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Disposition of mitomycin C in the treatment of liver metastases by chemoembolisation
IN VlVO ANTITUMOR ACTIVITY OF CIDI, A GLYCOLIPIDE FROM PITTOSPORUM TOBIRA B D. a ~ L. Salvetti, D. Guamieri*, C. D'Arrigo* RBM S:p.A.P.O. Box 226, 10015 - Ivrea (TO). *Laboratori di Ricerca IDI Farmaceutici S.p.A. Via dei Castelli Romani, 83/85 - 00040 Pomezia (RO) Italy. Introduction: CIDI is a gtycolipide (row. centered between 1,000 and 1,500) extracted from the berries of Pittosporum tobira (faro. Pittosporaceae) discovered and studied by C. D'Arrigo. Its pharmacological properties are still unknown. To confirm and assess in vivo its antitumor potential already shown in in vitro tests, CIDI was studied in three murine models: Lymphocytic Leukemia P 388 (p 388), Sarcoma 180 (SA 180) and Lewis Lung Carcinoma (LLC). Materials and Methods: the protocols from the U.S.A. National Cancer Institute were followed. In summary: mice # t u m o r n ° cells (~=5%) CIDI (mg/Kg)* DBA P 388 lxl06 i.p. 2.5/5/7.5 i.p. CD-1 SA 180 0.5x106 i.p. 0.375/0.75/1.5 i.p. C57 LLC 0.2x106 i.m. 0.5/1/2/4 i.p. • daily administration for 9 consecutive days. # 10 mice~group Positive control w a s cyclophosphamide (CP 20 mg/Kg i.p.). The lethality inhibition was recorded daily and the evaluation of survival time of mice administered CIDI or CP vs negative control mice was the parameter taken into account. Results: CIDI did not increase the survival time when administered to mice injected with P 388 at any tested dose. On the contrary, mice with SA 180 or LLC survived their controls significantly longer. In fact the index T/C x 100 was 133, 169 and 165 tbr the three doses of CIDI against SA 180 and 1i39, 143, 142 and 133 at the four doses tested against LLC. The corresponding CP values were 189 and 151. Discussion and Conclusions: CIDI showed antitumor activity in SA 180 and LLC models since it significantly and dose-dependently prolonged the survival of mice inoculated with the corresponding tumor cells. On the contrary, it was not able to antagonize lethality of mice injected with P 388 cells.
THE CALCIUM ANTAGONIST VERAPAMIL LIMITS ADRIAMYCIN A C C U M U L A T I O N IN RAT PERITONEAL MAST CELLS.
EFFECT OF TAXOL AND C R E M O P H O R EL ON S P O N T A N E O U S AND ADRIAMYClN-INDUCED HISTAMINE RELEASE IN RAT PERITONEAL MAST CELLS.
DISPOSITION OF MITOMYCIN C IN THE TREATMENT OF L I V E R METASTASES BY CHEMOEMBOLISATION W Blederblck, AFE Rump, S Botvlmk-Helhng, B Matthey, M Thelsohn, R Flschbach , K Lackner , W Klaus. • Institute of Pharmacology, **Department of Radiology, University of Cologne, Gleueler Str. 24, D-50931 K61n, Germany
L. Candussio, G. Decorti, L. Baldini and F, Bartoli Klugmann Department of Biomedical Sciences, University of Trieste, Via Giorgieri 7, 34100 Trieste, Italy. P-glycoprotein is a 170 kDa transmembrane protein which is overproduced in turnout cells exhibiting the multi drug resistance phenomenon. P-170 glycoprotein has been identified also in normal cells actively involved in absorptive/secretive processes. Recently we have demonstrated the presence of this glycoprotein on mast cell granule membranes by means of immunocytochemical and immunofluorescence techniques and immunoelectron microscopy. In addition the presence of a protein with the characteristics of P-170 has been shown also by immunoprecipitation techniques. In addition, we found that in mast cells the antineoplastic agent adriamycin is much more concentrated than in other normal and neoplastic cell lines We have hypothesised that P-glycoprotein is involved in the transport of adriamycin into the granules of these cells. To verify this hypothesis we tested the effect of the calcium antagonist verapamii, which is a known reverter of multidrug-resistance by acting on the Pglycoprotein pump of tumour cells. In this study we show that verapamil significantly limits adriamycin uptake in purified rat peritoneal mast cells; and that its effect was clearly dose and incubation time dependent. On the contrary the calcium antagonist did not limit the histamine releasing activity of adriamycin. The inhibitory effect of verapamil was dependent on the presence of calcium ions in the medium. Data presented hereby, further indicate that P-170 glycoprotein, demonstrated to be present in mast cells, is involved in the transport and accumulation of adriamycin in the granules of these cells. Research supported by grants from M.U.R•S.T• (40 and 60 %) and from C.N.R., P.F. A,C.R.O contract n ° 9302172.PF39=
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G Decorti, L. Candussio, L. Baldini and F. Bartoli Klu.qmann Department of Biomedical Sciences, University of Trieste, Via Giorgieri 7, 34100 Trieste, Italy. Taxol, an effective antitumor agent, causes a severe toxicity due to an hypersensitivity reaction. The mechanism of this side effect is uncertain, but histamine release by mast cells has been suggested as one possibility. In current clinical formulations, laxol is dissolved in a mixture (1:1) of Cremophor EL and ethanol and it has been suggested that Cremophor EL may also play a role in the hypersensitivity reaction. We have evaluated the effect Of taxol and its solvent on histamine release in purified rat peritoneal mast cells; in addition, since taxol is often used in association with anthracyciines, and since anthracyclines induce an important histamine release and are concentrated in mast cells, the effect of taxol and its solvent on adriamycin-induced histamine release and uptake has been also studied. We found that taxol dissolved in Cremophor EL induces a moderate histamine release that should be ascribed to the solvent and not to taxol• In addition, Cremophor EL reduces adriamycininduced histamine release and also adriamycin uptake in these cells. Previous studies have shown that Cremophor EL inhibits the Pglycoprotein pump in multi drug resistant cells. We have shown that P-glycoprotein is expressed in normal mast cells and have suggested that this protein is responsible of the uptake of adriamycin in rat peritoneal mast cells; hence it is not surprising that Cremophor EL limits the accumulation of adriamycin in the secretory granules of these cells. Adriamycin-induced histamine release and uptake in mast cells have been related to the cardiotoxicity of this antitumor agent. Studies are in progress to verify if the administration of Cremophor EL in conjunction with adriamycin, besides overcoming multidrug resistance would also limit the cardiotoxicity.
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In cancer treatment arterial blood flow reduction by embolisation followed by intra-arterial chemotherapy may be advantageous by achieving high and prolonged drug concentrations in the tumor and lower systemic drug exposure. Pharmacokinetics of mitomycin-C (MMC) were investigated in 4 colorectal cancer patients (body weight: 55-92 kg) with liver metastases undergoing chemoembolisation. After hepatic artery branch catheterization and microspheres injection (Polyvinylalcohol, circumference: 150-250 gm) 20 mg MMC dissolved in 20 ml 0.9% NaCI solution were infused in 5-8 rain. Serum MMC-concentrations were determined from peripheral venous blood samples by HPLC-system (C 18 -column, elntion: phosphate - buffer (0.01M, pH:6.5)) : methanol, V:V = 70:30, uv detection at 365 nm). Max. serum concentrations were observed at average Tmax was at 7.7 min after beginning of MMC-infusion. Mean Cmax was 1095 ng/ml (range: 562-1790 ng/ml). Mean steady state distribution volume was 0.56 l/kg with a central compartment volume of 0.22 l/kg. Concentration-time curves could be described by a distributional phase (Tin = 8.5 min) followed by a terminal elimination phase (TI/;= 72.4 min). Mean total clearance amounted to 8.6 ml x m i n 1 x kg. The area under the concentration time curve was 33 gg x rain. Pharmacokinetic parameters for MMC-disposition in this study do not substantially differ from those reported for similar MMCamounts administered as intravenous bolus or as intra-arterial bolus into the hepatic artery. Our findings give no evidence for reduced systemic MMC exposure following the embolisation procedure used.
Research supported by grants from MU.R.S.T. (40 and 60 %) and from C.N.R., P.F.A.C.R.O contract n ° 9302172.PF39.
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THE CALCIUM ANTAGONIST VERAPAMIL LIMITS ADRIAMYCIN A C C U M U L A T I O N IN RAT PERITONEAL MAST CELLS.
EFFECT OF TAXOL AND C R E M O P H O R EL ON S P O N T A N E O U S AND ADRIAMYClN-INDUCED HISTAMINE RELEASE IN RAT PERITONEAL MAST CELLS.
DISPOSITION OF MITOMYCIN C IN THE TREATMENT OF L I V E R METASTASES BY CHEMOEMBOLISATION W Blederblck, AFE Rump, S Botvlmk-Helhng, B Matthey, M Thelsohn, R Flschbach , K Lackner , W Klaus. • Institute of Pharmacology, **Department of Radiology, University of Cologne, Gleueler Str. 24, D-50931 K61n, Germany
L. Candussio, G. Decorti, L. Baldini and F, Bartoli Klugmann Department of Biomedical Sciences, University of Trieste, Via Giorgieri 7, 34100 Trieste, Italy. P-glycoprotein is a 170 kDa transmembrane protein which is overproduced in turnout cells exhibiting the multi drug resistance phenomenon. P-170 glycoprotein has been identified also in normal cells actively involved in absorptive/secretive processes. Recently we have demonstrated the presence of this glycoprotein on mast cell granule membranes by means of immunocytochemical and immunofluorescence techniques and immunoelectron microscopy. In addition the presence of a protein with the characteristics of P-170 has been shown also by immunoprecipitation techniques. In addition, we found that in mast cells the antineoplastic agent adriamycin is much more concentrated than in other normal and neoplastic cell lines We have hypothesised that P-glycoprotein is involved in the transport of adriamycin into the granules of these cells. To verify this hypothesis we tested the effect of the calcium antagonist verapamii, which is a known reverter of multidrug-resistance by acting on the Pglycoprotein pump of tumour cells. In this study we show that verapamil significantly limits adriamycin uptake in purified rat peritoneal mast cells; and that its effect was clearly dose and incubation time dependent. On the contrary the calcium antagonist did not limit the histamine releasing activity of adriamycin. The inhibitory effect of verapamil was dependent on the presence of calcium ions in the medium. Data presented hereby, further indicate that P-170 glycoprotein, demonstrated to be present in mast cells, is involved in the transport and accumulation of adriamycin in the granules of these cells. Research supported by grants from M.U.R•S.T• (40 and 60 %) and from C.N.R., P.F. A,C.R.O contract n ° 9302172.PF39=
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G Decorti, L. Candussio, L. Baldini and F. Bartoli Klu.qmann Department of Biomedical Sciences, University of Trieste, Via Giorgieri 7, 34100 Trieste, Italy. Taxol, an effective antitumor agent, causes a severe toxicity due to an hypersensitivity reaction. The mechanism of this side effect is uncertain, but histamine release by mast cells has been suggested as one possibility. In current clinical formulations, laxol is dissolved in a mixture (1:1) of Cremophor EL and ethanol and it has been suggested that Cremophor EL may also play a role in the hypersensitivity reaction. We have evaluated the effect Of taxol and its solvent on histamine release in purified rat peritoneal mast cells; in addition, since taxol is often used in association with anthracyciines, and since anthracyclines induce an important histamine release and are concentrated in mast cells, the effect of taxol and its solvent on adriamycin-induced histamine release and uptake has been also studied. We found that taxol dissolved in Cremophor EL induces a moderate histamine release that should be ascribed to the solvent and not to taxol• In addition, Cremophor EL reduces adriamycininduced histamine release and also adriamycin uptake in these cells. Previous studies have shown that Cremophor EL inhibits the Pglycoprotein pump in multi drug resistant cells. We have shown that P-glycoprotein is expressed in normal mast cells and have suggested that this protein is responsible of the uptake of adriamycin in rat peritoneal mast cells; hence it is not surprising that Cremophor EL limits the accumulation of adriamycin in the secretory granules of these cells. Adriamycin-induced histamine release and uptake in mast cells have been related to the cardiotoxicity of this antitumor agent. Studies are in progress to verify if the administration of Cremophor EL in conjunction with adriamycin, besides overcoming multidrug resistance would also limit the cardiotoxicity.
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In cancer treatment arterial blood flow reduction by embolisation followed by intra-arterial chemotherapy may be advantageous by achieving high and prolonged drug concentrations in the tumor and lower systemic drug exposure. Pharmacokinetics of mitomycin-C (MMC) were investigated in 4 colorectal cancer patients (body weight: 55-92 kg) with liver metastases undergoing chemoembolisation. After hepatic artery branch catheterization and microspheres injection (Polyvinylalcohol, circumference: 150-250 gm) 20 mg MMC dissolved in 20 ml 0.9% NaCI solution were infused in 5-8 rain. Serum MMC-concentrations were determined from peripheral venous blood samples by HPLC-system (C 18 -column, elntion: phosphate - buffer (0.01M, pH:6.5)) : methanol, V:V = 70:30, uv detection at 365 nm). Max. serum concentrations were observed at average Tmax was at 7.7 min after beginning of MMC-infusion. Mean Cmax was 1095 ng/ml (range: 562-1790 ng/ml). Mean steady state distribution volume was 0.56 l/kg with a central compartment volume of 0.22 l/kg. Concentration-time curves could be described by a distributional phase (Tin = 8.5 min) followed by a terminal elimination phase (TI/;= 72.4 min). Mean total clearance amounted to 8.6 ml x m i n 1 x kg. The area under the concentration time curve was 33 gg x rain. Pharmacokinetic parameters for MMC-disposition in this study do not substantially differ from those reported for similar MMCamounts administered as intravenous bolus or as intra-arterial bolus into the hepatic artery. Our findings give no evidence for reduced systemic MMC exposure following the embolisation procedure used.
Research supported by grants from MU.R.S.T. (40 and 60 %) and from C.N.R., P.F.A.C.R.O contract n ° 9302172.PF39.
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137
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