Abstract A066: The cytotoxic effects of oxaliplatin and 5-fluorouracil against low-grade serous ovarian cancer cells
Authors: Rewati Prakash, Alicia A. Goyeneche, Benjamin N. Forgie, Carlos M. Telleria
Journal: Cancer Research (2024)

Abstract Low-grade serous ovarian cancer (LGSOC) is considered a rare histopathological subtype of epithelial ovarian cancer, representing 10% of all cases. Although rare, LGSOC is known to have a poor response to standard chemotherapeutic drugs like the platinum (Pt) agents’ cisplatin (CDDP) and carboplatin (CP). Oxaliplatin (OXP) is a 3rd generation Pt-drug approved for gastrointestinal cancers such as colorectal cancer; however, off-label use of OXP for treating other subtypes of ovarian cancer have shown positive results. Therefore, alongside OXP’s better side effect profile and demonstrable lack of co-resistance risk with CDDP and CP, there is a strong potential to use OXP for treating LGSOC. As a screening method, cell lines for LGSOC (VOA7681 &amp; VOA6406) as well as high-grade serous (HGSOC) (PEO1 &amp; PEO4), clear cell (CCC) (TOV21G &amp; XVOA295), and endometrioid (EC) (TOV112D &amp; VOA4395) ovarian cancer were exposed to multiple doses of CDDP and OXP for a 3-hour period, before incubating in fresh media for 72-hours. These cells were then subjected to a clonogenic survival assay to assess the long-term toxicity of the drugs. The data was then compared to the drugs’ respective clinically derived maximum plasma concentration (Cmax) to produce a “normalized clonogenic survival %”. Whereas CDDP had a stronger effect on HGSOC, CCC, and EC cell lines, the LGSOC cell lines responded more favorably to OXP. Thus, based on these long-term clonogenic results, LGSOC cell lines were chosen as the focus of further research with OXP. To assess the impact of OXP following the 72-h treatment, the total cell proliferation as well as the progression of the cell cycle of LGSOC cells was assessed. LGSOC cells showed a substantial reduction in cell growth in the presence of OXP. Furthermore, OXP significantly reduced the proportion of cells present within the G1 phase of the cell cycle, with lower doses causing an increase in cells transiting the S and G2/M phases; interestingly, higher doses of OXP increased the cloud of cells carrying hypodiploid DNA content, consistent with cell death. In gastrointestinal cancers, OXP is often given alongside 5-fluorouracil (5-FU). Therefore, we repeated the experiments with OXP but included 100 µM 5-FU. The result was a further decrease in total cell proliferation with the addition of 5-FU to OXP-treated cells. Interestingly, the addition of 5-FU created two populations when assessing cell cycle progression. Low-dose OXP with 5-FU pushed cells towards the S and G2/M phases of the cell cycle, which then subsequently died, while higher doses of OXP and 5-FU killed cells transiting the G1 phase of the cell cycle. In summary, OXP shows better potential in reducing the growth of LGSOC cells when compared to the other ovarian cancer subtypes. Furthermore, 5-FU potentiates the cytotoxic effect of OXP in LGSOC cells. Citation Format: Rewati Prakash, Alicia A. Goyeneche, Benjamin N. Forgie, Carlos M. Telleria. The cytotoxic effects of oxaliplatin and 5-fluorouracil against low-grade serous ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A066.