Drug resistance is the most significant reason for treatment failure in cancer and there are several underlying causes for this phenomenon. Perhaps the most well-defined and researched factor is the presence of ABC transporters, including: P-glycoprotein (P-gp), the product of the MDR1 gene; the MRP or ABCC transporter subfamily; ABCG2, a mitox-antrone transporter (also known as the breast cancer resistance protein (BCRP); the ABC transporter in placenta (ABCP); and mitoxantrone-resistance gene (MXR) (Table 2).
An understanding of other methods of tumor escape from sensitivity to cytotoxicity has resulted in opportunities for new drugs such as inhibitors of the Bcl-2 family proteins, inhibitors of p53/mdm2 interactions, proteasome family proteins, and poly(ADP-ribose) polymerase (PARP).46,60-62 Bortezomib (Velcade: Millennium Pharmaceuticals) is an approved proteasome inhibitor that blocks nuclear factor kB (NFkB) by inhibiting the 26S proteasome and preventing IkB degradation, thereby preventing the activation of NFkB. Velcade has shown a significant effect on myeloma in clinical trials both in survival and the significant reduction of the M protein, a biomarker for myeloma. Velcade is also being tested in clinical trials to overcome cisplatin resistance in ovarian cancer.63
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