The study investigates the effects of commonly used chemotherapeutic agents on human colon cancer cell lines with specifically disrupted p53 pathways. The results show that p53 has a profound impact on drug responses, which vary significantly depending on the drug. P53-deficient cells are more sensitive to DNA-damaging agents like adriamycin and radiation due to the failure to induce the cyclin-dependent kinase inhibitor p21. In contrast, p53 disruption renders cells resistant to the antimetabolite 5-fluorouracil (5-FU), a key treatment for colorectal cancer. These effects are observed both in vitro and in vivo, are independent of p21, and appear to be related to perturbations in RNA metabolism rather than DNA metabolism. The findings have significant implications for maximizing therapeutic efficacy in patients with specific genetic alterations.The study investigates the effects of commonly used chemotherapeutic agents on human colon cancer cell lines with specifically disrupted p53 pathways. The results show that p53 has a profound impact on drug responses, which vary significantly depending on the drug. P53-deficient cells are more sensitive to DNA-damaging agents like adriamycin and radiation due to the failure to induce the cyclin-dependent kinase inhibitor p21. In contrast, p53 disruption renders cells resistant to the antimetabolite 5-fluorouracil (5-FU), a key treatment for colorectal cancer. These effects are observed both in vitro and in vivo, are independent of p21, and appear to be related to perturbations in RNA metabolism rather than DNA metabolism. The findings have significant implications for maximizing therapeutic efficacy in patients with specific genetic alterations.