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

Milène Volpato, Roger M. Phillips

Research output: Contribution to journalReview article

8 Citations (Scopus)

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.

LanguageEnglish
Pages175-186
Number of pages12
JournalCancer Genomics and Proteomics
Volume4
Issue number3
DOIs
Publication statusPublished - May 2007
Externally publishedYes

Fingerprint

Mitomycin
Tumors
Oxidoreductases
Neoplasms
Therapeutics
Biological Phenomena
Chemical activation
Cytology
Tumor Microenvironment
Enzymes
Pharmaceutical Preparations
NAD
Cell Biology
Drug delivery
Assays
Pharmacology
DNA
Testing

Cite this

@article{8e46998fe1cb414c9b33a840eab46ac0,
title = "Tailoring Targeted Therapy to Individual Patients: Lessons to be Learnt from the Development of Mitomycin C",
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 = "Bioreductive drugs, Mitomycin C, NQO1, Review, Superficial bladder cancer, Targeted therapeutics",
author = "Mil{\`e}ne Volpato and Phillips, {Roger M.}",
year = "2007",
month = "5",
doi = "http://cgp.iiarjournals.org/content/4/3/175.full.pdf+html",
language = "English",
volume = "4",
pages = "175--186",
journal = "Cancer Genomics and Proteomics",
issn = "1109-6535",
publisher = "International Institute of Anticancer Research",
number = "3",

}

Tailoring Targeted Therapy to Individual Patients : Lessons to be Learnt from the Development of Mitomycin C. / Volpato, Milène; Phillips, Roger M.

In: Cancer Genomics and Proteomics, Vol. 4, No. 3, 05.2007, p. 175-186.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Tailoring Targeted Therapy to Individual Patients

T2 - Cancer Genomics and Proteomics

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

VL - 4

SP - 175

EP - 186

JO - Cancer Genomics and Proteomics

JF - Cancer Genomics and Proteomics

SN - 1109-6535

IS - 3

ER -