Combining same-target drugs exhibits additive efficacy with minimal toxicity

Abstract Drug toxicity is a major concern in medicine, and toxicity is an unresolved obstacle to the efficacy of chemotherapy drugs for cancer. Based on our ‘additive effect’ and ‘toxicity scattering effect’ hypothesis, we propose a unique drug-combination strategy to overcome drug toxicities: combining 8–10 drugs that act on the same target at ineffective doses (much lower than their usual doses) to dramatically reduce the toxicity of each drug without weakening the efficacy of the combination. Using this strategy, we developed an anticancer combination of 8 drugs (topoisomerase II inhibitors); each drug was included at 7.7%–19.5% of its minimum effective dose. This combination prolonged life by 92.8% in ascites tumour-bearing mice and inhibited tumour growth by 54.3% in solid tumour-bearing mice, without causing mortality or detectable liver, cardiac, or renal toxicity. At an average of 1/3 of the combination dose, each drug alone resulted in ineffective tumour inhibition (only 24.6%–34.5% reduction) but caused a 10%–50% mortality. As number of drugs in the combination increased from 1 to 4 to 8, the dose of each drug and the overall toxicity progressively decreased. Combinations of four or six topoisomerase II inhibitors at low concentrations inhibited the proliferation of cancer cell lines and the activity of topoisomerase II, revealing an evident additive effect on the same target. These results demonstrate the significant advantage of this strategy in reducing toxicity. Although this strategy violates drug use principles, it may be a breakthrough in reducing toxicity and improving cancer treatment. This strategy can also be applied to other diseases with high drug toxicity.