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Review Article

Tailoring Targeted Therapy to Individual Patients: Lessons to be Learnt from the Development of Mitomycin C

MILÈNE VOLPATO and ROGER M. PHILLIPS
Cancer Genomics & Proteomics May 2007, 4 (3) 175-186;
MILÈNE VOLPATO
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  • For correspondence: m.volpato@bradford.ac.uk
ROGER M. PHILLIPS
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Abstract

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.

Keywords:
  • Superficial bladder cancer
  • mitomycin C
  • NQO1
  • targeted therapeutics
  • bioreductive drugs
  • review

Footnotes

  • Abbreviattions: MMC: Mitomycin C; NQO1: NAD(P)H:Quinone oxidoreductase-1; ROS: reactive oxygen species; SNP: single nucleotide polymorphism; 2,7-DAM: 2,7-diaminomitosene; BSO: L-buthionine-R,S-sulfoximine.

    • Received February 13, 2007.
    • Accepted February 20, 2007.
  • Copyright© 2007 International Institute of Anticaner Research (Dr. John G. Delinassios), All rights reserved
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Cancer Genomics - Proteomics: 4 (3)
Cancer Genomics & Proteomics
Vol. 4, Issue 3
May-June 2007
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Tailoring Targeted Therapy to Individual Patients: Lessons to be Learnt from the Development of Mitomycin C
MILÈNE VOLPATO, ROGER M. PHILLIPS
Cancer Genomics & Proteomics May 2007, 4 (3) 175-186;

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Tailoring Targeted Therapy to Individual Patients: Lessons to be Learnt from the Development of Mitomycin C
MILÈNE VOLPATO, ROGER M. PHILLIPS
Cancer Genomics & Proteomics May 2007, 4 (3) 175-186;
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