Tumoral drug metabolism: perspectives and therapeutic implications.
Drug metabolising enzymes (DME) in tumors are capable of biotransforming a variety of xenobiotics. Over a long period of time, many studies have reported the presence of DME in tumors, however quantitation and sampling techniques and heterogeneous patient populations have resulted in many generalisations, provoking more questions than they answer. In addition, many of the studies have focussed on a potential role of DME in procarcinogenesis rather than for modulation for therapeutic advantage. With the need to target anticancer therapies to tumor cells to avoid undesirable systemic effects, tumoral processes such as drug metabolism must be considered as both a potential mechanism of resistance to therapy and a potential means of achieving optimal therapy. This review discusses drug metabolism by tumors by firstly addressing the level and activity of individual DME in the common cancers: breast, gastrointestinal, brain, lung and haematological malignancies in comparison to peritumoral and nontumoral tissue. This is then put into perspective through consideration of the therapeutic implications of tumoral drug metabolism especially with regard to the new anticancer agents. The contribution of tumoral metabolism and its significance in cancer therapy must be ascertained through prospective studies. Only then can efforts be concentrated in the design of better prodrugs or combinations of therapy to improve intracellular drug concentrations. Various gene therapy approaches have been attempted experimentally with promising results. However, there are major gaps in understanding the implications of tumoral DME in disease progression (including metastasized tissue) and relapse.
Doherty
M M
MM
Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, 3052, Victoria, Australia. margaret.doherty@vcp.monash.edu.au
Michael
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins