PARP inhibitors chemopotentiate and synergize with cisplatin to inhibit bladder cancer cell survival and tumor growth.

BACKGROUND: Management of bladder cancer (BLCA) has not changed significantly in the past few decades, with platinum agent chemotherapy being used in most cases. Chemotherapy reduces tumor recurrence after resection, but debilitating toxicities render a large percentage of patients ineligible. Recently approved immunotherapy can improve outcomes in only a third of metastatic BLCA patients. Therefore, more options for therapy are needed. In this study, we explored the efficacy of PARP inhibitors (PARPi) as single agents or as combinations with platinum therapy. METHODS: We treated BLCA cells with PARPi (olaparib, niraparib, rucaparib, veliparib, or talazoparib) alone or as the combination of cisplatin with PARPi. We then measured their survival, proliferation, apoptosis, as well as their ability to form colonies. BLCA xenografts in male SCID mice were treated similarly, followed by the assessment of their growth, proliferation, and apoptosis. RESULTS: PARPi niraparib and talazoparib were effective in reducing BLCA cell survival as single agents. Combinations of Cisplatin with talazoparib and niraparib effectively reduced the survival of BLCA cells, while veliparib was not effective even at high concentrations. In vivo, the combinations of cisplatin with niraparib, rucaparib, or talazoparib reduced BLCA xenograft growth significantly. CONCLUSIONS: We provide evidence that PARPi can be effective against BLCA as single agents or as combinatorial therapy with cisplatin.

Evaluation of Academic Detailing to Impact Pharmacists' Compliance with an Outpatient Pharmacy Partial Fill Policy.

BACKGROUND: Pharmacists' compliance with a medication partial fill policy at a Veterans Affairs healthcare system has been underwhelming. Academic detailing, an educational outreach approach conducted by trained health care professionals to improve patient care, is an attractive method for improving pharmacists' compliance with the policy. OBJECTIVE: To evaluate the impact of academic detailing on pharmacists' compliance with the partial fill policy. METHODS: A pre-post analysis was performed to evaluate the impact of academic detailing outreach visits on pharmacists' compliance with the partial fill policy. Data collection included all partial fill medication orders verified during the study duration. Student's t-test was used to analyze the change in the day supply of partial fills following the academic detailing intervention. Total partial fill drug expense during the pre- and post-intervention phases was calculated as drug cost plus material cost for each partial fill. RESULTS: A total of 36 (97.3%) pharmacists received an academic detailing outreach visit. Total percentage of partial fills limited to a 7-day supply was significantly increased following academic detailing outreach visits (49.2% pre-intervention vs. 84.2% post-intervention, p-value <0.001). Total partial fill drug expense decreased from $12,144.42 to $9,713.50. Percentage of partial fills limited to a 7-day supply remained significant during the 6-month follow-up period (p-value = 0.03). CONCLUSIONS: Academic detailing is an effective method for improving pharmacists' compliance with an outpatient pharmacy partial fill policy and decreasing total partial fill drug expense for the pharmacy department.

The Emerging Role of Poly (ADP-Ribose) Polymerase Inhibitors as Effective Therapeutic Agents in Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is the sixth most common cancer in the US. However, no significant changes in management have occurred since the tyrosine kinase era until the recent breakthrough with checkpoint inhibitors. Therefore, the need for more therapeutic options is paramount. Our objective was to determine whether PARP inhibition represents a novel therapeutic option for RCC. We used publicly available COSMIC, GDC Data Portal, and cBioPortal databases to explore mutations in DNA repair genes in RCC tissues from the TCGA cohort. We treated a human normal renal epithelial cell line RPTEC/TERT1 and two human renal cancer cell lines ACHN and CAKI-2 with PARPi niraparib, olaparib, rucaparib, veliparib, and talazoparib. Cell survival, cell proliferation, clonogenic ability, and apoptosis were assessed. RCC xenografts in SCID mice were treated with PARPi to evaluate their efficacy in vivo. Data mining revealed that ~27-32% of RCC tissues contain mutations in homologous recombination genes. Niraparib and talazoparib were the most effective at reducing cell survival, proliferation, and clonogenic ability in vitro. Niraparib, talazoparib, and rucaparib were the most effective in reducing RCC xenograft growth in vivo. Agents such as PARPi that exploit mutations in DNA damage repair genes may be effective therapeutic options for RCC.