Changes affecting the drug metabolism are another reason for resistance. Tumor cells overexpressing detoxifying phase I and phase II enzymes possess an enhanced ability to inactivate cytotoxic drugs. An increased CYP3A4 activity, an enzyme of the cytochrome P450 family, inactivates for example paclitaxel in colorectal cancer cells. Furthermore, even a reduced expression of drug activators led to reduced drug sensitivity. For example carboxylesterases, normally involved in intracellular activation of irinotecan, are reduced in cancer cells with enhanced resistance to irinotecan. Here, CYP3A4 is linked to neoplasm.