The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning.

Small molecules can affect many cellular processes. The disambiguation of these effects to identify the causative mechanisms of cell death is extremely challenging. This challenge impacts both clinical development and the interpretation of chemical genetic experiments. CX-5461 was developed as a selective RNA polymerase I inhibitor, but recent evidence suggests that it may cause DNA damage and induce G-quadraplex formation. Here we use three complimentary data mining modalities alongside biochemical and cell biological assays to show that CX-5461 exerts its primary cytotoxic activity through topoisomerase II poisoning. We then show that acquired resistance to CX-5461 in previously sensitive lymphoma cells confers collateral resistance to the topoisomerase II poison doxorubicin. Doxorubicin is already a frontline chemotherapy in a variety of hematopoietic malignancies, and CX-5461 is being tested in relapse/refractory hematopoietic tumors. Our data suggest that the mechanism of cell death induced by CX-5461 is critical for rational clinical development in these patients. Moreover, CX-5461 usage as a specific chemical genetic probe of RNA polymerase I function is challenging to interpret. Our multimodal data-driven approach is a useful way to detangle the intended and unintended mechanisms of drug action across diverse essential cellular processes.

Perspectives Regarding Medications for Opioid Use Disorder Among Individuals with Mental Illness.

Most people with co-occurring opioid use disorder (OUD) and mental illness do not receive effective medications for treating OUD. To investigate perspectives of adults in a publicly-funded mental health system regarding medications for OUD (MOUD), we conducted semi-structured telephone interviews with 13 adults with OUD (current or previous diagnosis) receiving mental health treatment. Themes that emerged included: perceiving or using MOUDs as a substitute for opioids or a temporary solution to prevent withdrawal symptoms; negative perceptions about methadone/methadone clinics; and viewing MOUD use as "cheating". Readiness to quit was important for patients to consider MOUDs. All participants were receptive to discussing MOUDs with their mental health providers and welcomed the convenience of receiving care for their mental health and OUD at the same location. In conclusion, clients at publicly-funded mental health clinics support MOUD treatment, signaling a need to expand access and build awareness of MOUDs in these settings.

Opioid Use Disorder Among Clients of Community Mental Health Clinics: Prevalence, Characteristics, and Treatment Willingness.

OBJECTIVE: The authors examined the prevalence of co-occurring opioid use disorder and willingness to engage in treatment among clients of eight Los Angeles County Department of Mental Health outpatient clinics. METHODS: Adults presenting for an appointment over a 2-week period were invited to complete a voluntary, anonymous health survey. Clients who indicated opioid use in the past year were offered a longer survey assessing probable opioid use disorder. Willingness to take medication and receive treatment also was assessed. RESULTS: In total, 3,090 clients completed screening. Among these, 8% had a probable prescription (Rx) opioid use disorder and 2% a probable heroin use disorder. Of the clients with probable Rx opioid use or heroin use disorder, 49% and 25% were female, respectively. Among those with probable Rx opioid use disorder, 43% were Black, 33% were Hispanic, and 12% were White, and among those with probable heroin use disorder, 24% were Black, 22% were Hispanic, and 39% were White. Seventy-eight percent of those with Rx opioid use disorder had never received any treatment, and 82% had never taken a medication for this disorder; 39% of those with heroin use disorder had never received any treatment, and 39% had never received a medication. The strongest predictor of willingness to take a medication was believing that it would help stop opioid use (buprenorphine, ß=13.54, p=0.003, and naltrexone long-acting injection, ß=15.83, p<0.001). CONCLUSIONS: These findings highlight the need to identify people with opioid use disorder and to educate clients in mental health settings about medications for these disorders.

Training substance abuse treatment staff to care for co-occurring disorders.

Although co-occurring disorders have been associated with poorer substance abuse treatment outcomes and higher costs of care, few individuals with co-occurring disorders receive appropriate mental health care. This article describes the design and implementation of an intervention to improve the quality of mental health care provided in outpatient substance abuse treatment programs without requiring new treatment staff. The intervention focuses on individuals with affective and anxiety disorders and consists of three components: training and supervising staff, educating and activating clients, and linking with community resources. We evaluated three treatment programs (one intervention and two comparison) for the first component by having program staff complete both self-administered questionnaires and semistructured interviews. Staff knowledge and attitudes about co-occurring disorders, job satisfaction, and morale all indicated an improvement at the intervention relative to the comparison sites. The evaluation is still under way; results for implementation of the other two components and for outcomes will be reported later.