0360-3016192 $5.00 + .oO Copyright 0 1992 Per@non Press plc
hr. I. Radianon Oncology Bid. Phys., Vol. 22, pp 443-446 Printed in the U.S.A All rights reserved
??Session A: Tissue Oxygenation Manipulation and Tumor Blood Flow
EFFECTS OF CALCIUM CHANNEL BLOCKERS ON RENAL FUNCTION IN MICE D.
J. HONESS,
B.Sc.
AND
N. M.
BLEEHEN,
FRCP, FRCR, FACR (HoN)
Department of Clinical Oncology and Radiotherapeutics, Hills Road, CambridgeCB2 2QH, UK
Medical Research Council and University
Tumor blood flow modification is currently under investigation as a possible means of optimizing current cancer therapies, with particular respect to improving the effkacy of bioreductive agents. A variety of calcium channel blockers have been shown to modiiy tumor perfusion in model systems, and may be valuable as po tentiators of both bioreductive and conventional drugs. We report the effects of nifedipine, verapamil, flunarizine, and chmarizine on renal function in C3l-l mice, assayed by clearance of simuitaneously injected “Cr ethylenediamine tetraacetate. Nifedipine at 10 mgkg - ’ blocked “Cr ethylenediamine tetraacetate clearance for 30 min and reduced its subsequent rate of clearance by a factor (f 2 se) of 2.4 f 0.6. At 1 mgkg-’ it reduced the rate of clearance by a factor of 1.2 f 0.2. Verapamil at 10 mgkg-’ blocked “Cr ethylenediamine tetraacetate clearance for 10 min and reduced its subsequent rate of clearance by a factor of 1.5 f 0.3, but had no effect at 1 mgkg-‘. Flunarizine had no effect at 50 mgkg - ’ or at 5 mgkg- ‘, but cinnarizine at 50 mgkg-’ reduced clearance rate by a factor of 1.2 f 0.1. The data show that some of these vasoactive agents, nifedipine and verapamil in particular, can severely compromise renal function and may, therefore, affect the plasma pharmacokinetics of co-administered drugs that are cleared by the kidney. Calcium channel blockers, Nifedipine, Verapamil, Fhmarizine, Cinnarizine, Renal function.
The normal tissue effects of these tumor blood flow modifiers have not been thoroughly investigated. We have previously investigated the effects of hydralazine on renal function at a range of doses that reduce tumor blood flow. We assayed glomerular filtration rate by 51Cr ethylenediamine tetraacetate (‘lCrEDTA) clearance and found that this was reduced to about 25% of control by 5 mgkg-’ hydralazine, and to about 70% of control by 1.O mgkg- ‘, the lowest dose shown to be effective in reducing KHT tumor blood flow (10). Clearly, any impairment of the glomerular filtration system will result in reduced plasma elimination of co-administered drugs that are partially or entirely cleared by this mechanism, resulting in an increase in drug exposure. This may increase the normal tissue toxicity of the agent(s), which would then be apparent if the drug is being used within the toxic dose range. More importantly, the increase in drug exposure will almost certainly result in increased efficacy directly attributable to the changed plasma pharmacokinetics, in addition to any increased efficacy due to changes in tumor perfusion. The aim of the present study was to investigate the effects of a range of calcium channel blockers on renal function in mice to ascertain whether they also result in inhibition of renal function at the relevant doses. We have not studied the consequent effects on drug pharmacokinetics.
INTRODUCTION
Modification of tumor blood flow by means of vasoactive agents has been explored in recent years with studies directed toward either reduction or enhancement of tumor blood flow. Work on reduction of tumor blood flow has centered around the use of the hypotensive agent hydralazine, with likely applications in both hyperthermic and drug therapy. For drug-related use the aim has been primarily to create or intensify an existing reducing environment within the tumor in order to potentiate the activation of bioreductive (3, 5) or cytotoxic agents (6); and secondarily, to trap active drugs within the tumor to enhance tumor selectivity (15). Similar studies have been carried out with other hypotensive agents, particularly the dihydropyridine calcium channel blockers verapamil and nifedipine, to exploit their vasoactive properties (1). The opposite approach, that of increasing tumor blood flow and reducing hypoxia, thereby improving the delivery of drugs and/or the response to radiotherapy, has also been pursued using calcium channel blockers. These studies involved the diphenylalkylamines , such as fhmarizine and cinnarizine (16, 17), which have been shown to increase tumor blood flow under certain circumstances (8, 12).
Reprint requests to: D. J. Honess. Accepted for publication 3 July 1991.
Presented at the Seventh International Conference on Chemical Modifiers of Cancer Treatment, Clearwater, FL,, 1991 February 2-5. 443
I. J. Radiation Oncology ??Biology 0 Physics
444
Volume 22, Number 3, 1992
Table 1. The effect of a range of calcium channel blockers on 5’CrEDTA clearance curves in C3H mice Slope +- 2se (% ml-’ min-‘) X 100
Drw treatment
Slope time (min)*
Level of significancet
n for slope calculation
Slope ratio$ f 2se
Intercept rt 2se
Vehicle alone
6.39 (6.01-6.77)
30-60
Nifedipine 10.0 mgkg-’
2.66 (2.32-3.00)
30-120
pco.01
32
2.40 * 0.62
24.4 (14.1-42.4)
Nifedipine 1.0 mgkg-’
5.16 (4.50-5.82)
10-60
p
hr. I. Radianon Oncology Bid. Phys., Vol. 22, pp 443-446 Printed in the U.S.A All rights reserved
??Session A: Tissue Oxygenation Manipulation and Tumor Blood Flow
EFFECTS OF CALCIUM CHANNEL BLOCKERS ON RENAL FUNCTION IN MICE D.
J. HONESS,
B.Sc.
AND
N. M.
BLEEHEN,
FRCP, FRCR, FACR (HoN)
Department of Clinical Oncology and Radiotherapeutics, Hills Road, CambridgeCB2 2QH, UK
Medical Research Council and University
Tumor blood flow modification is currently under investigation as a possible means of optimizing current cancer therapies, with particular respect to improving the effkacy of bioreductive agents. A variety of calcium channel blockers have been shown to modiiy tumor perfusion in model systems, and may be valuable as po tentiators of both bioreductive and conventional drugs. We report the effects of nifedipine, verapamil, flunarizine, and chmarizine on renal function in C3l-l mice, assayed by clearance of simuitaneously injected “Cr ethylenediamine tetraacetate. Nifedipine at 10 mgkg - ’ blocked “Cr ethylenediamine tetraacetate clearance for 30 min and reduced its subsequent rate of clearance by a factor (f 2 se) of 2.4 f 0.6. At 1 mgkg-’ it reduced the rate of clearance by a factor of 1.2 f 0.2. Verapamil at 10 mgkg-’ blocked “Cr ethylenediamine tetraacetate clearance for 10 min and reduced its subsequent rate of clearance by a factor of 1.5 f 0.3, but had no effect at 1 mgkg-‘. Flunarizine had no effect at 50 mgkg - ’ or at 5 mgkg- ‘, but cinnarizine at 50 mgkg-’ reduced clearance rate by a factor of 1.2 f 0.1. The data show that some of these vasoactive agents, nifedipine and verapamil in particular, can severely compromise renal function and may, therefore, affect the plasma pharmacokinetics of co-administered drugs that are cleared by the kidney. Calcium channel blockers, Nifedipine, Verapamil, Fhmarizine, Cinnarizine, Renal function.
The normal tissue effects of these tumor blood flow modifiers have not been thoroughly investigated. We have previously investigated the effects of hydralazine on renal function at a range of doses that reduce tumor blood flow. We assayed glomerular filtration rate by 51Cr ethylenediamine tetraacetate (‘lCrEDTA) clearance and found that this was reduced to about 25% of control by 5 mgkg-’ hydralazine, and to about 70% of control by 1.O mgkg- ‘, the lowest dose shown to be effective in reducing KHT tumor blood flow (10). Clearly, any impairment of the glomerular filtration system will result in reduced plasma elimination of co-administered drugs that are partially or entirely cleared by this mechanism, resulting in an increase in drug exposure. This may increase the normal tissue toxicity of the agent(s), which would then be apparent if the drug is being used within the toxic dose range. More importantly, the increase in drug exposure will almost certainly result in increased efficacy directly attributable to the changed plasma pharmacokinetics, in addition to any increased efficacy due to changes in tumor perfusion. The aim of the present study was to investigate the effects of a range of calcium channel blockers on renal function in mice to ascertain whether they also result in inhibition of renal function at the relevant doses. We have not studied the consequent effects on drug pharmacokinetics.
INTRODUCTION
Modification of tumor blood flow by means of vasoactive agents has been explored in recent years with studies directed toward either reduction or enhancement of tumor blood flow. Work on reduction of tumor blood flow has centered around the use of the hypotensive agent hydralazine, with likely applications in both hyperthermic and drug therapy. For drug-related use the aim has been primarily to create or intensify an existing reducing environment within the tumor in order to potentiate the activation of bioreductive (3, 5) or cytotoxic agents (6); and secondarily, to trap active drugs within the tumor to enhance tumor selectivity (15). Similar studies have been carried out with other hypotensive agents, particularly the dihydropyridine calcium channel blockers verapamil and nifedipine, to exploit their vasoactive properties (1). The opposite approach, that of increasing tumor blood flow and reducing hypoxia, thereby improving the delivery of drugs and/or the response to radiotherapy, has also been pursued using calcium channel blockers. These studies involved the diphenylalkylamines , such as fhmarizine and cinnarizine (16, 17), which have been shown to increase tumor blood flow under certain circumstances (8, 12).
Reprint requests to: D. J. Honess. Accepted for publication 3 July 1991.
Presented at the Seventh International Conference on Chemical Modifiers of Cancer Treatment, Clearwater, FL,, 1991 February 2-5. 443
I. J. Radiation Oncology ??Biology 0 Physics
444
Volume 22, Number 3, 1992
Table 1. The effect of a range of calcium channel blockers on 5’CrEDTA clearance curves in C3H mice Slope +- 2se (% ml-’ min-‘) X 100
Drw treatment
Slope time (min)*
Level of significancet
n for slope calculation
Slope ratio$ f 2se
Intercept rt 2se
Vehicle alone
6.39 (6.01-6.77)
30-60
Nifedipine 10.0 mgkg-’
2.66 (2.32-3.00)
30-120
pco.01
32
2.40 * 0.62
24.4 (14.1-42.4)
Nifedipine 1.0 mgkg-’
5.16 (4.50-5.82)
10-60
p
