Novel Anti-Cancer Drugs Based On Hsp90 Inhibitory Mechanisms: A Recent Report
Debarshi Kar Mahapatra, Sanjay Kumar Bharti in Medicinal Chemistry with Pharmaceutical Product Development, 2019
Cisplatin is an inorganic DNA intercalating agent that is used for the treatment of various types of cancer (Figure 3.13). It is used alone or in combination with other antineoplastic agents for the treatment of testicular, ovarian, bladder and lung cancer [162]. It has been demonstrated that cisplatin binds to a region proximal to the C domain’s ATP binding pocket. The amino acid residues involved in its binding is still not elucidated [163]. Resistance and side effects associated with cisplatin treatment limit its therapeutic potential as an anticancer agent [164–166]. Hence, researchers did not get stimulation to explore further the Hsp90 binding potential of cisplatin. Nevertheless, this will provide a pathway for the design of novel cisplatin derivatives as Hsp90 inhibitors.
Antiemetics and Cancer Chemotherapy
John Kucharczyk, David J. Stewart, Alan D. Miller in Nausea and Vomiting: Recent Research and Clinical Advances, 2017
A double-blind randomized crossover study by Frytak et al.34 in 1981 involving 100 patients showed the superiority of metoclopramide over prochlorperazine. Patients received cisplatin in doses varying from 40 to 120 mg/m2. Metoclopramide was given 20 mg p.o. t.i.d. Prochlorperazine was given 10 mg p.o. t.i.d. Although metoclopramide was shown to be superior to prochlorperazine, both drugs were limited in their overall effectiveness. An open trial by Kahn et al.35 with 35 patients receiving cisplatin in a dose of 100 mg/m2 suggested a more beneficial role for this drug. In this study, a single metoclopramide dose of 20 mg p.o. seemed to provide 92% protection against vomiting. However, the results of this trial were not confirmed in our studies, such as that of Moertel et al.36 in 1969 which utilized oral metoclopramide 20 mg in a double-blind randomized crossover design. In this trial metoclopramide appeared ineffective.
Toxicity and morbidity of IP drug therapy
Wim P. Ceelen, Edward A. Levine in Intraperitoneal Cancer Therapy, 2015
Whether and how much the addition of heat may augment the toxicity of cisplatin is unclear. In an animal study, the addition of heat to IP cisplatin did not change the drug level in tumor or plasma, suggesting that the toxicity profile should be the same [25]. In reports of HIPEC with cisplatin, multiple drugs are used. The incidence of hematologic toxicity is similar between cisplatin combined with MMC and MMC alone (see Table 27.2). Kusamura et al. [19] describe their results in 209 patients using either cisplatin 25 mg/m2/L and MMC 3.3 mg/m2/L or cisplatin 43 mg/L and doxorubicin 15.25 mg/L for 60–90 minutes at 42°C–43°C outflow temperature. The complications are described for the group as a whole, but the incidence of grade 3 hematologic toxicity was only 1.4 %, with grade 3 or 4 renal toxicity of 2%. There were two patients who ultimately required hemodialysis and developed chronic renal failure. The group did find on univariate and multivariate analysis that a dose of cisplatin >240 mg significantly correlated with major morbidity, and no prior chemotherapy had borderline significance in increasing morbidity. In a later review from the same center, Baratti et al. [26] looked at 108 patients with mesothelioma who received cisplatin 45 mg/L and doxorubicin 15 mg/L for 90 minutes at 42.5°C. The rates of toxicity were higher, with 14 (12.9%) leak or perforation, 7 (6.5%) hematologic toxicity, and 10 (9.2%) renal toxicity. The mean dose of cisplatin was below 240 mg, and in this review the factors contributing to complications, such as prior chemotherapy, were not analyzed.
BEZ235 reduction of cisplatin resistance on wild-type EGFR non-small cell lung cancer cells
Published in Journal of Chemotherapy, 2023
Ruikai Wang, Amin Li, Jiachang Liu, Ming Fang, Yan Zhu, Juan Huang, Yinjie Liu, Long Huo, Qinghai You
Cisplatin is an important DNA-damaging anticancer drug used to treat many cancer types [16]. However, the effectiveness of cisplatin treatment diminishes quickly as cancer cells develop resistance to the drug, which eventually results in treatment failure. In our study, we explored the sensitization of BEZ235 on cisplatin-resistant wtEGFR NSCLC cells to cisplatin. We successfully induced cisplatin-resistant cell lines H358R and A549R. However, we found abnormal activation of DNA repair kinases ATM/ATR/DNA-PKcs and their downstream signal pathway AKT/mTOR in the cells (Figure 1), which could be inhibited by BEZ235. The effects of DNA damage, apoptosis, and anti-proliferation, as well as the inhibition of migration of H358R and A549R cells treated with BEZ235 in combination with cisplatin, were significantly enhanced compared with those after treatment with cisplatin alone. Therefore, we believed that BEZ235 could effectively reduce cisplatin resistance and improve the anticancer efficacy. ATM/ATR/DNA-PKcs and AKT/mTOR pathway might be one of the important molecular mechanisms of cisplatin resistance.
Aqueous core epigallocatechin gallate PLGA nanocapsules: characterization, antibacterial activity against uropathogens, and in vivo reno-protective effect in cisplatin induced nephrotoxicity
Published in Drug Delivery, 2022
Badriyah Alotaibi, Thanaa A. El-Masry, Engy Elekhnawy, Aya H. El-Kadem, Asmaa Saleh, Walaa A. Negm, Dalia H. Abdelkader
Additionally, severe renal dysfunction and acute kidney tissue injury are also associated with administering multiple chemotherapeutic agents such as cisplatin. Cisplatin is a common anti-neoplastic medication used to treat malignancies such as breast, ovarian, lung, head and neck, and urinary bladder. Although most chemotherapy regimens include it, nephrotoxicity is a prevalent side effect limiting its efficacy (Mehmood et al., 2014). As a result, minimizing kidney injury in cisplatin-treated patients is critical, and the pathogenesis of cisplatin should be elucidated to design a new medicine to moderate the nephrotoxicity induced by cisplatin (Aldossary, 2019). Despite current research into the pathophysiological foundation of cisplatin nephrotoxicity, the molecular mechanism of cisplatin-induced kidney injury has yet to be determined. However, necrosis, oxidative stress, inflammation, and apoptosis may play essential roles in cisplatin-induced nephrotoxicity (Pabla & Dong, 2008).
Tetramodal therapy with transurethral resection followed by chemoradiation in combination with hyperthermia for muscle-invasive bladder cancer: early results of a multicenter phase IIB study
Published in International Journal of Hyperthermia, 2022
Oliver Riesterer, Adela Ademaj, Emsad Puric, Brigitte Eberle, Marcus Beck, Silvia Gomez, Dietmar Marder, Eva Oberacker, Susanne Rogers, Roger A. Hälg, Thomas Kern, Sonja Schwenne, Jürgen Stein, Emanuel Stutz, Olaf Timm, Sebastian Zschaeck, Mathias S. Weyland, Paraskevi D. Veltsista, Stephen Wyler, Peter Wust, Stephan Scheidegger, Stephan Bodis, Pirus Ghadjar
Patients received weekly chemotherapy with cisplatin or carboplatin for a minimum of six and a maximum of seven cycles. Cisplatin with 40 mg/m2 was given intravenously according to the institutional protocol. If the creatinine clearance was <60 ml/min, weekly carboplatin (AUC2) was administered instead of cisplatin. Deep RHT was administered in accordance with the quality assurance guidelines published by the European Society for Hyperthermic Oncology (ESHO) [13,14]. The BSD 2000/3 D system with the Sigma-60 or Sigma-Eye phased array applicator (BSD Medical Cooperation/Pyrexar, Salt Lake City, UT, USA) was used. RHT was performed once a week for a minimum of six and a maximum of seven sessions. After an induction period of approximately 30 min, RHT was delivered for 60 min. Thermal mapping with multichannel thermometry probes was mandatory to measure the temperature achieved at the reference points. The temperature probes were placed in the rectum, bladder, vagina (for female patients) and additionally on the anal margin (rima ani). The temperature was measured at 10-second intervals, starting before treatment and stopping five minutes after switching off the radiofrequency power. Based on these measurements, the Cumulative Equivalent Minutes (CEM43 °C) were calculated to describe the thermal dose applied to the bladder [15]. According to protocol, HT was initiated within two hours prior to or after RT.
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