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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The platinum complexes are unusual among modern pharmaceuticals in that they are inorganic compounds possessing a metallic element whereas most drugs are purely organic. Platinum-based antineoplastic agents are sometimes described as “alkylating agents”, which is incorrect as they do not contain an alkyl group; “platinating agents” would be a more technically correct term. The success of the prototypic cisplatin (Figure 5.32) is due to a number of reasons including a broad spectrum of antitumor activity against drug-resistant as well as drug-sensitive tumors, and activity against slow-growing and rapidly growing tumors, and both primary solid and disseminated tumors. In animal models it is active against viral- and chemical-induced tumors and transplantable tumors, and shows no strain or species specificity, which is why it is widely used in veterinary medicine. Structures of cisplatin, carboplatin (ParaplatinTM), and oxaliplatin (EloxatinTM).
PD-1 blockade synergizes with oxaliplatin-based, but not cisplatin-based, chemotherapy of gastric cancer
Published in OncoImmunology, 2022
Peng Liu, Jianzhou Chen, Liwei Zhao, Antoine Hollebecque, Oliver Kepp, Laurence Zitvogel, Guido Kroemer
Platinum-based antineoplastic drugs are among the most widely used chemotherapeutic agents employed for the treatment of solid tumors including but not limited to lung, colorectal, gastric, and head and neck cancers1. Cisplatin is a first-generation platinum drug initially approved by the FDA for testicular and ovarian cancers and has been, and still is, one of the most employed chemotherapeutic agents in clinical routine.2 Despite the landmark success during the dawn of chemotherapy in the 1970s, major limitations of cisplatin are the (inevitable) occurrence of drug resistance as well as considerable side effects.3 Since then, new generation analogues with equivalent or increased antitumor activity and decreased risk of adverse effects have been developed and introduced into clinical oncology.4 Oxaliplatin, a second generation anticancer agent, turned out to be as efficient as cisplatin in the treatment of gastric cancers. Systematic meta-analysis of clinical trials in advanced gastric cancer comparing oxaliplatin-based treatment regimens with cisplatin-mediated effects revealed equivalent or superior antineoplastic effects of oxaliplatin that were coupled to a favorable safety profile associated with less neutropenia and fewer thromboembolic events, but with increased neurotoxicity.5–10 Of note, accumulating evidence suggests that the improved anticancer efficacy of oxaliplatin depends at least in part on the induction of immunogenic cell death (ICD),11–13 which stimulates potent antitumor immune responses.
ARAP1 is an independent prognostic biomarker in older women with ovarian high-grade serous adenocarcinoma receiving first-line platinum-based antineoplastic therapy
Published in Acta Oncologica, 2020
Sambavy Nadaraja, Doris Schledermann, Jørn Herrstedt, Olga Østrup, Henrik J. Ditzel
Formalin-fixed, paraffin-embedded (FFPE), tumor samples from 50 women aged >70 years with primary HGSC were identified in a retrospective cohort (discovery cohort). All patients had received first-line platinum-based antineoplastic therapy following surgery or as neoadjuvant chemotherapy, or chemotherapy as the sole treatment. The FFPE tumor samples predominately originated from the local biobank at the Department of Pathology, Odense University Hospital (OUH), and were collected for diagnostic purposes from 1997 to 2015. Samples were grouped according to time of progression after first-line platinum-based anti-neoplastic therapy, with 20 patients experiencing progression within 6 months, and 30 patients progressing >12 months after, or not at all. In addition, FFPE tumor tissue from an additional 14 women with HGSC and aged ≥70 years were collected as a validation cohort. Eight had early disease progression (<6 months) and six had late progression (>12 months). These samples also predominately originated from the local biobank at the Department of Pathology, OUH and were from the same time period as the discovery population.
Cisplatin-induced oxidative stress stimulates renal Fas ligand shedding
Published in Renal Failure, 2018
Hitesh Soni, Damian Kaminski, Rajashekhar Gangaraju, Adebowale Adebiyi
Platinum-based antineoplastic drugs are poorly water-soluble. Thus, cisplatin is commonly solubilized in organic solvents for use in laboratory research [36]. A recent literature review suggested that cisplatin is predominantly prepared in DMSO for research [36]. However, DMSO may interfere with the structure of platinum complexes [36,37]. Both in vitro and in vivo studies have also demonstrated that dissolution of cisplatin in DMSO inactivates its biological activities. For example, DMSO diminished the cytotoxic effects of cisplatin in cultured thyrocytes and cancer cell lines [36,38,39]. The lack of significant effect of a cisplatin formulation against appendicular osteosarcoma in dogs has also been associated with its inactivation by DMSO [40]. Therefore, solubilization of cisplatin in an appropriate medium is critical for its biological activity. To investigate cisplatin nephrotoxicity, we solubilized cisplatin in SBE-β-CD (Captisol), a pharmaceutical excipient [41–43]. Renal tubular damage and apoptosis were absent in the kidneys of Captisol-treated mice. In addition, plasma creatinine and urine ACR levels were less than 0.1 mg/dL and 0.2, respectively in the mice. These findings corroborate other studies that demonstrated an apparent lack of SBE-β-CD-induced renal toxicity [41,43].