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K Ota - One of the best experts on this subject based on the ideXlab platform.
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Effect of DeoxySpergualin on Vascular Rejection in Canine Kidney Transplantation
The Journal of Urology, 1994Co-Authors: Kazunari Tanabe, Hiroshi Toma, K Takahashi, K Nemoto, M Okada, M Yasuo, Y Hayasaka, K OtaAbstract:AbstractDeoxySpergualin (DSG), an analogue of Spergualin produced by Bacillus laterosporus, has a strong immunosuppressive effect in various transplantation models. In this study, we investigated the effect of DSG on vascular rejection in canine kidney transplantation.To enhance vascular rejection, donor-specific blood transfusion (DST) was carried out on days 28, 21 and 14 preceding kidney transplantation. After DST, the donor kidney was transplanted to the recipient iliac fossa. The recipient animals were divided into five groups: namely, Group 1 (n = 7), no treatment; Group 2 (n = 6), DST only; Group 3 (n = 5), DSG only (treated with DSG intravenously at 1.2 mg./kg./day for the first 3 days after transplantation, 1.0mg./kg./day for the following 3days and 0.8mg./kg./day for the following 8 days); Group 4 (n = 6), DST and DSG treatment (same protocol as Group 3); and Group 5 (n = 5), DST and cyclosporine (CsA) (treated with CsA orally at 10mg./kg./day for 14days after transplantation).In Group 2, DST tr...
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Effect of deoxySpergualin on vascular rejection in canine kidney transplantation.
The Journal of urology, 1994Co-Authors: Kazunari Tanabe, Hiroshi Toma, K Takahashi, K Nemoto, M Okada, M Yasuo, Y Hayasaka, K OtaAbstract:DeoxySpergualin (DSG), an analogue of Spergualin produced by Bacillus laterosporus, has a strong immunosuppressive effect in various transplantation models. In this study, we investigated the effect of DSG on vascular rejection in canine kidney transplantation. To enhance vascular rejection, donor-specific blood transfusion (DST) was carried out on days 28, 21 and 14 preceding kidney transplantation. After DST, the donor kidney was transplanted to the recipient iliac fossa. The recipient animals were divided into five groups: namely, Group 1 (n = 7), no treatment; Group 2 (n = 6), DST only; Group 3 (n = 5), DSG only (treated with DSG intravenously at 1.2 mg./kg./day for the first 3 days after transplantation, 1.0 mg./kg./day for the following 3 days and 0.8 mg./kg./day for the following 8 days); Group 4 (n = 6), DST and DSG treatment (same protocol as Group 3); and Group 5 (n = 5), DST and cyclosporine (CsA) (treated with CsA orally at 10 mg./kg./day for 14 days after transplantation). In Group 2, DST treatment significantly reduced kidney graft survival time (8.6 +/- 2.2 days) compared with Group 1 (14.1 +/- 5.5 days). Despite DST, DSG treatment (Group 4) significantly prolonged graft survival time (29.5 +/- 2.6 days), whereas treatment with CsA (Group 5) did not prolong survival time (14.1 +/- 5.5 days) (Group 4 versus 5, p < 0.01). The onset of rejection was significantly delayed in Group 4 (22.1 +/- 2.7 days) compared with Groups 2 (5.7 +/- 2.4 days) and 5 (13.0 +/- 5.7 days) (p < 0.01). In contrast, the interval between rejection onset and animal death was significantly reduced in Groups 2 (3.0 +/- 0.6 days) and 5 (2.4 +/- 1.0 days) compared with Group 4 (7.3 +/- 1.7 days) (p < 0.01). These findings suggest that DSG successfully prevented humoral-type (accelerated acute-type) rejections. Histologically, nonDST groups (Groups 1 and 3) showed minimum vascular rejection. In contrast, all recipients in Group 2 showed severe vascular rejection, as did 80% of CsA treated-animals (Group 5). Despite DST, however, 84% of DSG treated-animals (Group 4) showed minimal or mild vascular rejection and only 17% had severe rejection (Group 4 versus 5, p < 0.04). These data suggest that both clinically and histologically, DSG has more potent immunosuppressive effects against humoral and vascular rejection than CsA.
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DeoxySpergualin. A novel immunosuppressant: experimental and clinical studies
Organ Transplantation 1990, 1991Co-Authors: Amemiya H, K Takahashi, K Ota, S. Suzuki, T. Sonoda, M. Ishibashi, R. Omoto, I. Koyama, K. Dohi, Yasuhiko FukudaAbstract:DeoxySpergualin (DSG) is an analogue of an antibiotic having antitumor effect, Spergualin (1), which was isolated from the culture filtrate of Bacillus laterosporus in 1981. In 1985, it was reported that DSG had immunosuppressive effect (2, 3), and thereafter the characteristics of the agent as an immunosuppressant against rejection has been examined in detail. Figure 1 shows the chemical structure of DSG, which has a molecular weight of 496.91, occurs as white powder, and is very soluble in water and stable for a long period at 15 °C and below.
Kazunari Tanabe - One of the best experts on this subject based on the ideXlab platform.
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Synergistic effect of donor-specific blood transfusion and a short course of deoxySpergualin in rat kidney transplantation
Transplant International, 1996Co-Authors: Kazunari Tanabe, Hiroshi Toma, Kyuichi Nemoto, Mineko Yasuo, Kota Takahashi, Kazuo OtaAbstract:DeoxySpergualin (DSG), an analogue of Spergualin produced by B. laterosporus , has a strong immunosuppressive effect in various transplantation models. We have investigated the mechanism of donor-specific prolongation of survival time in rat kidney grafting by donor-specific blood transfusion (DST) and a short course of DSG. Lewis (LEW) kidney allografts were transplanted into fully allogeneic BN rats. Fresh, whole LEW blood 1.0 ml, was injected i.v. into BN rats 2 days prior to transplantation. Then, DSG, 6 mg/kg per day, was administered by i.m. injection on days 0, 1, and 2 after transplantation. The recipients were divided into five groups: group 1 ( n =6) no treatment: group 2 ( n =6) DST only; group 3 ( n =7) DSG only; group 4 ( n =7) DST and DSG; and group 5 ( n =6), third party (ACI rats) blood transfusion and DSG. Lymphocytes (cervical lymph nodes) and serum were harvested from BN recipients on day 7 postgrafting. For suppressor cell assays, lymphocytes from BN recipients in each group were added as a third cell to the mixed lymphocyte reaction (MLC) between nontransplanted BN lymphocytes (responder) and LEW or other third party (PVGC, ACI, WKA rats) lymphocytes (stimulator). Antidonor lymphocytotoxic antibody (ADLA) was checked by microcytotoxicity assays. Median survival times (MST) for each group were: group 1, 10 days; group 1, 10 days; group 3, 13 days; group 4, 75 days; and group 5, 13 days. Remarkable prolongation of MST was only noted in group 4. In the suppressor cell assay, group 4 showed significant suppression (40%; P
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Effect of DeoxySpergualin on Vascular Rejection in Canine Kidney Transplantation
The Journal of Urology, 1994Co-Authors: Kazunari Tanabe, Hiroshi Toma, K Takahashi, K Nemoto, M Okada, M Yasuo, Y Hayasaka, K OtaAbstract:AbstractDeoxySpergualin (DSG), an analogue of Spergualin produced by Bacillus laterosporus, has a strong immunosuppressive effect in various transplantation models. In this study, we investigated the effect of DSG on vascular rejection in canine kidney transplantation.To enhance vascular rejection, donor-specific blood transfusion (DST) was carried out on days 28, 21 and 14 preceding kidney transplantation. After DST, the donor kidney was transplanted to the recipient iliac fossa. The recipient animals were divided into five groups: namely, Group 1 (n = 7), no treatment; Group 2 (n = 6), DST only; Group 3 (n = 5), DSG only (treated with DSG intravenously at 1.2 mg./kg./day for the first 3 days after transplantation, 1.0mg./kg./day for the following 3days and 0.8mg./kg./day for the following 8 days); Group 4 (n = 6), DST and DSG treatment (same protocol as Group 3); and Group 5 (n = 5), DST and cyclosporine (CsA) (treated with CsA orally at 10mg./kg./day for 14days after transplantation).In Group 2, DST tr...
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Effect of deoxySpergualin on vascular rejection in canine kidney transplantation.
The Journal of urology, 1994Co-Authors: Kazunari Tanabe, Hiroshi Toma, K Takahashi, K Nemoto, M Okada, M Yasuo, Y Hayasaka, K OtaAbstract:DeoxySpergualin (DSG), an analogue of Spergualin produced by Bacillus laterosporus, has a strong immunosuppressive effect in various transplantation models. In this study, we investigated the effect of DSG on vascular rejection in canine kidney transplantation. To enhance vascular rejection, donor-specific blood transfusion (DST) was carried out on days 28, 21 and 14 preceding kidney transplantation. After DST, the donor kidney was transplanted to the recipient iliac fossa. The recipient animals were divided into five groups: namely, Group 1 (n = 7), no treatment; Group 2 (n = 6), DST only; Group 3 (n = 5), DSG only (treated with DSG intravenously at 1.2 mg./kg./day for the first 3 days after transplantation, 1.0 mg./kg./day for the following 3 days and 0.8 mg./kg./day for the following 8 days); Group 4 (n = 6), DST and DSG treatment (same protocol as Group 3); and Group 5 (n = 5), DST and cyclosporine (CsA) (treated with CsA orally at 10 mg./kg./day for 14 days after transplantation). In Group 2, DST treatment significantly reduced kidney graft survival time (8.6 +/- 2.2 days) compared with Group 1 (14.1 +/- 5.5 days). Despite DST, DSG treatment (Group 4) significantly prolonged graft survival time (29.5 +/- 2.6 days), whereas treatment with CsA (Group 5) did not prolong survival time (14.1 +/- 5.5 days) (Group 4 versus 5, p < 0.01). The onset of rejection was significantly delayed in Group 4 (22.1 +/- 2.7 days) compared with Groups 2 (5.7 +/- 2.4 days) and 5 (13.0 +/- 5.7 days) (p < 0.01). In contrast, the interval between rejection onset and animal death was significantly reduced in Groups 2 (3.0 +/- 0.6 days) and 5 (2.4 +/- 1.0 days) compared with Group 4 (7.3 +/- 1.7 days) (p < 0.01). These findings suggest that DSG successfully prevented humoral-type (accelerated acute-type) rejections. Histologically, nonDST groups (Groups 1 and 3) showed minimum vascular rejection. In contrast, all recipients in Group 2 showed severe vascular rejection, as did 80% of CsA treated-animals (Group 5). Despite DST, however, 84% of DSG treated-animals (Group 4) showed minimal or mild vascular rejection and only 17% had severe rejection (Group 4 versus 5, p < 0.04). These data suggest that both clinically and histologically, DSG has more potent immunosuppressive effects against humoral and vascular rejection than CsA.
Peter R. Twentyman - One of the best experts on this subject based on the ideXlab platform.
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The activity of deoxySpergualin in multidrug-resistant cells
Cancer Chemotherapy and Pharmacology, 1995Co-Authors: Julie A. Holmes, Peter R. TwentymanAbstract:DeoxySpergualin, a synthetic analogue of the immunosuppressive anti-tumour antibiotic Spergualin, has been shown to possess potent in vitro and in vivo antitumour activity and is currently in the National Cancer Institute (NCI) decision network. DeoxySpergualin shows similarities in properties and mechanisms of action to the natural-product immunosuppressive agents cyclosporin A and FK506, each of which can act as a modifier of multi-drug resistance. We therefore decided to examine the comparative activity of deoxySpergualin in parent and multidrug-resistant cells. DeoxySpergualin contains the polyamine spermidine within its structure. Bovine serum copper amine oxidase catalyses the oxidative deamination of spermidine to produce an aminoaldehyde, ammonia and hydrogen peroxide. These aminoaldehydes are believed to be responsible for the toxicity of polyamines in vitro in the presence of bovine serum. For this reason, all experiments were carried out in medium containing bovine serum and in medium containing horse serum (which is low in copper amine oxidase content). We used the tetrazolium (MTT) colorimetric assay to determine drug sensitivity and tritiated daunorubicin accumulation together with inhibition of azidopine binding to study specific mechanisms of resistance modulation. The murine cell lines EMT6/P and EMT6/AR1.0 and the human cell lines H69/P and H69/LX4 were, respectively, 32-, 32-, 372- and 483-fold more sensitive to spermidine and 175-, 133-, 321- and 444-fold more sensitive to spermine in the presence of calf serum than in the presence of horse serum. However, these large differential effects were not seen for deoxySpergualin. It appears that in the presence of horse serum, deoxySpergualin may exert its effect by a mechanism other than polyamine oxidation. DeoxySpergualin did not enhance the accumulation of [^3H]-daunorubicin in EMT6/AR1.0 cells. Furthermore, deoxySpergualin (1–20 μ M ) did not restore the sensitivity of EMT6/AR1.0 or H69/LX4 cells to that of the parent lines. P-glycoprotein (Pgp) in membranes prepared from H69/LX4 cells was photo-affinity-labeled with [^3H]-azidopine. DeoxySpergualin did not inhibit this labeling. Although deoxySpergualin appears to exert its immunosuppressive effect via a mechanism similar to that of cyclosporin A and FK506, it does not share their ability to modify Pgp-mediated multidrug resistance. However, its lack of cross-resistance and potent in vivo anti-tumour activity make deoxySpergualin a promising candidate for development as an anti-cancer agent.
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The activity of deoxySpergualin in multidrug-resistant cells
Cancer Chemotherapy and Pharmacology, 1995Co-Authors: Julie A. Holmes, Peter R. TwentymanAbstract:DeoxySpergualin, a synthetic analogue of the immunosuppressive anti-tumour antibiotic Spergualin, has been shown to possess potent in vitro and in vivo antitumour activity and is currently in the National Cancer Institute (NCI) decision network. DeoxySpergualin shows similarities in properties and mechanisms of action to the natural-product immunosuppressive agents cyclosporin A and FK506, each of which can act as a modifier of multi-drug resistance. We therefore decided to examine the comparative activity of deoxySpergualin in parent and multidrug-resistant cells. DeoxySpergualin contains the polyamine spermidine within its structure. Bovine serum copper amine oxidase catalyses the oxidative deamination of spermidine to produce an aminoaldehyde, ammonia and hydrogen peroxide. These aminoaldehydes are believed to be responsible for the toxicity of polyamines in vitro in the presence of bovine serum. For this reason, all experiments were carried out in medium containing bovine serum and in medium containing horse serum (which is low in copper amine oxidase content). We used the tetrazolium (MTT) colorimetric assay to determine drug sensitivity and tritiated daunorubicin accumulation together with inhibition of azidopine binding to study specific mechanisms of resistance modulation. The murine cell lines EMT6/P and EMT6/AR1.0 and the human cell lines H69/P and H69/LX4 were, respectively, 32-, 32-, 372- and 483-fold more sensitive to spermidine and 175-, 133-, 321- and 444-fold more sensitive to spermine in the presence of calf serum than in the presence of horse serum. However, these large differential effects were not seen for deoxySpergualin. It appears that in the presence of horse serum, deoxySpergualin may exert its effect by a mechanism other than polyamine oxidation. DeoxySpergualin did not enhance the accumulation of [^3H]-daunorubicin in EMT6/AR1.0 cells. Furthermore, deoxySpergualin (1–20 μ M ) did not restore the sensitivity of EMT6/AR1.0 or H69/LX4 cells to that of the parent lines. P-glycoprotein (Pgp) in membranes prepared from H69/LX4 cells was photo-affinity-labeled with [^3H]-azidopine. DeoxySpergualin did not inhibit this labeling. Although deoxySpergualin appears to exert its immunosuppressive effect via a mechanism similar to that of cyclosporin A and FK506, it does not share their ability to modify Pgp-mediated multidrug resistance. However, its lack of cross-resistance and potent in vivo anti-tumour activity make deoxySpergualin a promising candidate for development as an anti-cancer agent.
Hiroshi Toma - One of the best experts on this subject based on the ideXlab platform.
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Synergistic effect of donor-specific blood transfusion and a short course of deoxySpergualin in rat kidney transplantation
Transplant International, 1996Co-Authors: Kazunari Tanabe, Hiroshi Toma, Kyuichi Nemoto, Mineko Yasuo, Kota Takahashi, Kazuo OtaAbstract:DeoxySpergualin (DSG), an analogue of Spergualin produced by B. laterosporus , has a strong immunosuppressive effect in various transplantation models. We have investigated the mechanism of donor-specific prolongation of survival time in rat kidney grafting by donor-specific blood transfusion (DST) and a short course of DSG. Lewis (LEW) kidney allografts were transplanted into fully allogeneic BN rats. Fresh, whole LEW blood 1.0 ml, was injected i.v. into BN rats 2 days prior to transplantation. Then, DSG, 6 mg/kg per day, was administered by i.m. injection on days 0, 1, and 2 after transplantation. The recipients were divided into five groups: group 1 ( n =6) no treatment: group 2 ( n =6) DST only; group 3 ( n =7) DSG only; group 4 ( n =7) DST and DSG; and group 5 ( n =6), third party (ACI rats) blood transfusion and DSG. Lymphocytes (cervical lymph nodes) and serum were harvested from BN recipients on day 7 postgrafting. For suppressor cell assays, lymphocytes from BN recipients in each group were added as a third cell to the mixed lymphocyte reaction (MLC) between nontransplanted BN lymphocytes (responder) and LEW or other third party (PVGC, ACI, WKA rats) lymphocytes (stimulator). Antidonor lymphocytotoxic antibody (ADLA) was checked by microcytotoxicity assays. Median survival times (MST) for each group were: group 1, 10 days; group 1, 10 days; group 3, 13 days; group 4, 75 days; and group 5, 13 days. Remarkable prolongation of MST was only noted in group 4. In the suppressor cell assay, group 4 showed significant suppression (40%; P
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Effect of DeoxySpergualin on Vascular Rejection in Canine Kidney Transplantation
The Journal of Urology, 1994Co-Authors: Kazunari Tanabe, Hiroshi Toma, K Takahashi, K Nemoto, M Okada, M Yasuo, Y Hayasaka, K OtaAbstract:AbstractDeoxySpergualin (DSG), an analogue of Spergualin produced by Bacillus laterosporus, has a strong immunosuppressive effect in various transplantation models. In this study, we investigated the effect of DSG on vascular rejection in canine kidney transplantation.To enhance vascular rejection, donor-specific blood transfusion (DST) was carried out on days 28, 21 and 14 preceding kidney transplantation. After DST, the donor kidney was transplanted to the recipient iliac fossa. The recipient animals were divided into five groups: namely, Group 1 (n = 7), no treatment; Group 2 (n = 6), DST only; Group 3 (n = 5), DSG only (treated with DSG intravenously at 1.2 mg./kg./day for the first 3 days after transplantation, 1.0mg./kg./day for the following 3days and 0.8mg./kg./day for the following 8 days); Group 4 (n = 6), DST and DSG treatment (same protocol as Group 3); and Group 5 (n = 5), DST and cyclosporine (CsA) (treated with CsA orally at 10mg./kg./day for 14days after transplantation).In Group 2, DST tr...
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Effect of deoxySpergualin on vascular rejection in canine kidney transplantation.
The Journal of urology, 1994Co-Authors: Kazunari Tanabe, Hiroshi Toma, K Takahashi, K Nemoto, M Okada, M Yasuo, Y Hayasaka, K OtaAbstract:DeoxySpergualin (DSG), an analogue of Spergualin produced by Bacillus laterosporus, has a strong immunosuppressive effect in various transplantation models. In this study, we investigated the effect of DSG on vascular rejection in canine kidney transplantation. To enhance vascular rejection, donor-specific blood transfusion (DST) was carried out on days 28, 21 and 14 preceding kidney transplantation. After DST, the donor kidney was transplanted to the recipient iliac fossa. The recipient animals were divided into five groups: namely, Group 1 (n = 7), no treatment; Group 2 (n = 6), DST only; Group 3 (n = 5), DSG only (treated with DSG intravenously at 1.2 mg./kg./day for the first 3 days after transplantation, 1.0 mg./kg./day for the following 3 days and 0.8 mg./kg./day for the following 8 days); Group 4 (n = 6), DST and DSG treatment (same protocol as Group 3); and Group 5 (n = 5), DST and cyclosporine (CsA) (treated with CsA orally at 10 mg./kg./day for 14 days after transplantation). In Group 2, DST treatment significantly reduced kidney graft survival time (8.6 +/- 2.2 days) compared with Group 1 (14.1 +/- 5.5 days). Despite DST, DSG treatment (Group 4) significantly prolonged graft survival time (29.5 +/- 2.6 days), whereas treatment with CsA (Group 5) did not prolong survival time (14.1 +/- 5.5 days) (Group 4 versus 5, p < 0.01). The onset of rejection was significantly delayed in Group 4 (22.1 +/- 2.7 days) compared with Groups 2 (5.7 +/- 2.4 days) and 5 (13.0 +/- 5.7 days) (p < 0.01). In contrast, the interval between rejection onset and animal death was significantly reduced in Groups 2 (3.0 +/- 0.6 days) and 5 (2.4 +/- 1.0 days) compared with Group 4 (7.3 +/- 1.7 days) (p < 0.01). These findings suggest that DSG successfully prevented humoral-type (accelerated acute-type) rejections. Histologically, nonDST groups (Groups 1 and 3) showed minimum vascular rejection. In contrast, all recipients in Group 2 showed severe vascular rejection, as did 80% of CsA treated-animals (Group 5). Despite DST, however, 84% of DSG treated-animals (Group 4) showed minimal or mild vascular rejection and only 17% had severe rejection (Group 4 versus 5, p < 0.04). These data suggest that both clinically and histologically, DSG has more potent immunosuppressive effects against humoral and vascular rejection than CsA.
Yozo Suzuoki - One of the best experts on this subject based on the ideXlab platform.
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Phase I study of NKT-01
Cancer Chemotherapy and Pharmacology, 1995Co-Authors: Kazuo Tamura, Hisanobu Niitani, Masao Oguro, Ryuzo Ohno, Kazumi Sanpi, Hisashi Majima, Tohru Masaoka, Ikuro Kimura, Jiro Inagaki, Yozo SuzuokiAbstract:A phase I study of NKT-01 (deoxySpergualin), which is a derivative of an antitumor antibiotic, Spergualin, was performed by a cooperative study group. NKT-01 was given intravenously by 3-h infusion. The effect of single administration was studied prior to evaluation of daily administration for 5 consecutive days. In all, 5 and 33 patients with various malignancies, including leukemia, were entered into the trials of single and daily administration, respectively. In the single-administration study, all patients were evaluable and no clear adverse effect was observed at doses ranging from 20 to 320 mg/m^2. In the daily-administration study, 28 evaluable patients (16 men and 12 women; median age, 55.5 years) were treated with a daily dose of 20–500 mg/m^2. Toxicities such as myelosuppression, mild nausea/vomiting, anorexia, alopecia, tongue and perioral numbness, and hypotension were observed dose-dependently during or after the treatment. Grade 2 leukopenia, thrombocytopenia, and anemia were experienced at a dose of 500 mg/m^2. These usually recovered to normal values by approximately 3 weeks after treatment. A pharmacokinetic analysis of single administration revealed rapid plasma clearance, with mean half-lives for the α and β phases being 28 min and 6.9 h, respectively. Approximately 12% of the infused dose was excreted into the urine in unmetabolized form. The pharmacokinetic parameters obtained after 5-day administration were similar to those recorded after single administration. Concerning treatment response, a transient but significant reduction in the number of leukemic cells was observed in one patient with adult T-cell leukemia. In this study, perioral numbness, hypotension, and hematological toxicity were concluded to be dose-limiting, with the maximal acceptable dose being 500 mg/m^2. The recommended dose for a phase II study of NKT-01 against solid tumors was judged to be 400 mg/m^2 given daily by 3-h infusion for 5 days, every 3 weeks. In hematological malignancies, however, higher myelosuppressive schedules of administration should be investigated.
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Phase I study of NKT-01.
Cancer chemotherapy and pharmacology, 1995Co-Authors: Kazuo Tamura, Hisanobu Niitani, Masao Oguro, Ryuzo Ohno, Kazumi Sanpi, Hisashi Majima, Tohru Masaoka, Ikuro Kimura, Jiro Inagaki, Yozo SuzuokiAbstract:A phase I study of NKT-01 (deoxySpergualin), which is a derivative of an antitumor antibiotic, Spergualin, was performed by a cooperative study group. NKT-01 was given intravenously by 3-h infusion. The effect of single administration was studied prior to evaluation of daily administration for 5 consecutive days. In all, 5 and 33 patients with various malignancies, including leukemia, were entered into the trials of single and daily administration, respectively. In the single-administration study, all patients were evaluable and no clear adverse effect was observed at doses ranging from 20 to 320 mg/m2. In the daily-administration study, 28 evaluable patients (16 men and 12 women; median age, 55.5 years) were treated with a daily dose of 20-500 mg/m2. Toxicities such as myelosuppression, mild nausea/vomiting, anorexia, alopecia, tongue and perioral numbness, and hypotension were observed dose-dependently during or after the treatment. Grade 2 leukopenia, thrombocytopenia, and anemia were experienced at a dose of 500 mg/m2. These usually recovered to normal values by approximately 3 weeks after treatment. A pharmacokinetic analysis of single administration revealed rapid plasma clearance, with mean half-lives for the alpha and beta phases being 28 min and 6.9 h, respectively. Approximately 12% of the infused dose was excreted into the urine in unmetabolized form. The pharmacokinetic parameters obtained after 5-day administration were similar to those recorded after single administration. Concerning treatment response, a transient but significant reduction in the number of leukemic cells was observed in one patient with adult T-cell leukemia. In this study, perioral numbness, hypotension, and hematological toxicity were concluded to be dose-limiting, with the maximal acceptable dose being 500 mg/m2. The recommended dose for a phase II study of NKT-01 against solid tumors was judged to be 400 mg/m2 given daily by 3-h infusion for 5 days, every 3 weeks. In hematological malignancies, however, higher myelosuppressive schedules of administration should be investigated.