Helen Lowe

Importance: Platinum-based chemotherapy is widely used in the management of solid tumors, and up to 60% of patients will experience ototoxic side effects, including hearing loss and tinnitus. The advent of novel otoprotective drugs generates a need for more flexible and innovative real-time approaches to drug-induced ototoxicity monitoring in cancer patients. Objective: To assess the feasibility of recruitment and compliance to monitoring of ototoxicity with mobile out-of-booth audiometry, Distortion Product Otoacoustic Emission (DPOAE) testing, and serum biomarker measurements. Design: Prospective observational study. Setting: Cancer ambulatory care. Participants: Patients undergoing platinum-based chemotherapy for bone or testicular cancer. Results: Twenty-three patients were enrolled between February 2021 and June 2023. The mean age was 17.5 years (range: 13 to 36 y). Average compliance to monitoring assessments was 86.5% for audiometry, 84.8% for DPOAEs, and 84.3% for serum biomarker measurements. End-of-treatment audiometric changes indicative of ototoxicity were found in 18 (78.2%) of the participants. Conclusions and relevance: High compliance with serial mobile audiometry and otoacoustic emissions testing, and serum biomarker measurement suggests that ototoxicity monitoring can be successfully performed in cancer ambulatory care rather than in an audiology department setting. Further investigation is required to understand the role of serum prestin and otolin-1 in monitoring ototoxicity.

Background: DNA interstrand cross-links (ICLs) are critical lesions produced by several cancer chemotherapy agents including platinum drugs and nitrogen mustards. We have previously shown in haematological (multiple myeloma) and solid tumours (ovarian cancer) that clinical sensitivity to such agents can result from a defect in DNA ICL processing leading to their persistence. Conversely, enhanced repair can result in clinical acquired resistance following chemotherapy. The repair of ICLs is complex but it is assumed that the ‘unhooking’ step is common to all ICLs. Methods: Using a modification of the single cell gel electrophoresis (Comet) assay we measured the formation and unhooking of melphalan and cisplatin-induced ICLs in cell lines and clinical samples. DNA damage response in the form of γ-H2AX foci formation and the formation of RAD51 foci as a marker of homologous recombination were also determined. Real-time PCR of 84 genes involved in DNA damage signalling pathways was also examined pre- and post-treatment. Results: Plasma cells from multiple myeloma patients known to be clinically resistant to melphalan showed significant unhooking of melphalan-induced ICLs at 48 hours, but did not unhook cisplatin-induced ICLs. In ovarian cancer cells obtained from patients following platinum-based chemotherapy, unhooking of cisplatin-induced ICLs was observed at 48 hours, but no unhooking of melphalan-induced ICLs. In vitro, A549 cells were proficient at unhooking both melphalan and cisplatin-induced ICLs. γ-H2AX foci formation closely followed the formation of ICLs for both drugs, and rapidly declined following the peak of formation. RPMI8226 cells unhooked melphalan, but not cisplatin-induced ICLs. In these cells, although cross-links form with cisplatin, the γ-H2AX response is weak. In A549 cells, addition of 3nM gemcitabine resulted in complete inhibition of cisplatin-induced ICL unhooking but no effect on repair of melphalan ICLs. The RAD51 foci response was both drug and cell line specific. Real time PCR studies highlighted differences in the damage response to melphalan and cisplatin following equi-ICL forming doses. Conclusions: These data suggest that the mechanisms by which melphalan and cisplatin-induced ICLs are ‘unhooked’ in vitro are distinct, and the mechanisms of clinical acquired resistance involving repair of ICLs, are drug specific.