Curing metastatic testicular cancer

Einhorn, Lawrence H.

doi:10.1073/pnas.072067999

Cited by 346 publications

(231 citation statements)

References 24 publications

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“…Platinum-based anticancer drugs, cisplatin, carboplatin and oxaliplatin, have been used world-wide to treat various cancers including testicular, ovarian and colorectal tumours in clinical settings [16,58]. The anticancer action of these platinum drugs results from their capacity to form DNAplatinum covalent adducts, which ultimately lead to apoptosis of cancer cells [76].…”

Section: Introductionmentioning

confidence: 99%

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

et al. 2011

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Platinum-based DNA metallointercalators are structurally different from the covalent DNA binders such as cisplatin and its derivatives but have potent in vitro activity in cancer cell lines. However, limited understanding of their molecular mechanisms of cytotoxic action greatly hinders their further development as anticancer agents. In this study, a lead platinum-based metallointercalator, [(5,6-dimethyl-1,10-phenanthroline) (1S,2S-diaminocyclohexane) platinum(II)] 2+ (56MESS) was found to be 163-fold more active than cisplatin in a cisplatin-resistant cancer cell line. By using transcriptomics in a eukaryotic model organism, yeast Saccharomyces cerevisiae, we identified 93 genes that changed their expressions significantly upon exposure of 56MESS in comparison to untreated controls (p≤0.05). Bioinformatic analysis of these genes demonstrated that iron and copper metabolism, sulfur-containing amino acids and stress response were involved in the cytotoxicity of 56MESS. Follow-up experiments showed that the iron and copper concentrations were much lower in 56MESS-treated cells compared to controls as measured by inductively coupled plasma optical emission spectrometry. Deletion mutants of the key genes in the iron and copper metabolism pathway and glutathione synthesis were sensitive to 56MESS. Taken together, the study demonstrated that the cytotoxic action of 56MESS is mediated by its ability to disrupt iron and copper metabolism, suppress the biosynthesis of sulfur-containing amino acids and attenuate cellular defence capacity. As these mechanisms are in clear contrast to the DNA binding mechanism for cisplatin and its derivative, 56MESS may be able to overcome cisplatinresistant cancers. These findings have provided basis to further develop the platinum-based metallointercalators as anticancer agents.

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Section: Introductionmentioning

confidence: 99%

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

et al. 2011

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“…Despite the paucity, however, TGCT have become a model for a curable neoplasm even in advanced stages. The breakthrough in the treatment of metastatic TGCT was achieved by the drug cisdiamminedichloroplatinum (cisplatin, CDDP) (Higby et al, 1974;Einhorn, 2002). Cisplatin is a potent inducer of apoptosis in different cell types and is one of the most effective and widely used chemotherapeutic agents in the treatment of human cancers.…”

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confidence: 99%

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

et al. 2004

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Testicular germ cell tumours (TGCT) represent the most common malignancies in young males. Whereas in 1970s, the survival rate in patients with metastatic testicular tumours was only 5%, these days, 80% of the patients treated by modern chemotherapy will survive their disease. The drug that revolutionised the cure rate for patients with metastatic testicular tumours was cisdiamminedichloroplatinum (cisplatin, CDDP). In vitro experiments on neoplastic germ cell lines showed that their exquisite sensitivity to CDDP could be attributed to p53-dependent and -independent pathways. Applying cDNA macroarray, semiquantitative RT -PCR and Western blot analyses, blocking experiments, caspase activity assays, and morphological methods, we sought here to define the p53-independent pathway(s) involved in the CDDP-induced apoptosis. For this purpose, we used the human TGCT cell line NCCIT, the mutated p53 of which is known to remain inactive during the course of CDDP-induced apoptosis. Our experiments showed that within hours of CDDP application, two prototype members of the 'mitogen-activated protein kinase' (MAPK) family, designated 'MAPK ERK kinase' (MEK) and 'extracellular signal-regulated kinase' (ERK), were dually phosphorylated and caspase-3 became active. Functional assays using MEK inhibitors demonstrated that the phosphorylation of MEK and ERK was required for the activation of caspase-3 as the executing caspase. Interestingly, experiments with the human malignant germ cell line NTERA, which is known to possess wild-type p53, revealed the same results. Thus, our data suggest that CDDP mediates its p53-independent apoptosis-inducing effect on the malignant human testicular germ cells -at least partially -through activation of the MEK -ERK signalling pathway.

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“…2 With the widespread use of a standard regimen of BEP since 1987, 3 treatment outcomes of NSGCT have improved drastically, especially in poor-prognosis cases. 2,4 van Dijk et al carried out a meta-analysis based on 1775 cases of NSGCT treated after 1987, and estimated the 5-year OS of poor-prognosis cases as 71%. 5 Because of such progress in treatment outcomes, several investigators have proposed a new model to identify a high-risk group (so-called "very poor" cases) among poor-progno-sis cases.…”

Section: Introductionmentioning

confidence: 99%

Identification of a subgroup with worse prognosis among patients with poor‐risk testicular germ cell tumor

et al. 2015

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Results: The median follow-up period of all patients was 57 months. A total of 50 patients (43%) were classified as having intermediate prognosis, and 67 patients (57%) as poor prognosis according to the International Germ Cell Cancer Collaborative Group classification. As first-line chemotherapy, 92 patients (79%) received bleomycin, etoposide and cisplatin. Of all patients, 74 patients (63%) received second-line chemotherapy. The most commonly used second-line chemotherapy regimens were a combination of taxanes, ifosfamide and platinum in 49 cases (66%). Overall, 33 patients (28%) received third-line chemotherapy. A total of 88 patients (75%) underwent post-chemotherapy surgery. The 5-year overall survival for intermediate (n = 50) and poor prognosis (n = 67) was 89% and 83% (P = 0.21), respectively. In poor prognosis patients, patients with two or more risk factors (any of high lactic dehydrogenase, alpha-fetoprotein and human chorionic gonadotropin levels, and presence of non-pulmonary visceral metastases) had significantly worse survival than those with only one risk factor (71% and 91%, respectively, P = 0.01). Conclusions:The 5-year overall survivals of poor-prognosis testicular nonseminomatous germ cell tumor patients reached 83%. Further stratification of poorprognosis patients based on a number of risk factors has the potential to further identify those with poorer prognosis.

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Curing metastatic testicular cancer

Cited by 346 publications

References 24 publications

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

Identification of a subgroup with worse prognosis among patients with poor‐risk testicular germ cell tumor

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