Dose-response relationships in intravesical chemotherapy

I. K. Walsh*, S. R. McKeown, V. J. McKelvey-Martin, J. J A McAleer, S. R. Johnston

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Introduction: In the management of superficial bladder cancer with intravesical chemotherapy (IVCT), the relationship between agent dose, treatment efficacy and the incidence of damage to healthy urothelium remains unclear. Most IVCT agents act by injuring DNA. We examined the relationship between IVCT agent concentration and induced DNA damage in superficial bladder cancer and normal urothelium. Materials and methods: Single-cell suspensions (110) were derived from transurethral biopsies of superficial bladder tumour (13 patients) and normal urothelium (eight patients). Each cell suspension was incubated for l h with either saline (control) or IVCT agent (doxorubicin, epirubicin. mitomycin C or thiotepa) at a concentration of 2. 20 or 200 ug/mL. Each cell suspension was then processed via a gel electrophoresis (comet) assay which quantifies nuclear damage (DNA strand breaks) in individual cells. Results: For all IVCT agents, there was an increase in the frequency of DNA strand breaks with increasing drug concentration. This rise was more marked for bladder tumour than for normal urothelium. IVCT agent Mean (SD) % DNA damage concentration normal urotheliwn bladder tumour (μg/ml.) Efi MMC f-pi MMC 0 5.7(1.7) 6.4(1.3) 22.7(7.3) 14.7(1.1) 2 28.8(6.7)* 13.0(3.7)* 46.3(6.71* 38.0(4.2)* 20 31.2(5.5)* 24.8(4.6)* 48.2(7.7)* 38.4(5.3)* 200 42.5(5.6)* 32.5(4.3)* 66.5(6.8)* 41.4(5.3)* * P < 0.05) when compared with control values by Mann-Whitney U-nonparametric testing; Epi. epirubicin. Similar dose-response relationships were also found for doxorubicln and thiotepa. Conclusion: The most commonly used IVCT agents cause doserelated DNA damage. Increasing agent dose may be more effective in ablating tumours or preventing recurrence, but may also increase damage to healthy urothelial DNA.

Original languageEnglish
Pages (from-to)25-26
Number of pages2
JournalBritish journal of urology
Volume81
Issue numberSUPPL. 4
Publication statusPublished - 01 Dec 1998
Externally publishedYes

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Urothelium
Urinary Bladder Neoplasms
Drug Therapy
Thiotepa
DNA Damage
Suspensions
Epirubicin
DNA Breaks
Comet Assay
DNA
Mitomycin
Doxorubicin
Electrophoresis
Gels
Biopsy
Recurrence
Incidence
Pharmaceutical Preparations
Neoplasms

Cite this

Walsh, I. K., McKeown, S. R., McKelvey-Martin, V. J., McAleer, J. J. A., & Johnston, S. R. (1998). Dose-response relationships in intravesical chemotherapy. British journal of urology, 81(SUPPL. 4), 25-26.
Walsh, I. K. ; McKeown, S. R. ; McKelvey-Martin, V. J. ; McAleer, J. J A ; Johnston, S. R. / Dose-response relationships in intravesical chemotherapy. In: British journal of urology. 1998 ; Vol. 81, No. SUPPL. 4. pp. 25-26.
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abstract = "Introduction: In the management of superficial bladder cancer with intravesical chemotherapy (IVCT), the relationship between agent dose, treatment efficacy and the incidence of damage to healthy urothelium remains unclear. Most IVCT agents act by injuring DNA. We examined the relationship between IVCT agent concentration and induced DNA damage in superficial bladder cancer and normal urothelium. Materials and methods: Single-cell suspensions (110) were derived from transurethral biopsies of superficial bladder tumour (13 patients) and normal urothelium (eight patients). Each cell suspension was incubated for l h with either saline (control) or IVCT agent (doxorubicin, epirubicin. mitomycin C or thiotepa) at a concentration of 2. 20 or 200 ug/mL. Each cell suspension was then processed via a gel electrophoresis (comet) assay which quantifies nuclear damage (DNA strand breaks) in individual cells. Results: For all IVCT agents, there was an increase in the frequency of DNA strand breaks with increasing drug concentration. This rise was more marked for bladder tumour than for normal urothelium. IVCT agent Mean (SD) {\%} DNA damage concentration normal urotheliwn bladder tumour (μg/ml.) Efi MMC f-pi MMC 0 5.7(1.7) 6.4(1.3) 22.7(7.3) 14.7(1.1) 2 28.8(6.7)* 13.0(3.7)* 46.3(6.71* 38.0(4.2)* 20 31.2(5.5)* 24.8(4.6)* 48.2(7.7)* 38.4(5.3)* 200 42.5(5.6)* 32.5(4.3)* 66.5(6.8)* 41.4(5.3)* * P < 0.05) when compared with control values by Mann-Whitney U-nonparametric testing; Epi. epirubicin. Similar dose-response relationships were also found for doxorubicln and thiotepa. Conclusion: The most commonly used IVCT agents cause doserelated DNA damage. Increasing agent dose may be more effective in ablating tumours or preventing recurrence, but may also increase damage to healthy urothelial DNA.",
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Walsh, IK, McKeown, SR, McKelvey-Martin, VJ, McAleer, JJA & Johnston, SR 1998, 'Dose-response relationships in intravesical chemotherapy', British journal of urology, vol. 81, no. SUPPL. 4, pp. 25-26.

Dose-response relationships in intravesical chemotherapy. / Walsh, I. K.; McKeown, S. R.; McKelvey-Martin, V. J.; McAleer, J. J A; Johnston, S. R.

In: British journal of urology, Vol. 81, No. SUPPL. 4, 01.12.1998, p. 25-26.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dose-response relationships in intravesical chemotherapy

AU - Walsh, I. K.

AU - McKeown, S. R.

AU - McKelvey-Martin, V. J.

AU - McAleer, J. J A

AU - Johnston, S. R.

PY - 1998/12/1

Y1 - 1998/12/1

N2 - Introduction: In the management of superficial bladder cancer with intravesical chemotherapy (IVCT), the relationship between agent dose, treatment efficacy and the incidence of damage to healthy urothelium remains unclear. Most IVCT agents act by injuring DNA. We examined the relationship between IVCT agent concentration and induced DNA damage in superficial bladder cancer and normal urothelium. Materials and methods: Single-cell suspensions (110) were derived from transurethral biopsies of superficial bladder tumour (13 patients) and normal urothelium (eight patients). Each cell suspension was incubated for l h with either saline (control) or IVCT agent (doxorubicin, epirubicin. mitomycin C or thiotepa) at a concentration of 2. 20 or 200 ug/mL. Each cell suspension was then processed via a gel electrophoresis (comet) assay which quantifies nuclear damage (DNA strand breaks) in individual cells. Results: For all IVCT agents, there was an increase in the frequency of DNA strand breaks with increasing drug concentration. This rise was more marked for bladder tumour than for normal urothelium. IVCT agent Mean (SD) % DNA damage concentration normal urotheliwn bladder tumour (μg/ml.) Efi MMC f-pi MMC 0 5.7(1.7) 6.4(1.3) 22.7(7.3) 14.7(1.1) 2 28.8(6.7)* 13.0(3.7)* 46.3(6.71* 38.0(4.2)* 20 31.2(5.5)* 24.8(4.6)* 48.2(7.7)* 38.4(5.3)* 200 42.5(5.6)* 32.5(4.3)* 66.5(6.8)* 41.4(5.3)* * P < 0.05) when compared with control values by Mann-Whitney U-nonparametric testing; Epi. epirubicin. Similar dose-response relationships were also found for doxorubicln and thiotepa. Conclusion: The most commonly used IVCT agents cause doserelated DNA damage. Increasing agent dose may be more effective in ablating tumours or preventing recurrence, but may also increase damage to healthy urothelial DNA.

AB - Introduction: In the management of superficial bladder cancer with intravesical chemotherapy (IVCT), the relationship between agent dose, treatment efficacy and the incidence of damage to healthy urothelium remains unclear. Most IVCT agents act by injuring DNA. We examined the relationship between IVCT agent concentration and induced DNA damage in superficial bladder cancer and normal urothelium. Materials and methods: Single-cell suspensions (110) were derived from transurethral biopsies of superficial bladder tumour (13 patients) and normal urothelium (eight patients). Each cell suspension was incubated for l h with either saline (control) or IVCT agent (doxorubicin, epirubicin. mitomycin C or thiotepa) at a concentration of 2. 20 or 200 ug/mL. Each cell suspension was then processed via a gel electrophoresis (comet) assay which quantifies nuclear damage (DNA strand breaks) in individual cells. Results: For all IVCT agents, there was an increase in the frequency of DNA strand breaks with increasing drug concentration. This rise was more marked for bladder tumour than for normal urothelium. IVCT agent Mean (SD) % DNA damage concentration normal urotheliwn bladder tumour (μg/ml.) Efi MMC f-pi MMC 0 5.7(1.7) 6.4(1.3) 22.7(7.3) 14.7(1.1) 2 28.8(6.7)* 13.0(3.7)* 46.3(6.71* 38.0(4.2)* 20 31.2(5.5)* 24.8(4.6)* 48.2(7.7)* 38.4(5.3)* 200 42.5(5.6)* 32.5(4.3)* 66.5(6.8)* 41.4(5.3)* * P < 0.05) when compared with control values by Mann-Whitney U-nonparametric testing; Epi. epirubicin. Similar dose-response relationships were also found for doxorubicln and thiotepa. Conclusion: The most commonly used IVCT agents cause doserelated DNA damage. Increasing agent dose may be more effective in ablating tumours or preventing recurrence, but may also increase damage to healthy urothelial DNA.

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Walsh IK, McKeown SR, McKelvey-Martin VJ, McAleer JJA, Johnston SR. Dose-response relationships in intravesical chemotherapy. British journal of urology. 1998 Dec 1;81(SUPPL. 4):25-26.