Influence of modes of ACNU administration on tissue and blood drug concentration in malignant brain tumors

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✓ The water-soluble nitrosourea compound ACNU is also lipid-soluble at normal physiological pH levels. It lacks toxic effects on vision that nitrosoureas occasionally produce following intra-arterial administration. In 28 cases of both primary and secondary malignant brain tumors, ACNU was administered at surgery or angiography by three different modes: intravenous injection in Group I (10 cases), intra-arterial injection via the carotid artery in Group II (11 cases), and intra-arterial injection via the carotid artery after opening the blood-brain barrier (BBB) by means of mannitol in Group III (seven cases). Tumor tissue and blood samples were taken serially at various time intervals after ACNU injection, and ACNU was measured by high-performance liquid chromatography. The time-concentration curve for ACNU was calculated in each case by the two- and one-compartment open models for determination of ACNU levels in blood and tissue, respectively. Pharmacokinetic parameters including biological half-life, blood and tissue levels (0-t minutes and 0-∞ minutes), total plasma clearance, and distribution volume of the β phase were compared. Statistical analysis of tissue ACNU levels at 0-t minutes revealed higher concentrations in Group III patients than in Groups II and I: levels in Group II were significantly higher than in Group I. Mean biological half-life was 30.3, 23.0, and 38.5 minutes in Groups I, II, and III, respectively. Levels of ACNU were significantly increased in tumor tissue as well as in peritumoral tissue in one Group III patient with multiple metastatic anaplastic adenocarcinoma. In this series, treatment of malignant brain tumor by intra-arterial administration of ACNU produced significantly higher tissue levels of ACNU than did the systemic intravenous route.

Abstract

✓ The water-soluble nitrosourea compound ACNU is also lipid-soluble at normal physiological pH levels. It lacks toxic effects on vision that nitrosoureas occasionally produce following intra-arterial administration. In 28 cases of both primary and secondary malignant brain tumors, ACNU was administered at surgery or angiography by three different modes: intravenous injection in Group I (10 cases), intra-arterial injection via the carotid artery in Group II (11 cases), and intra-arterial injection via the carotid artery after opening the blood-brain barrier (BBB) by means of mannitol in Group III (seven cases). Tumor tissue and blood samples were taken serially at various time intervals after ACNU injection, and ACNU was measured by high-performance liquid chromatography. The time-concentration curve for ACNU was calculated in each case by the two- and one-compartment open models for determination of ACNU levels in blood and tissue, respectively. Pharmacokinetic parameters including biological half-life, blood and tissue levels (0-t minutes and 0-∞ minutes), total plasma clearance, and distribution volume of the β phase were compared. Statistical analysis of tissue ACNU levels at 0-t minutes revealed higher concentrations in Group III patients than in Groups II and I: levels in Group II were significantly higher than in Group I. Mean biological half-life was 30.3, 23.0, and 38.5 minutes in Groups I, II, and III, respectively. Levels of ACNU were significantly increased in tumor tissue as well as in peritumoral tissue in one Group III patient with multiple metastatic anaplastic adenocarcinoma. In this series, treatment of malignant brain tumor by intra-arterial administration of ACNU produced significantly higher tissue levels of ACNU than did the systemic intravenous route.

Nitrosoureas are most suitable for administration via the carotid artery in the treatment of human malignant brain tumors. They cross the blood-brain barrier (BBB) via the capillaries in a short half-life and do not require enzymatic activation since they are soluble in lipids.

One of the nitrosourea compounds developed in Japan is ACNU (1-(4-amino-2-methyl pyridimine-5-yl)-methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride), a drug that is soluble in water as well as in lipids, as shown by its low log p (1-octanol/water partition coefficient) of 0.92.14 In Japan, ACNU has been widely used in treating malignant brain tumors. Its clinical effectiveness by intra-arterial and systemic intravenous administration has been described in several reports.7,14,16,24 One disadvantage of intra-arterially injected nitrosoureas is the occasional toxicity to vision that is probably related to the ethanol solvent.9 No such toxicity has been reported with water-soluble ACNU.16,24

Criticisms concerning chemotherapy of brain tumors have included the difficulty in attaining an effective drug concentration in the areas adjacent to the main tumor.1 A high concentration is desired because of the infiltrative character of most malignant brain tumors and because of the infiltration of malignant cells into areas of normal brain before neovascularization is induced by tumor. Unlike the primary tumor, the permeability characteristics in these regions are determined by normal or nearly normal capillaries. Lipophilic drugs such as BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) have proven to be more effective than water-soluble drugs with respect to the concentration of drug in the brain adjacent to tumor.6,11,12,23

In one study in which ACNU was injected intra-arterially into rat brain tumors, a higher concentration of ACNU was obtained in the tumor tissue than in other parts of the brain.8 One method of increasing ACNU levels in tumor tissue as well as in the surrounding tumor-infiltrated brain is to open the BBB with a hyperosmotic agent before intra-arterial drug injection.19–21

In this paper we summarize clinical studies that we performed in an attempt to clarify the advantage of intra-arterial over intravenous injection and also the advantage of moderate BBB opening plus intra-arterial injection over intra-arterial injection alone in enhancing the tissue concentration of ACNU.

Clinical Material and Methods
Summary of Cases

Between 1980 and 1985, 28 patients with both primary and secondary malignant brain tumors of various histology were treated with ACNU using varying modes of drug administration. Informed consent was obtained in all cases. The drug was given at the time of operation or angiography.

The patients were divided into three groups: Group I included 10 patients who underwent intravenous injection of ACNU; Group II comprised 11 patients who underwent intra-arterial injection of ACNU by means of an indwelling catheter placed in the internal carotid artery by a cervical or femoral percutaneous Seldinger's technique either at craniotomy or at angiography; and Group III included seven patients who underwent intra-arterial injection of ACNU after BBB opening using mannitol. The clinical data, including age, sex, tumor location, tumor pathology, and ACNU doses, are summarized in Tables 1 and 2. At the beginning of this study, ACNU was administered at a dose of 100 or 150 mg/patient and thus the dose/body weight differed with each case. However, the dose used in each case reported here was equivalent to 2 mg/kg. Steroids, anticonvulsant agents,15,16 or other drugs used were essentially the same in all three groups.

TABLE 1

ACNU levels in blood in three groups of brain-tumor patients treated by intravenous or intra-arterial injection*

Case No.Age (yrs), SexTumor Site & PathologyACNU Dose (mg/kg)ACNU Levels in Blood
5 Min10 Min15 Min30 Min45 Min60 Min90 Min    
Group I
118, Frt frontal malignant ependymoma2.002.071.770.640.740.340.130.13
258, Mlt parietal anaplastic glioma2.172.370.960.940.740.360.270.17
351, Mrt frontal oligodendroglioma1.436.692.391.820.600.620.410.36
441, Mlt frontotemporal astrocytoma grade III1.528.305.394.463.432.462.091.25
534, Flt parieto-occipital metastasis (adenocarcinoma)2.004.963.842.931.520.670.43
670, Mlt temporal glioblastoma2.003.172.081.821.200.850.530.35
776, Mlt occipital metastasis (adenocarcinoma)1.751.441.271.040.590.560.410.32
mean ± SE1.844.142.531.951.260.870.640.43
± 0.11± 0.98± 0.59± 0.51± 0.38± 0.33± 0.25± 0.14
Group II
1137, Flt occipital metastasis (adenocarcinoma)2.003.904.253.352.151.41
1265, Flt parietal malignant meningioma2.002.772.101.271.081.120.710.58
1351, Mrt occipital metastasis (adenocarcinoma)1.614.043.192.972.091.390.880.72
1431, Frt frontal astrocytoma grade II1.672.614.123.241.600.51
1535, Mlt temporal glioblastoma1.751.351.221.330.810.660.590.39
mean ± SE1.812.932.982.231.871.061.040.55
± 0.08± 0.49± 0.58± 0.54± 0.43± 0.21± 0.20± 0.07
Group III
2237, Mrt frontal metastasis (adenocarcinoma)3.005.933.532.531.120.790.650.41
2374, Frt frontal metastasis (squamous cell carcinoma)2.004.432.592.001.260.960.760.53
2434, Mlt frontal astrocytoma grade III2.004.932.921.991.380.980.69
2550, Flt parietal malignant lymphoma2.006.563.322.981.551.000.580.50
2657, Mrt temporal astrocytoma grade III2.006.206.482.811.321.030.740.55
mean ± SE2.205.613.772.461.330.950.680.50
± 0.20± 0.40± 0.70± 0.20± 0.07± 0.04± 0.03± 0.03

For a description of the three treatment groups see text. SE = standard error.

Levels of ACNU in blood were calculated in 2-mg/kg equivalents at various times after injection.

TABLE 2

ACNU levels in tissue in three groups of brain-tumor patients treated by intravenous or intra-arterial injection*

Case No.Age (yrs), SexTumor Site & PathologyACNU Dose (mg/kg)ACNU Levels in Tumor Tissue (µg ⋅ min/gm)
5 Min10 Min15 Min30 Min45 Min60 Min     
Group I
118, Frt frontal malignant ependymoma2.002.802.142.862.2589.4
258, Mlt parietal anaplastic glioma2.173.822.491.121.111.0194.8
351, Mrt frontal oligodendroglioma1.432.482.391.891.370.5299.0
441, Mlt frontotemporal astrocytoma grade III1.522.772.861.89121.2
534, Flt parieto-occipital metastasis (adenocarcinoma)2.002.033.1018.0
84, Mrt frontal ependymoma2.001.631.021.250.5439.0
957, Frt frontal astrocytoma grade III2.503.033.601.7866.0
1071, Mrt parieto-occipital malignant lymphoma2.000.841.760.7024.6
mean ± SE1.951.832.482.221.521.460.7769.0
± 0.12± 0.41± 0.35± 0.43± 0.30± 0.23± 0.25± 13.5
Group II
1660, Frt temporal glioblastoma2.009.516.219.884.921.65326.4
1761, Mlt temporal glioblastoma2.007.8114.145.455.311.75310.8
1818, Frt frontal malignant ependymoma2.001.751.352.581.9451.6
1936, Flt temporal astrocytoma grade III3.0012.476.004.12246.6
2047, Flt temporal astrocytoma grade III3.003.962.211.642.19165.6
2150, Mlt parietal glioblastoma2.534.392.2563.6
mean ± SE2.425.767.285.983.721.96194.1
± 0.20± 1.77± 2.61± 1.50± 0.63± 0.15± 49.0
Group III
2237, Mrt frontal metastasis (adenocarcinoma)3.0010.7716.979.054.413.172.38408.6
2374, Frt frontal metastasis (squamous cell carcinoma)2.0020.779.938.653.792.131.62351.0
2434, Mlt frontal astrocytoma grade III2.002.104.784.181.911.64180.6
2759, Mlt temporal glioblastoma2.006.6810.2318.997.995.934.46610.8
2861, Mlt temporal glioblastoma2.0010.0011.365.993.083.012.64282.6
mean ± SE2.2010.0612.129.494.693.232.55366.7
± 0.20± 3.08± 1.64± 2.51± 0.86± 0.72± 0.52± 71.7

For a description of the three treatment groups see text. SE = standard error.

Levels of ACNU in actual viable tumor tissue were calculated in 2-mg/kg equivalents at various times after injection.

= area under the curve from 0 to t minutes. For a description of the pharmacokinetic parameters see text.

Method of Injection

The predetermined dose of ACNU was dissolved in 30 ml of sterilized distilled water. In Group I, the ACNU was injected into the right antecubital vein over a 5-minute period either manually or mechanically by a syringe infusion pump.* In Group II, injection was via the internal carotid artery on the side of the tumor over a 5-minute period. In Group III, the drug was injected in the same manner as in Group II but was administered 10 minutes after intra-arterial injection of 200 ml of filtered 20% mannitol.

Measurement of ACNU After Injection

Levels of ACNU in tissue were measured at the first operation to exclude the influence of radiotherapy or other factors and were determined again after tumor pathology was confirmed, by freezing the operative specimens. Blood and tissue specimens were collected at 5, 10, 15, 30, 45, 60, and 90 minutes after ACNU administration. About 2 ml of whole blood was withdrawn from the left antecubital vein with indwelling needles, and at least 500 mg or more of tumor tissue and a sample of surrounding tumor-infiltrated edematous tissue were obtained. The site selected for tumor biopsy was a macroscopically viable part of the tumor, and necrotic portions of the tumor were excluded intentionally.

After brief washing with saline solution to remove blood, followed by simple blotting, the tissues were immediately transferred into a dry-ice chamber and preserved until assay. After measurement of tissue weight, the ACNU was extracted with 1-2-dichloroethane in an ice-cooled shaded atmosphere and measured by high-performance liquid chromatography (HPLC). The lower assay limit was 40 ng/ml in both blood and tissue (accuracy within ± 6%). As a tissue control, brain tissue from the crab-eating monkey brain was used. The control used for blood was 1 ml of a standard ACNU solution (2 or 4 mg of standard ACNU dissolved in 25 ml of distilled water). The drug was detected by absorption at 254 nm, and the quantity was estimated from its peak height.

Parameters for ACNU levels in blood and tissue were determined by non-linear regression analysis according to the relevant formulas13 and by a non-linear run on an IBM 4341 computer using a two-compartment open model. For parameters showing only a single phase, analysis was performed by a one-compartment open model.

Levels of ACNU in tissue following intra-arterial administration with BBB opening (Group III) could be analyzed by a two-compartment open model with the first-order transfer rate constant for tumor tissue. The analysis following intravenous and intra-arterial administration (Groups I and II, respectively) could be performed by a one-compartment open model with a first-order transfer rate constant.

In each case, the following pharmacokinetic parameters were calculated (see Table 3): biological half-life (t½ = 0.693/β or Kel); area under the time-blood or tissue concentration curve from 0 to ∞ minutes ; area under the time-blood or tissue concentration curve from 0 to t minutes ; elimination rate constant at the terminal phase of the time-blood or tissue concentration curve (Kel or β); blood or tissue concentrations at t minutes , (or Kel), where was calculated by the trapezoidal rule from the area under the time-concentration curve); total plasma clearance (CLp, calculated as ); and distribution volume of the β phase (Vd), calculated as ().

TABLE 3

Pharmacokinetic parameters of blood ACNU calculated by the compartment open model*

Case No.Age (yrs), Sex (µg ⋅ min/ml) (µg ⋅ min/ml)β (min−1)t½ (min)Clearance (ml/min/kg)Vd Area (liter/kg)
Group I
118, F53.4058.380.026126.634.31.31
258, M51.4861.780.016542.032.41.93
351, M96.42133.530.009771.715.01.54
441, M263.92338.320.016841.25.90.35
534, F134.04154.420.021132.913.00.61
670, M92.34109.250.020733.518.30.88
776, M55.3484.430.011063.723.72.15
mean106.71134.300.017444.520.41.25
SE28.5836.570.00206.43.90.25
Group II
1137, F143.76219.980.018537.59.10.49
1265, F94.74147.470.011063.113.61.23
1351, M148.62184.260.020234.310.90.54
1431, F216.50235.890.026326.48.50.32
1535, M67.4193.240.015145.921.51.42
mean134.21176.170.018241.412.70.80
SE25.5825.740.00256.32.40.22
Group III
2237, M85.97111.120.016342.618.01.10
2374, F133.65170.710.014348.611.70.82
2434, M116.35145.710.023529.513.70.58
2550, F137.05163.650.018836.912.20.65
2657, M119.35156.760.014747.212.80.87
mean118.47149.590.017541.013.70.80
SE9.0510.460.00143.51.10.09

For a description of the pharmacokinetic parameters see text. No significant differences in parameters were obtained among the three groups. SE = standard error.

The results in the three groups were statistically compared using the Wilcoxon rank-sum test.

Results
ACNU Levels in Blood

Table 1 shows ACNU levels in blood measured at various times after the administration of the drug at a predetermined dose in seven cases in Group I, five cases in Group II, and five cases in Group III. Figure 1 left demonstrates the mean ACNU levels in blood in graph form. The parameters of the blood level calculated in each case were t½, clearance, Vd area, , and (Table 3).

Fig. 1.
Fig. 1.

Graphs showing the levels of ACNU following intravenous administration (IV), administration into the internal carotid artery (IC) only, or IC administration with BBB opening using mannitol. Left: Determinations of ACNU concentrations in blood revealed no significant differences in the pharmacokinetic parameters and blood ACNU levels among the three groups. Right: Tissue ACNU levels were significantly different between groups: Group III (IC and mannitol) had higher levels than Groups I (IV) and II (IC only) (p = 0.0022 and 0.0414, respectively). Comparison between Groups II and I showed that Group II had significantly higher tissue levels than Group I (p = 0.0407, determined by the Wilcoxon rank-sum test).

There were no significant differences in pharmacokinetic parameters and blood ACNU levels among the three groups.

ACNU Levels in Brain-Tumor Tissue

Levels of ACNU in tumor tissue were determined at various times after injection in eight Group I cases, six Group II cases, and five Group III cases (Table 2) by administering ACNU at prescribed doses during operation. The calculated values of tissue ACNU are also shown in Table 2.

Statistical analysis performed using these values demonstrated significantly different tissue levels of ACNU among the three groups. Group III had higher tissue concentrations of ACNU than either Group I (p = 0.0022) or Group II (p = 0.0414). Levels in Group II were significantly higher than those in Group I (p = 0.0407), as determined by the Wilcoxon rank-sum test.

Mean ACNU tissue levels over time in each group were pharmacokinetically analyzed, and the curves generated are shown as in Fig. 1 right based on the pharmacokinetic parameters obtained. Also, the mean biological half-life of ACNU in tissue in Groups I, II, and III was calculated to be 30.3, 23.0, and 38.5 minutes, respectively. These comparisons indicate that intra-arterial injection results in a higher ACNU level in tumor tissue than does intravenous injection, and intra-arterial injection with BBB opening gives a higher ACNU level in tumor tissue than does intra-arterial injection only. There were no significant differences in blood ACNU levels and pharmacokinetic parameters among the three groups.

The following two illustrative cases show the increase of ACNU concentrations in tumor tissue as well as in peritumoral tissue after BBB opening.

Illustrative Cases

The patient in the first case (Case 22, Group III) was a 37-year-old man who was admitted because of right frontal multiple metastatic anaplastic adenocarcinoma from the lung. He underwent a right frontal lobectomy with intra-arterial administration of 3 mg/kg ACNU after BBB opening. During the operation, metastatic tumor tissue (Fig. 2 left) and surrounding edematous tissue were obtained to determine the concentration of ACNU in tissue at various times after administration. The results of the analysis are shown in Table 4. Significantly increased ACNU concentrations were observed not only in tumor tissue but also in the surrounding edematous tissue.

Fig. 2.
Fig. 2.

Computerized tomography scans in two illustrative cases showing the site where frontal metastatic tumor tissue (arrow) and surrounding edematous tissue were taken during surgery to examine the tissue concentration of ACNU. The results of analysis are shown in Table 4. Left: Case 22. Scan from a 37-year-old man with a right frontal multiple metastatic anaplastic adenocarcinoma from the lung who underwent intra-arterial administration of 3 mg/kg of ACNU after blood-brain barrier (BBB) opening. The ACNU levels in this patient were significantly increased not only in the tumor tissue but also in the surrounding edematous tissue. Right: Scan from a 65-year-old woman (supplemental case described in the text) with a right frontal metastatic adenocarcinoma from the rectum who received 2 mg/kg of ACNU intra-arterially without BBB opening. The ACNU levels in tumor tissue from this patient were higher than in the surrounding area.

TABLE 4

Tissue concentrations (in µg/gm) of ACNU in specimens from illustrative cases*

Biopsy SiteACNU Levels in Tissue
5 Min10 Min15 Min30 Min45 Min60 Min 
Case 22
 tumor tissue16.225.513.66.65.33.4
 surrounding area30.014.110.65.44.22.9
Supplementary case
 tumor tissue6.64.53.01.20.80.4
 surrounding area2.62.21.30.80.60.4

The patient in Case 22 had a metastatic anaplastic adenocarcinoma from the lung. He received 3 mg/kg of ACNU intra-arterially with blood-brain barrier (BBB) opening, and the patient in the supplementary case described in the text had a metastatic adenocarcinoma from the rectum. She received 2 mg/kg of ACNU intra-arterially without BBB opening. Tissue levels of ACNU were assessed at various times after injection. For further description of the two cases see text and Fig. 2.

A supplementary case, not included in Tables 1, 2, and 3, is described to show the difference in tissue ACNU concentration from that in Case 22 because the nature and location of the tumor was homogeneous in both cases. This patient was a 65-year-old woman who was operated on because of right frontal metastatic adenocarcinoma from the rectum. She had a right frontal lobectomy with intra-arterial administration of 2 mg/kg ACNU without BBB opening. During the operation, metastatic tumor tissue (Fig. 2 right) and surrounding edematous tissue were taken in the same manner as in Case 22. The analytical results of ACNU concentration in tumor tissues and peritumoral tissues are shown in Table 4. Uptake of ACNU by tumor tissue seemed to be higher than in the surrounding tissue in this case.

Discussion

In terms of tissue concentration of the parent form of ACNU in human malignant brain tumors, intra-arterial administration with and without BBB modification has clear superiority over the intravenous route. No differences in ACNU levels in blood were demonstrated between the two intra-arterial methods. To compare the intravenous route with the intra-arterial route, we measured ACNU by HPLC instead of measuring active deoxyribonucleic acid-bound ACNU. However, Shigehara, et al.,22 reported a significant correlation between ACNU in blood and tissues and active macromolecule-bound ACNU (including active deoxyribonucleic acid-bound ACNU) levels using carbon-14-labeled ACNU in experimental animals. Considering these findings and the limited scope of clinical studies of this type in comparing the influence of routes of injection on ACNU concentration in human malignant brain-tumor tissues and blood, the analytical method used here can be justified and the data and conclusions obtained should be reliable.

A critical problem of brain-tumor chemotherapy is to increase the drug level at the interface between tumor and brain tissue. Although the sensitivity of tumors to ACNU or BCNU has been reported to vary significantly from one strain to another,2–4 it is generally considered to be dose-related, and even a relatively small increase in delivery of agents might be beneficial. A method to augment ACNU delivery both to tumor tissue and to the surrounding areas is by intra-arterial injection of ACNU after BBB modification by means of intra-arterial administration of a hypertonic solution. Neuwelt, et al.,19–21 reported a clinical benefit when the BBB was opened by 25% mannitol, with the chemotherapeutic drug administered immediately or 5 minutes later. We adopted this BBB-opening technique for selected patients after obtaining informed consent, using 200 ml of 20% mannitol followed by ACNU injection 10 minutes after BBB opening. Since the degree of BBB opening is reported to correlate with the concentration of mannitol and time after mannitol injection,5 our protocol is presumed to be slightly more moderate than that of Neuwelt, et al. However, ACNU delivery to tumor tissue in the presence of mannitol was significantly increased over intra-arterial injection without BBB modification and, in a case of anaplastic adenocarcinoma (Case 22), ACNU in peritumoral tissue was also significantly elevated after BBB opening.

Further studies, including more extensive study of the tissue surrounding the tumor, and long-term clinical follow-up monitoring are mandatory to demonstrate the advantages of the treatment used in Group III over that used in Group II. In this clinical study, it was not possible to obtain large samples of tissue surrounding the tumor. In evaluating the use of chemotherapy with BBB opening for brain tumors, the neurotoxicity resulting from the increased delivery of chemotherapeutic agents must be considered although resistance of normal brain to BCNU or ACNU may be stronger than the reported resistance of 9L tumor cells to these drugs.3,4 For this reason the use of chemotherapy with BBB opening should be limited to patients with metastatic brain tumors, primary malignant lymphomas, and recurrent diffuse malignant gliomas, and to patients who need a reduction of the systemic dose because of myelotoxicity.10,17–21

In conclusion, intra-arterial administration of ACNU is useful for treatment of human malignant brain tumors for four reasons: 1) the lack of alcohol-related toxicity to vision; 2) the ease of suspending the agent without causing vascular pain or toxicity; 3) the rapid biological half-life and rapid tissue distribution; and 4) the significant increase in ACNU delivery to malignant brain-tumor tissue compared to the intravenous route. A definite conclusion will require further cumulative studies in cases of brain tumors of homogeneous location, type, and histology.

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    Neuwelt EAHill SAFrenkel EP: Osmotic blood-brain barrier modification and combination chemotherapy: concurrent tumor regression in areas of barrier opening and progression in brain regions distant to barrier opening. Neurosurgery 15:3623661984Neurosurgery 15:

  • 22.

    Shigehara ETanaka M: Whole-body autoradiographic studies on tissue distribution of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride in tumor-bearing mice and rats. Gann 69:7097141978Gann 69:

  • 23.

    Yamada KBremer AMWest CRet al: Intra-arterial BCNU therapy in the treatment of metastatic brain tumor from lung carcinoma. A preliminary report. Cancer 44:200020071979Cancer 44:

  • 24.

    Yamashita JHanda HTokuriki Yet al: Intra-arterial ACNU therapy for malignant brain tumors. Experimental studies and preliminary clinical results. J Neurosurg 59:4244301983J Neurosurg 59:

Syringe infusion pump, Model STC-521, manufactured by Terumo, Japan.

Article Information

Address reprint requests to: Tomokatsu Hori, M.D., Division of Neurosurgery, Institute of Neurological Sciences, Tottori University School of Medicine, 86 Nishimachi, Yonago 683, Japan.

© AANS, except where prohibited by US copyright law.

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Figures

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    Graphs showing the levels of ACNU following intravenous administration (IV), administration into the internal carotid artery (IC) only, or IC administration with BBB opening using mannitol. Left: Determinations of ACNU concentrations in blood revealed no significant differences in the pharmacokinetic parameters and blood ACNU levels among the three groups. Right: Tissue ACNU levels were significantly different between groups: Group III (IC and mannitol) had higher levels than Groups I (IV) and II (IC only) (p = 0.0022 and 0.0414, respectively). Comparison between Groups II and I showed that Group II had significantly higher tissue levels than Group I (p = 0.0407, determined by the Wilcoxon rank-sum test).

  • View in gallery

    Computerized tomography scans in two illustrative cases showing the site where frontal metastatic tumor tissue (arrow) and surrounding edematous tissue were taken during surgery to examine the tissue concentration of ACNU. The results of analysis are shown in Table 4. Left: Case 22. Scan from a 37-year-old man with a right frontal multiple metastatic anaplastic adenocarcinoma from the lung who underwent intra-arterial administration of 3 mg/kg of ACNU after blood-brain barrier (BBB) opening. The ACNU levels in this patient were significantly increased not only in the tumor tissue but also in the surrounding edematous tissue. Right: Scan from a 65-year-old woman (supplemental case described in the text) with a right frontal metastatic adenocarcinoma from the rectum who received 2 mg/kg of ACNU intra-arterially without BBB opening. The ACNU levels in tumor tissue from this patient were higher than in the surrounding area.

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