The Best Defense Against Multidrug Resistance

Several reasons can explain the failure of anticancer drugs to kill cancer cells. Chemotherapeutic compounds are given systemically and are therefore subject to variations in absorption, metabolism and delivery to target tissues that can be patient-specific. Tumors can be located in parts of the body drugs do not easily penetrate and could be protected by environmental conditions in their vicinity such as increased tissue hydrostatic pressure and altered tumor vasculature. Similarly to the study of antibiotic resistance in microorganisms, research on drug resistance in cancer has focused on the specific nature and genetic background of the cancer cell itself and on the genetic changes observed upon treatment with cytotoxic drugs. Until recently, the primary method for discovering mechanisms of multidrug resistance (MDR) was to positively select cancer cells surviving the presence of cytotoxic drugs and use cellular and molecular biology techniques to identify the altered expression of genes capable of conferring drug resistance on naïve cancer cells. Such studies determined that the most commonly encountered mechanism of MDR is the increased efflux of a broad class of hydrophobic cytotoxic drugs mediated by a family of energy-dependent transporters known as ATP-binding cassette (ABC) transporters.

Since their first description in the 1970s, several members of the ABC transporter family have been linked with MDR such as P-glycoprotein (Pgp, also referred to as ABCB1 or MDR1), MRP1-5 and BCRP. The lack of substrate specificity and the abundance of ABC transporter proteins (48 known ABC transporters in humans) might account for the difficulties encountered over the last 30 years in attempting to circumvent ABC-mediated MDR in vivo. Cancer specialists have worked to develop drugs that either evade efflux or inhibit the function of efflux transporters, and although progress in this area has been slow, the rationale for this approach is still strong. Taking the example of acute myeloid leukemia (AML), it still remains a challenging hematological malignancy with an estimated 14,000 new cases and 10,000 per year in the United States alone. The prognostic is particularly poor in older individuals because of a lower tolerance for the intensive chemotherapy regimen required to achieve remission and a higher prevalence of MDR primarily mediated through ABC transporters such as P-glycoprotein. As an alternative to systemic chemotherapy, monoclonal antibodies targeting CD33, a protein over-expressed in the vast majority of patients with AML, have been the focus of several preclinical and clinical investigations. Although unconjugated anti-CD33 antibodies were found to be largely ineffective in AML patients, encouraging results were obtained with gemtuzumab ozogamicin (GO), a CD33-targeting antibody conjugated with calicheamicin as the toxic moiety and capable of delivering the drug directly to the target cells with limited side-effects.

More recently, Dr. Kung Sutherland and collaborators from Seattle Genetics and the University of Washington reported the preclinical development and characterization of a novel antibody-drug conjugate (ADC) termed SGN-CD33A and consisting of an anti-CD33 monoclonal antibody conjugated to a novel synthetic pyrrolobenzodiazepine (PBD) dimer structurally related to anthramycin and isolated from Streptomyces refuineus. Molecules in the PBD family cause cell death by cross-linking of DNA and interruption of cell division. Using Enzo’s eFluxx-ID multidrug resistance kits and cell viability tests, they showed that SGN-CD33A has robust activity in vitro against a broad panel of AML cell lines and primary patient samples regardless of their MDR status and in vivo using preclinical AML models. It was also shown to be significantly more efficient than GO. Altogether, this study demonstrated that an efficient delivery system combined with a potent drug with proven cytotoxicity could circumvent a lot of the reasons why chemotherapies are often unsuccessful in patients including MDR and offered promises for the treatment of AML as well as other forms of cancer.

Enzo Life Sciences offers a comprehensive product portfolio to understand and assess multidrug resistance including our eFluxx-ID multidrug resistance assay kits. In addition, Enzo offers antibodies, recombinant proteins and small molecules, some of which are described below:

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