5-FU does not synergize with DNA-damaging agents such as oxaliplatin or irinotecan

Traditionally, 5-fluorouracil (5-FU) has been used in combination with DNA-damaging chemotherapy drugs like oxaliplatin and irinotecan to treat colorectal cancer (CRC). However, in this study, researchers found that combining 5-FU with these DNA-damaging agents does not result in the expected synergistic tumor-killing effects in CRC. Instead, 5-FU primarily exerts its cytotoxic effects through RNA damage, specifically disrupting ribosomal RNA (rRNA) biogenesis, rather than through DNA damage.

The researchers showed that when combined with drugs that modulate RNA synthesis, 5-FU’s efficacy could be enhanced. For example, they found that inhibiting KDM2A, which regulates rRNA transcription, could increase the cytotoxicity of 5-FU. This suggests that for patients with GI cancers, a new therapeutic strategy could be to combine 5-FU with agents that affect RNA synthesis or ribosome biogenesis, rather than relying on DNA-damaging drugs.

This represents a potential shift in the way 5-FU is used in clinical settings for treating colorectal and possibly other gastrointestinal cancers.

mTOR inhibitors (e.g., rapamycin) reduce overall protein synthesis by inhibiting pathways that promote ribosome biogenesis. Inhibiting mTOR can lead to decreased rRNA synthesis because mTORC1 is a key regulator of ribosomal production.