single agent use.Altogether,temsirolimus shows promising results in the therapy of patients with heavily MCL,and especially responses in chemotherapy refractory patients,providing a novel approaches to treatment of MCL.
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Therapies targeting endocrine receptors and human epidermal growth factor receptor 2 have become important treat-ment modes for patients with hormone receptor breast cancer. Despite the availability of these options, however, development of prima-ry or secondary drug resistance and subsequent disease progression in patients with advanced disease continue to occur. Mammalian tar-get of rapamycin (mTOR), a key regulator of cell growth and proliferation, has been implicated in the induction of cellular processes leading to the uncontrolled growth of cancer cells. Recent studies have suggested that overactivation of the mTOR pathway may be in-volved in the development of endocrine resistance. Interrupting this signaling cascade may alleviate such resistance and help restore drug sensitivity. A number of agents targeting the mTOR pathway have shown potent anti-tumorigenic effects in vitro, and several agents show great potential for treating breast cancer patients. Many clinical studies have shown that combining endocrine therapy with mTOR inhibitors could significantly increase the survival rate of breast cancer patients. In this study, we focus on recent research prog-ress on mTOR and its inhibitors in endocrine therapy resistance in breast cancer.
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A 49-year-old man presented with an incidentally detected right renal mass on a health examination. The abdominal computed tomography and magnetic resonance imaging showed a 3-cm right renal mass suspected of being a hypovascular tumor, such as papillary renal cell carcinoma, and an osteoblastic metastatic lesion on the right iliac bone. However, we missed a bone lesion at the time of diagnosis. A laparoscopic radical nephrectomy was performed and the final pathology confirmed unclassified renal cell carcinoma. The follow-up imaging studies showed several neck lymph nodes and multiple bone metastases at the lumbar spine, right iliac bone, and left femur. Thirteen cycles of temsirolimus were administered to the patient, but follow-up positron emission tomography showed newly developed liver and left adrenal metastasis and increased bone metastasis. It is important to note that T1a renal cell carcinoma can present with distant metastasis and thus demands scrupulous examination even though the tumor size may be small.
Subject(s)
Humans , Middle Aged , Carcinoma, Renal Cell , Femur , Follow-Up Studies , Liver , Lymph Nodes , Magnetic Resonance Imaging , Neck , Neoplasm Metastasis , Neoplasms by Histologic Type , Nephrectomy , Osteoblasts , Positron-Emission Tomography , Sirolimus , SpineABSTRACT
The clinical experience of the novel drug temsirolimus on eight patients with metastatic renal cell carcinoma and who were refractory to other forms of treatment is reported. Although none of the patients showed complete or partial response, three patients had stable disease. One patient was prematurely withdrawn due to pneumonitis. Five patients died during the period of observation of twenty months and the median survival time from start of treatment was ten months. Three patients showed no evidence of adverse events (AE). Five patients showed dyslipidemia and two had pneumonitis for which, the drug had to be withdrawn in one of them. None had significant leucopenia. We conclude that temsirolimus has activity even in heavily pretreated patients in advanced renal cell carcinoma and in addition, has the benefits of ease of administration and good tolerability.