Biochemical assessment of the effects of acivicin and dipyridamole given as a continuous 72-hour intravenous infusion

P. H. Fischer, J. K V Willson, C. Risueno, K. Tutsch, J. Bruggink, A. Ranhosky, D. L. Trump

Research output: Contribution to journalArticle

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Abstract

Since this Phase I trial was based on a strategy of biochemical modulation, namely, the inhibition of nucleoside uptake by dipyridamole, a biochemical assessment of the actions of acivicin and dipyridamole was undertaken in order to aid our interpretation of the clinical findings. The primary biochemical objectives of this trial were: (a) to determine whether plasma levels of dipyridamole sufficient to inhibit nucleoside uptake could be achieved with a 72-h continuous i.v. infusion; (b) to monitor the effects of acivicin on two key enzymatic targets, CTP synthetase and GMP synthetase; and (c) to evaluate changes in cellular ribonucleoside triphosphate pools during therapy. Since peripheral blood mononuclear cells have relevant biochemical targets and can be serially obtained during the course of therapy, the biochemcial effects of acivicin and dipyridamole were determined in these cells. At the maximally tolerated dose of dipyridamole (23.1 mg/kg/72 h), the steady-state concentrations of total and free dipyridamole averaged 11.9 μM and 27.8 nM, respectively. These levels were sufficient to inhibit cytidine (1 μM) uptake by greater than 50% in the lymphocytes of five of six patients so treated. Using lymphocytes obtained from 14 normal volunteers the concentration of free dipyridamole needed to inhibit the uptake of 1 μM cytidine by 50% averaged 13.8 ± 1.1 nM. The plasma levels of α1-acid glycoprotein, which tightly binds dipyridamole, ranged from 60 to 300 mg/dl in the patients in this study. As a consequence there were wide variations in the percentage of dipyridamole present as the unbound, pharmacologically active form and in the rates of dipyridamole clearance. The decreased rate of dipyridamole clearance seen in patients with high levels of α1-acid glycoprotein resulted in higher plasma concentrations of total dipyridamole and compensated for the reduced fraction of free drug. Therefore, the plasma concentration of free dipyridamole varied much less than the total drug concentration in these patients. CTP synthetase and GMP synthetase activities were measured in patients' peripheral mononuclear cells prior to and at various times during therapy. CTP synthetase activity was inhibited in a time-dependent fashion by greater than 75% in seven of 13 evaluable courses; GMP synthetase was similarly inhibited in only three of ten cases. Ribonucleoside triphosphate pools were also measured in the patient's lymphocytes. CTP pool reductions of 30 to 50% were seen in nine of 19 courses, but in only four cases was the inhibition greater than 50%. Similarly, in six of 19 courses GTP pool reduction of 30 to 50% was evident, and in four of 19 cases the inhibition was greater than 50%. Considering data from all courses, drug therapy did not significantly reduce any of the ribonucleoside triphosphate pools. Taken together, these results suggest that blood levels of dipyridamole sufficient to inhibit nucleoside salvage can be achieved in vivo; however, the lack of a consistent, pronounced effect of acivicin on de novo nucleotide biosynthesis precludes analysis of the role of salvage in modulating the toxicity of acivicin in vivo.

Original languageEnglish (US)
Pages (from-to)5591-5596
Number of pages6
JournalCancer Research
Volume48
Issue number19
StatePublished - 1988

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acivicin
Dipyridamole
Intravenous Infusions
GMP synthase (glutamine-hydrolyzing)
CTP synthetase
Ribonucleosides
Nucleosides
Cytidine
Lymphocytes
Glycoproteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Fischer, P. H., Willson, J. K. V., Risueno, C., Tutsch, K., Bruggink, J., Ranhosky, A., & Trump, D. L. (1988). Biochemical assessment of the effects of acivicin and dipyridamole given as a continuous 72-hour intravenous infusion. Cancer Research, 48(19), 5591-5596.

Biochemical assessment of the effects of acivicin and dipyridamole given as a continuous 72-hour intravenous infusion. / Fischer, P. H.; Willson, J. K V; Risueno, C.; Tutsch, K.; Bruggink, J.; Ranhosky, A.; Trump, D. L.

In: Cancer Research, Vol. 48, No. 19, 1988, p. 5591-5596.

Research output: Contribution to journalArticle

Fischer, PH, Willson, JKV, Risueno, C, Tutsch, K, Bruggink, J, Ranhosky, A & Trump, DL 1988, 'Biochemical assessment of the effects of acivicin and dipyridamole given as a continuous 72-hour intravenous infusion', Cancer Research, vol. 48, no. 19, pp. 5591-5596.
Fischer PH, Willson JKV, Risueno C, Tutsch K, Bruggink J, Ranhosky A et al. Biochemical assessment of the effects of acivicin and dipyridamole given as a continuous 72-hour intravenous infusion. Cancer Research. 1988;48(19):5591-5596.
Fischer, P. H. ; Willson, J. K V ; Risueno, C. ; Tutsch, K. ; Bruggink, J. ; Ranhosky, A. ; Trump, D. L. / Biochemical assessment of the effects of acivicin and dipyridamole given as a continuous 72-hour intravenous infusion. In: Cancer Research. 1988 ; Vol. 48, No. 19. pp. 5591-5596.
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abstract = "Since this Phase I trial was based on a strategy of biochemical modulation, namely, the inhibition of nucleoside uptake by dipyridamole, a biochemical assessment of the actions of acivicin and dipyridamole was undertaken in order to aid our interpretation of the clinical findings. The primary biochemical objectives of this trial were: (a) to determine whether plasma levels of dipyridamole sufficient to inhibit nucleoside uptake could be achieved with a 72-h continuous i.v. infusion; (b) to monitor the effects of acivicin on two key enzymatic targets, CTP synthetase and GMP synthetase; and (c) to evaluate changes in cellular ribonucleoside triphosphate pools during therapy. Since peripheral blood mononuclear cells have relevant biochemical targets and can be serially obtained during the course of therapy, the biochemcial effects of acivicin and dipyridamole were determined in these cells. At the maximally tolerated dose of dipyridamole (23.1 mg/kg/72 h), the steady-state concentrations of total and free dipyridamole averaged 11.9 μM and 27.8 nM, respectively. These levels were sufficient to inhibit cytidine (1 μM) uptake by greater than 50{\%} in the lymphocytes of five of six patients so treated. Using lymphocytes obtained from 14 normal volunteers the concentration of free dipyridamole needed to inhibit the uptake of 1 μM cytidine by 50{\%} averaged 13.8 ± 1.1 nM. The plasma levels of α1-acid glycoprotein, which tightly binds dipyridamole, ranged from 60 to 300 mg/dl in the patients in this study. As a consequence there were wide variations in the percentage of dipyridamole present as the unbound, pharmacologically active form and in the rates of dipyridamole clearance. The decreased rate of dipyridamole clearance seen in patients with high levels of α1-acid glycoprotein resulted in higher plasma concentrations of total dipyridamole and compensated for the reduced fraction of free drug. Therefore, the plasma concentration of free dipyridamole varied much less than the total drug concentration in these patients. CTP synthetase and GMP synthetase activities were measured in patients' peripheral mononuclear cells prior to and at various times during therapy. CTP synthetase activity was inhibited in a time-dependent fashion by greater than 75{\%} in seven of 13 evaluable courses; GMP synthetase was similarly inhibited in only three of ten cases. Ribonucleoside triphosphate pools were also measured in the patient's lymphocytes. CTP pool reductions of 30 to 50{\%} were seen in nine of 19 courses, but in only four cases was the inhibition greater than 50{\%}. Similarly, in six of 19 courses GTP pool reduction of 30 to 50{\%} was evident, and in four of 19 cases the inhibition was greater than 50{\%}. Considering data from all courses, drug therapy did not significantly reduce any of the ribonucleoside triphosphate pools. Taken together, these results suggest that blood levels of dipyridamole sufficient to inhibit nucleoside salvage can be achieved in vivo; however, the lack of a consistent, pronounced effect of acivicin on de novo nucleotide biosynthesis precludes analysis of the role of salvage in modulating the toxicity of acivicin in vivo.",
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T1 - Biochemical assessment of the effects of acivicin and dipyridamole given as a continuous 72-hour intravenous infusion

AU - Fischer, P. H.

AU - Willson, J. K V

AU - Risueno, C.

AU - Tutsch, K.

AU - Bruggink, J.

AU - Ranhosky, A.

AU - Trump, D. L.

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N2 - Since this Phase I trial was based on a strategy of biochemical modulation, namely, the inhibition of nucleoside uptake by dipyridamole, a biochemical assessment of the actions of acivicin and dipyridamole was undertaken in order to aid our interpretation of the clinical findings. The primary biochemical objectives of this trial were: (a) to determine whether plasma levels of dipyridamole sufficient to inhibit nucleoside uptake could be achieved with a 72-h continuous i.v. infusion; (b) to monitor the effects of acivicin on two key enzymatic targets, CTP synthetase and GMP synthetase; and (c) to evaluate changes in cellular ribonucleoside triphosphate pools during therapy. Since peripheral blood mononuclear cells have relevant biochemical targets and can be serially obtained during the course of therapy, the biochemcial effects of acivicin and dipyridamole were determined in these cells. At the maximally tolerated dose of dipyridamole (23.1 mg/kg/72 h), the steady-state concentrations of total and free dipyridamole averaged 11.9 μM and 27.8 nM, respectively. These levels were sufficient to inhibit cytidine (1 μM) uptake by greater than 50% in the lymphocytes of five of six patients so treated. Using lymphocytes obtained from 14 normal volunteers the concentration of free dipyridamole needed to inhibit the uptake of 1 μM cytidine by 50% averaged 13.8 ± 1.1 nM. The plasma levels of α1-acid glycoprotein, which tightly binds dipyridamole, ranged from 60 to 300 mg/dl in the patients in this study. As a consequence there were wide variations in the percentage of dipyridamole present as the unbound, pharmacologically active form and in the rates of dipyridamole clearance. The decreased rate of dipyridamole clearance seen in patients with high levels of α1-acid glycoprotein resulted in higher plasma concentrations of total dipyridamole and compensated for the reduced fraction of free drug. Therefore, the plasma concentration of free dipyridamole varied much less than the total drug concentration in these patients. CTP synthetase and GMP synthetase activities were measured in patients' peripheral mononuclear cells prior to and at various times during therapy. CTP synthetase activity was inhibited in a time-dependent fashion by greater than 75% in seven of 13 evaluable courses; GMP synthetase was similarly inhibited in only three of ten cases. Ribonucleoside triphosphate pools were also measured in the patient's lymphocytes. CTP pool reductions of 30 to 50% were seen in nine of 19 courses, but in only four cases was the inhibition greater than 50%. Similarly, in six of 19 courses GTP pool reduction of 30 to 50% was evident, and in four of 19 cases the inhibition was greater than 50%. Considering data from all courses, drug therapy did not significantly reduce any of the ribonucleoside triphosphate pools. Taken together, these results suggest that blood levels of dipyridamole sufficient to inhibit nucleoside salvage can be achieved in vivo; however, the lack of a consistent, pronounced effect of acivicin on de novo nucleotide biosynthesis precludes analysis of the role of salvage in modulating the toxicity of acivicin in vivo.

AB - Since this Phase I trial was based on a strategy of biochemical modulation, namely, the inhibition of nucleoside uptake by dipyridamole, a biochemical assessment of the actions of acivicin and dipyridamole was undertaken in order to aid our interpretation of the clinical findings. The primary biochemical objectives of this trial were: (a) to determine whether plasma levels of dipyridamole sufficient to inhibit nucleoside uptake could be achieved with a 72-h continuous i.v. infusion; (b) to monitor the effects of acivicin on two key enzymatic targets, CTP synthetase and GMP synthetase; and (c) to evaluate changes in cellular ribonucleoside triphosphate pools during therapy. Since peripheral blood mononuclear cells have relevant biochemical targets and can be serially obtained during the course of therapy, the biochemcial effects of acivicin and dipyridamole were determined in these cells. At the maximally tolerated dose of dipyridamole (23.1 mg/kg/72 h), the steady-state concentrations of total and free dipyridamole averaged 11.9 μM and 27.8 nM, respectively. These levels were sufficient to inhibit cytidine (1 μM) uptake by greater than 50% in the lymphocytes of five of six patients so treated. Using lymphocytes obtained from 14 normal volunteers the concentration of free dipyridamole needed to inhibit the uptake of 1 μM cytidine by 50% averaged 13.8 ± 1.1 nM. The plasma levels of α1-acid glycoprotein, which tightly binds dipyridamole, ranged from 60 to 300 mg/dl in the patients in this study. As a consequence there were wide variations in the percentage of dipyridamole present as the unbound, pharmacologically active form and in the rates of dipyridamole clearance. The decreased rate of dipyridamole clearance seen in patients with high levels of α1-acid glycoprotein resulted in higher plasma concentrations of total dipyridamole and compensated for the reduced fraction of free drug. Therefore, the plasma concentration of free dipyridamole varied much less than the total drug concentration in these patients. CTP synthetase and GMP synthetase activities were measured in patients' peripheral mononuclear cells prior to and at various times during therapy. CTP synthetase activity was inhibited in a time-dependent fashion by greater than 75% in seven of 13 evaluable courses; GMP synthetase was similarly inhibited in only three of ten cases. Ribonucleoside triphosphate pools were also measured in the patient's lymphocytes. CTP pool reductions of 30 to 50% were seen in nine of 19 courses, but in only four cases was the inhibition greater than 50%. Similarly, in six of 19 courses GTP pool reduction of 30 to 50% was evident, and in four of 19 cases the inhibition was greater than 50%. Considering data from all courses, drug therapy did not significantly reduce any of the ribonucleoside triphosphate pools. Taken together, these results suggest that blood levels of dipyridamole sufficient to inhibit nucleoside salvage can be achieved in vivo; however, the lack of a consistent, pronounced effect of acivicin on de novo nucleotide biosynthesis precludes analysis of the role of salvage in modulating the toxicity of acivicin in vivo.

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