Multiple drug resistance (MDR)

• MDR protein is an ATP-dependent pump that throws things out of the cells

• expressed in kidney and liver, so kidney and liver tumors are naturally very resistant to chemotherapy agents

Drugs affected by MDR

• vinca alkaloids

• taxanes

• topo inhibitors

• basically, any of the so-called “natural” agents (it’s true that now they are all synthesized, but we call them “natural” because they were first discovered in plants)

Approaches to overcome resistance

• combine agents with different mechanisms of action/toxicities

  • R-CHOP regimen to treat lymphoma: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone

• sequential or alternating chemotherapy

• dose intensity

  • maximal cell killing before development of resistance

  • high-dose therapy with hematopoietic stem cell rescue

  • when we are treating with intent of cure, the treatments are pretty brutal

  • “it’s not because oncologists are sadists”

• sensitize cells with targeted agents

  • EGFR inhibitors, VEGF inhibitors

• MDR modulating drugs—no trials over the past 10 years have been even close to successful

Category: Pharmacology Notes