Summary
A rat glioma model was employed to estimate the Ca2+ kinetics in the tumor arteriolar smooth muscle cells. Electron microcytochemistry revealed that the density of intracellular Ca2+ deposits in the intra-tumor arteriolar smooth muscle cells was significantly greater, with slightly higher membrane Ca2+-adenosine triphosphatase (ATPase) activity, compared to the contralateral cerebral arterioles. Furthermore, the administration of tyrphostin, a tyrosine kinase inhibitor, specifically increased only the intra-tumor blood flow. These findings suggest that the condition of the intra-tumor arteriole alters the susceptibility to contraction by the accelerated Ca2+ influx into the cytoplasm mediated through the tyrosine kinase pathway. After the administration of diltiazem, which also has a blocking effect on the Ca2+-channel mediated through this pathway, the local intra-tumor blood flow showed an increase of 39% with a marked decrease of intracellular Ca2+ concentration of the arteriolar smooth muscle cells in the tumor, while the blood flow in the basal ganglia increased by only 8%. The intra-tumor concentration of Nimustine-HCI (ACNU) with co-administration of diltiazem was significantly increased compared to that without the co-administration. Co-administration of diltiazem may be a valuable strategy in chemotherapy for glioma in affording the selective increase of intra-tumor concentration of the anti-cancer drug.
Similar content being viewed by others
References
Ando T, Fujimoto K, Yamahara H, Miyajima H, Ogawa K: A new one-step method for the histochemistry of Ca2+-ATPase activity. Acta Histochem Cytochem 14: 705–726,1981
Baba T, Fukui M, Takeshita I, Ichiya Y, Kuwabara Y, Hasuo K: Selective enhancement of intratumoral blood flow in malignant gliomas using intra-arterial adenosine triphosphate. J Neurosurg 72: 907–911,1990
Baba T, Fukui S, Sakata S, Tashima T, Takeshita I, Nakamura T, Inoue T: Selective enhancement of intratumoral blood flow in malignant gliomas: Experimental study in rats by intracarotid administration of adenosine or adenosine triphosphate. Acta Neurochir (Wien) 101: 66–74,1989
Berk BC, Alexander RW, Brock TA, Gimbrone MA Jr Webb RC: Vasoconstriction: A new activity for platelet-derived growth factor. Science 232: 87–90,1986
Berk BC, Brock TA, Webb RC, Taubman MB, Atkinson WJ, Gimbrone MA Jr, Alexander RW: Epidermal growth factor, a vascular smooth muscle nitrogen, induces rat aortic contraction. J Clin Invest 75:11083–1086,1985
Betsholtz C, Heidin CH, Nister M, Ek B, Wasteson A, Westermark B: Synthesis of a PDGF-like growth factor in human glioma and sarcoma cells suggests the expression of the cellular homologue to the transforming protein on simian sarcoma virus. Biochem Biophys Res Commun 117:176–182, 1983
Blasberg RG, Groothuis DR: Chemotherapy of brain tumors: Physiological and pharmocokinetic consideration. Semin Oncol 13: 70–82,1986
Block LH, Emmons LR, Vogt E, Sachinidis A, Vetter W, Hoppe J: Ca2+-channel blockers inhibit the action of recombinant platelet-derived growth factor in vascular smooth muscle cells. Proc Natl Acad Sci USA 86: 2388–2392,1989
Borgers M, Thone F, Verheyen A, Ter Keurs HEDJ: Localization of calcium in skeltal and cardiac muscle. Histochem J 16:295–309,1984
deBlois D, Drapeau G, Petitclerc E, Marceau F: Synergism between the contractile effect of epidermal growth factor and that of des-Arg9-bradykinin or of a-thrombin in rabbit aortic rings. Br J Pharmacol 105: 959–967,1992
DiPolo R, Beaugé L: Physiological role of ATP-driven calcium pump in squid axon. Nature 278: 271–273,1979
Edvinsson L, Johansson BB, Larsson B, MacKenzie ET, Skaa by T, Young AR: Calcium antagonist: effects on cerebral blood flow and blood-brain barrier permeability in the rat. Br J Pharmac 79:141–148,1983
Fross RD, Warnke PC, Groothuis DR: Blood flow and blood-to-tissue transport in 9L gliosarcoma: the role of the brain tumor model in drug delivery research. J Neuro-Oncol 11:185–197,1991
Levin VA: A pharmacologic basis for brain tumor chemotherapy. Semin Oncol 2: 57–61,1975
Merkel LA, Rivera LM, Colussi DJ, Perrone MH: Inhibition of EGF-induced vasoconstriction in isolated rabbit aortic rings with the tyrosine kinase inhibitor RG50864. Biochemical and Biophysical Research Communications 192: 1319–1326,1993
Lopez-Rivas A, Mendoza SA, Nanberg E, Sinnett-Smith J, Rozengurt E: Ca2+-mobilizing actions of platelet-derived growth factor differ from those of bombesin and vasopressin in Swiss 3T3 mouse cells. Proc Natl Acad Sci USA 84:5768–5772, 1987
Saburo MD, Thomas B: Tyrphostin attenuates platelet-derived growth factor-induced contraction in aortic smooth muscle through inhibition of protein tyrosine kinese(s). J Pharmacol Exp Ther 267:1119–1125,1993
Murphy RA, Aksoy MO, Dillon PF, Gerthoffer WT, Kamm KE: The role of myosin light chain phosphorylation in reguration of the cross-bridge cycle. Fed Proc 42: 51–56,1983
Nakamura K, Asami M, Kawada K, Sasahara K: Quantitative determination of ACNU (3-[4-amino-2-methyl-5pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride), a new water-soluble anti-tumor nitrosourea, in biological fluids and tissues of patients by high-performance liquid chromatography. Analytical method and pharmacokinetics. Ann Rep Sankyo Res Lab 29: 66–74,1977
Neuwelt EA, Barnett PA, Binger DD, Frenkel EP: Effects of adrenal cortical steroids and osmotic blood-brain barrier opening on methotrexate delivery to gliomas in the rodent: The factor of the blood-brain barrier. Proc Natl Acad Sci USA 79: 4420–4423,1982
Neuwelt EA, Frenkel EP, Diehhl J, Vu LH, Rapoport S, Hill S: Reversible osmotic blood-brain barrier disruption in humans: Implications for the chemotherapy of malignant brain tumors. Neurosurgery 7: 44–52,1980
Nister M, Heldin CH, Wasteson A, Westermark B: A glioma-derived analog to platelet-derived growth factor: demonstration of receptor competing activity and immunological crossreactivity. Proc Natl Acad Sci USA 81: 926–930, 1984
Panter LA, Baumbach GL, Bigner DD et al.: Vasoactive drugs produce selective changes in flow to experimental brain tumors. Ann Neurol 18: 712–715,1985
Penniston JT: Plasma membrane Ca2+-ATPases as active Ca2+ pump. In: Cheung WY (ed.) Academic Press; New York 1983; Vol.4, pp 100–149
Rhodin JAG: The ultrastructure of mammalian arterioles and precapillary sphincters. J Ultrastruc Res 18: 181–223, 1967
San-Galli F, Vrignaud P, Robert J, Coindre JM, Cohadon F: Assessment of the experimental model of transplanted C6 glioblastoma in wistar rats. J Neuro-Oncol 7: 299–304,1989
Shapiro WR, Hiesiger EM, Cooney GA, Basler GA, Lipschutz LE, Posner JB: Temporal effects of dexamethazone on blood-to-brain and blood-to-tumor transport of 14C-al-pha-aminoisobutyric acid in rat C6 glioma. J Neuro-Oncol 8: 197–204,1990
Sherry JMF, Gorecka A, Aksoy MO, Dabrowska R, Hartshorne DJ: Role of calcium and phosphorylation in the reguration of the activity of gizzard myosin. Biochemistry 17: 4411–4418,1978
Shigehara E, Tanaka M: Whole-body autoradiographic studies on tissue distribution of 3-[(4-amino-2-methyl-5pyrimidinyl)methyl[l-(2-chloroethyl)-1-nitrosourea hydro chloride in tumor-bearing mice and rats. Gann 69: 907–914, 1978
Small JV, Sobieszek A: Ca2+ regulation of mammalian smooth muscle actomyosin via a kinase-phosphate-dependent phosphorylation and dephosphorylation of the 20000Mr light chain of myosin. Eur J Biochem 76: 521–530,1977
Terada T, Miyamoto K, Hyotano G, Tsuura M, Nakamura Y, Nishiguchi T, Itakura T, Hayashi S, Komai N: Local blood flow changes in malignant brain tumors under induced hypertension. Acta Neurochir 118:108–111,1992
Westermark B, Nister M, Heldin CH: Growth factors and oncogenes in human malignant glioma. Neurol Clin 3: 785–799, 1985
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Zenke, K., Nakagawa, K., Kumon, Y. et al. A strategy for selective anti-cancer drug concentration increase in rat glioma tissue with Ca2+-channel blocker co-administration: calcium kinetics in intra-glioma arteriolar smooth muscle cells. J Neuro-Oncol 30, 25–36 (1996). https://doi.org/10.1007/BF00177440
Issue Date:
DOI: https://doi.org/10.1007/BF00177440