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Darinaparsin, an active ingredient of DARVIAS ® Injection 135 ‍mg, is a novel organic arsenical compound of dimethylated arsenic conjugated to glutathione. Darinaparsin is thought to induce apoptosis and cell-cycle arrest and suppress tumor growth by disrupting mitochondrial functions and increasing production of intracellular reactive oxygen species. Darinaparsin is processed at the cell surface by γ-glutamyltranspeptidase (γ-GT), leading to formation of dimethylarsino-cysteine, which is imported via a cystine transporter expressed on cell surface membranes. Numerous tumor cells express high levels of γ-GT and cystine transporter, to maintain high levels of glutathione as an intracellular antioxidant. Darinaparsin is a novel antineoplastic agent designed to exploit the characteristics of tumor cells and to be efficiently taken up by tumor cells to inhibit their growth. In a global phase 2 pivotal study of darinaparsin in Asian patients with relapsed or refractory peripheral T-cell lymphoma (r/r PTCL), the overall response rate was 19.3% (90% confidence interval: 11.2-29.9%) and grade ≥3 drug-related adverse events with an incidence rate ≥5% included neutropenia (9.2%, n = 6), anemia (6.2%, n = 4) and thrombocytopenia (6.2%, n = 4) in 65 patients receiving darinaparsin. Based on the results of this phase 2 trial, which demonstrated the anti-tumor activity and acceptable safety profile of darinaparsin in patients with r/r PTCL, Solasia pharma K.K. received approval for darinaparsin for the treatment of r/r PTCL in June 2022, and Nippon Kayaku Co., Ltd. launched this drug in August 2022. Darinaparsin is expected to contribute to the clinical practice of PTCL as a new treatment option for this disease.

Arsenic is widely distributed in nature, and humans are exposed to arsenic through air, water, beverages, and food. On the bases of previous studies of highly exposed populations, arsenic is designated as a Group 1 human carcinogen by the International Agency for Research on Cancer (IARC), and IARC has established a causal role for arsenic in cancers of the urinary bladder, lung, and skin in humans. However, there are very few epidemiological studies of the association between low-moderate arsenic exposure and cancer. In particular, there is only one study of the association between arsenic intake from food and cancer. Further epidemiological studies are needed.

Toxicological studies of arsenic compounds were conducted in cultured mammalian cells to investigate the effects of glutathione (GSH) depletion. Dimethylarsinate DMA(V) was not cytotoxic in cells depleted of GSH, but was found to be cytotoxic when GSH was present outside the cells. The results suggested that a reactive form of DMA(V) was generated through interaction with GSH. Dimethylarsine iodide DMI(III) was used as a model compound of DMA(III), and the biological effects were investigated. DMI(III) was about 10000 times more toxic to the cells than DMA(V). Chromosome structural aberrations and numerical changes, such as aneuploidy, were induced by DMI(III). DMA(V) induced multiple foci of the centrosome protein, γ-tubulin, which were colocalized with multipolar spindles in mitotic cells. The multiple foci coalesced into a single dot on disruption of the microtubules (MT). However, reorganization of the MT caused multiple foci of γ-tubulin, suggesting that the induction of centrosome abnormalities by DMA(V) required intact MT. Inhibition of the MT-dependent motor, kinesin, prevented formation of multiple foci of γ-tubulin, which pointed to the involvement of the MT-dependent mitotic motor, kinesin, in the maintenance of centrosome abnormalities. DMI(III) caused abnormal cytokinesis (multipolar division). In addition, DMI(III) caused morphological transformation in Syrian hamster embryo cells. Consideration of the overall process following the centrosome abnormalities caused by DMA(V) suggested a mode of cytotoxicity in which the mitotic centrosome is a critical target.

Naturally occurring inorganic arsenic is known to increase the risk of cancers of the skin and several other organs, including the urinary bladder, lung, and liver. Epidemiological studies have also indicated that gestational arsenic exposure is associated with increased incidences of cancers in several organs, including the bladder and liver, in adulthood. Previous studies have shown that epigenetic changes are involved in arsenic-induced carcinogenesis. Among epigenetic changes, DNA methylation changes that are specific to arsenic-induced tumors would be useful for distinguishing such tumors from tumors induced by other factors and for clarifying arsenic carcinogenesis. It has been reported that gestational arsenic exposure of C3H mice, whose males tend to spontaneously develop liver tumors, increases the incidence of tumors in the male offspring. Using the same experimental protocol, we found a number of regions where the DNA methylation status was altered in the liver tumors compared with the normal liver tissues by the methylated DNA immunoprecipitation (MeDIP)-CpG island microarray method. Among such regions, we demonstrated using real-time methylation-specific PCR and bisulfite sequencing that a gene body region of the oncogene Fosb underwent alteration in DNA methylation following gestational arsenic exposure. We also showed that the Fosb expression level significantly increased following gestational arsenic exposure. These findings suggest that the DNA methylation status of the Fosb region is implicated in tumor augmentation and can also be utilized for characterizing tumors induced by gestational arsenic exposure.

Arsenic is ubiquitously distributed in nature throughout Earth's crust and thus the major source of exposure to this metalloid for the general population is naturally polluted drinking water from wells. In East Asia, more than 30 million people are chronically exposed to arsenic. Interestingly, the manifestations of vascular diseases caused by prolonged exposure to arsenic are consistent with those induced by impaired production of endothelium-derived nitric oxide (NO). However, no information has been available on the relation between NO synthesis and chronic arsenic poisoning in humans. A cross-sectional study in an endemic area of chronic arsenic poisoning in Inner Mongolia and experimental animal studies indicated that long-term exposure to arsenic by drinking water causes reduction of NO production in endothelial cells. Subsequent examinations with rabbits showed that decreased NO production during arsenic exposure is, at least in part, due to an "uncoupling" of endothelial NO synthase evoked by decreased levels of (6R)-5,6,7,8-tetrahydro-L-biopterin (BH(4)), a cofactor of the enzyme, leading to endothelial dysfunction. Furthermore, an intervention study in the area of chronic arsenic poisoning in Inner Mongolia suggested that decreased NO levels and peripheral vascular disease in arsenosis patients can be reversed by exposure cessation. In our cellular experiments, we found that arsenic exposure causes adaptive responses against oxidative stress and arsenic cytotoxicity through Nrf2 activation. This review summarizes the results of our recent studies on a fusion of field and laboratory studies on the chronic arsenic poisoning and cellular protection against the metalloid.

It has been clinically reported that chronic exposure to diphenylarsinic acid (DPAA) induced prominent cerebellar symptoms in apartment building residents in Kamisu, Japan. The aim of the present study was then to investigate the effect of chronic treatment with DPAA on the central motor impairment in mice. In the present study, we found that chronic in vivo exposure to a high dose of DPAA induced motor impairment in adult mice. This impairment was reversed by withdrawal following chronic DPAA treatment. The [35S]GTPgammaS binding assay showed the down-regulation of the dopamine receptor function in the striatum in adult mice treated with DPAA. We also found that neonatal exposure to a low dose of DPAA induced motor learning impairment in mice. Furthermore, treatment with an extremely low dose of DPAA caused the activation of caspase-3, the increase in glial fibrillary acidic protein-like immunoreactivity (IR) and the reduction in levels of myelin-associated glycoprotein-IR in mouse cerebellum neuron/glia co-cultures. In addition, we found that neonatal exposure to a low dose of DPAA induced anxiogenic behavior in a plus maze in mice. Taken together, these results suggest that chronic treatment with DPAA may induce motor impairment in adult mice. Moreover, neonatal exposure to DPAA leads to the irreversible motor impairment associated with abnormalities in the cerebellum.

A 77-year-old man suffered from acute pancreatitis during the treatment of relapsed acute promyelocytic leukemia with As2O3. He presented with epigastralgia on day 25 during the treatment with As2O3. Pancreatic enzyme levels were elevated and the computed tomography scan of the abdomen showed swelling of the pancreas. As acute pancreatitis due to As2O3 was suspected, As2O3 was discontinued. Intravenous gabexate mesilate was administered, and the pancreatitis improved. Acute pancreatitis should be considered as a possible complication during treatment with As2O3.

It has been shown that arsenic trioxide (As2O3) may induce hematologic remissions in patients with acute promyelocytic leukemia (APL) refractory to all-trans retinoic acid (ATRA). We reported on a patient with ATRA and drug-resistant APL that was successfully treated with As2O3. The patient had been given a diagnosis of typical APL and was treated with ATRA and chemotherapy for 12 months. He achieved complete remission (CR), but leukemia relapsed with 43% APL cells in the bone marrow in the 16th month of treatment. ATRA and cytarabine plus daunorubicin were administered; however, the APL cells in the bone marrow increased to 97.2%. As2O3 was initiated intravenously, and bone marrow showed a decrease of APL cells (6.7%) and a partial differentiation after 9 days. The patient received idarubicin (IDA) and steroid pulse because of the development of ATRA-like syndrome, and achieved CR 37 days after the initiation of As2O3. He received an additional 2 courses of As2O3 with IDA, and is in CR. These results demonstrated the therapeutic efficacy of As2O3 in treating ATRA and drug-resistant APL.