TY - JOUR
T1 - Tailoring Targeted Therapy to Individual Patients
T2 - Lessons to be Learnt from the Development of Mitomycin C
AU - Volpato, Milène
AU - Phillips, Roger M.
PY - 2007/5
Y1 - 2007/5
N2 - The modern era of targeted therapeutics offers the potential to tailor therapy to individual patients whose tumours express a specific target. Previous attempts to forecast tumour response to conventional chemotherapeutics based on similar principles have however been disappointing. Mitomycin C (MMC), for example, is a bioreductive drug that requires metabolic activation by cellular reductases for activity. The enzyme NAD(P)H:Quinone oxidoreductase-1 (NQO1) can reduce MMC to DNA damaging species but attempts to establish the relationship between tumour response to MMC and NQO1 expression have generated conflicting reports of good and poor correlations. Several other reductases are known to activate MMC. This, in conjunction with the fact that various physiological and biochemical factors influence therapeutic response, suggests that the mechanism of action of MMC is too complex to allow tumour response to be predicted on the basis of a single enzyme. Alternative approaches using more complex biological and pharmacological systems that reflect the spectrum of reductases present within the tumour have been developed and it remains to be seen whether or not the predictive value of these approaches is enhanced. With regards to targeted therapeutics, the experience with MMC suggests that prediction of tumour response based on analysis of a single target may be too simplistic. Multiple mechanisms of action and the influence of tumour microenvironment on cell biology and drug delivery are likely to influence the final outcome of therapy. The challenge for the future progression of this field is to develop assays that reflect the overall biological and pharmacological processes involved in drug activation whilst retaining the simplicity and robustness required for routine chemosensitivity testing in a clinical setting.
AB - The modern era of targeted therapeutics offers the potential to tailor therapy to individual patients whose tumours express a specific target. Previous attempts to forecast tumour response to conventional chemotherapeutics based on similar principles have however been disappointing. Mitomycin C (MMC), for example, is a bioreductive drug that requires metabolic activation by cellular reductases for activity. The enzyme NAD(P)H:Quinone oxidoreductase-1 (NQO1) can reduce MMC to DNA damaging species but attempts to establish the relationship between tumour response to MMC and NQO1 expression have generated conflicting reports of good and poor correlations. Several other reductases are known to activate MMC. This, in conjunction with the fact that various physiological and biochemical factors influence therapeutic response, suggests that the mechanism of action of MMC is too complex to allow tumour response to be predicted on the basis of a single enzyme. Alternative approaches using more complex biological and pharmacological systems that reflect the spectrum of reductases present within the tumour have been developed and it remains to be seen whether or not the predictive value of these approaches is enhanced. With regards to targeted therapeutics, the experience with MMC suggests that prediction of tumour response based on analysis of a single target may be too simplistic. Multiple mechanisms of action and the influence of tumour microenvironment on cell biology and drug delivery are likely to influence the final outcome of therapy. The challenge for the future progression of this field is to develop assays that reflect the overall biological and pharmacological processes involved in drug activation whilst retaining the simplicity and robustness required for routine chemosensitivity testing in a clinical setting.
KW - Bioreductive drugs
KW - Mitomycin C
KW - NQO1
KW - Review
KW - Superficial bladder cancer
KW - Targeted therapeutics
UR - http://www.scopus.com/inward/record.url?scp=34249298353&partnerID=8YFLogxK
UR - http://cgp.iiarjournals.org/
U2 - http://cgp.iiarjournals.org/content/4/3/175.full.pdf+html
DO - http://cgp.iiarjournals.org/content/4/3/175.full.pdf+html
M3 - Review article
C2 - 17878521
AN - SCOPUS:34249298353
VL - 4
SP - 175
EP - 186
JO - Cancer Genomics and Proteomics
JF - Cancer Genomics and Proteomics
SN - 1109-6535
IS - 3
ER -