Direct evidence that heterogeneity necessitates and limits the use of multidrug chemotherapy in colon cancer

Abstract

Considerable progress in the form of multidrug chemotherapy has recently been made in chemotherapy for the prolongation of survival in advanced colon cancer. It is generally accepted that colon cancer is biologically heterogeneous for multiple properties, including sensitivity to chemotherapeutic agents and metastasis. Although this partly explains the success of multidrug chemotherapy, there has been no direct evidence that multidrug regimens affect individual heterogenous cancer characteristics in colon cancer. Here, we present a case of metachronous ovarian metastasis in a colon cancer patient with dissemination who underwent irinotecan-based followed by oxaliplatin-based chemotherapy. We were able to obtain three samples from the patient, one of primary cancer and two of metastatic tumors from secondary surgery. Of note, both chemoresistant and chemosensitive tumors were present in the patient at the same time. To understand the influence of multidrugs on individual cancer characteristics, we examined differences in the molecular characteristics of the three samples using RT-PCR, focusing in particular on alterations in chemoresistant genes. In shrunken peritoneal metastasis, we found a significant increase in the mRNA levels of an irinotecan-sensitive gene, although other molecular factors were resistant to both 5-FU and oxaliplatin. We also confirmed that the recurrent ovarian tumor showed significant resistance to all three drugs: 5-FU, irinotecan and oxaliplatin. These results suggest that the heterogeneity of colon cancer necessitates and limits the use of multidrug chemotherapy.