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Tumoral drug metabolism: perspectives and therapeutic implications
1Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, 3052, Victoria, Australia. margaret.doherty@vcp.monash.edu.au
Abstract:
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.
Insights
Tumors contain drug metabolising enzymes (DME) that can alter anticancer drug efficacy. Understanding tumoral drug metabolism is crucial for developing targeted therapies and improving treatment outcomes.
Area of Science:
- Pharmacology
- Oncology
- Biochemistry
Background:
- Drug metabolising enzymes (DME) are present in tumors and can transform xenobiotics.
- Previous studies on tumoral DME are generalized due to quantitation, sampling, and population heterogeneity issues.
- Research has often focused on DME's role in cancer development rather than therapeutic applications.
Purpose of the Study:
- To review the level and activity of individual DME in common cancers (breast, GI, brain, lung, hematological) compared to normal tissues.
- To explore the therapeutic implications of tumoral drug metabolism, particularly for novel anticancer agents.
- To highlight the need for prospective studies to understand DME's role in cancer progression and relapse.
Main Methods:
- Comparative analysis of DME levels and activity in tumor versus peritumoral and non-tumoral tissues across various cancer types.
- Literature review focusing on the impact of tumoral drug metabolism on anticancer therapy.
- Discussion of potential therapeutic strategies, including prodrug design and combination therapy.
Main Results:
- DME activity varies significantly across different tumor types and cancer diagnoses.
- Tumoral drug metabolism presents a dual role: a potential mechanism for anticancer drug resistance and a target for therapeutic optimization.
- Existing data is insufficient, necessitating further investigation into DME's precise role in disease progression and treatment response.
Conclusions:
- Tumoral drug metabolism significantly impacts anticancer therapy effectiveness and necessitates further research.
- Prospective studies are essential to quantify DME's contribution and guide the development of improved therapeutic strategies.
- Understanding tumoral DME is critical for optimizing drug delivery, designing effective prodrugs, and potentially utilizing gene therapy for cancer treatment.