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1.
Chem Pharm Bull (Tokyo) ; 49(10): 1280-7, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11605654

ABSTRACT

A series of novel pyrrolo[2,3-d]pyrimidine derivatives was designed and synthesized as thymidylate synthase (TS) inhibitors. Molecular design was performed on the human TS complex model built on the basis of the reported structure of TS-deoxyuridinemonophosphate (dUMP)-CB3717 ternary complex. From a docking study, we expected that a one-carbon bridge between pyrrolo[2,3-d]pyrimidine and an aromatic ring was suitable. Moreover, we found that the bridge carbon could be replaced with an alkyl group to fill out the unoccupied space. Based on this design, we synthesized five pyrrolo[2,3-d]pyrimidine derivatives with one-carbon bridge and evaluated their TS inhibitory activities. All synthesized compounds inhibited TS more potently than compound 2 (LY231514), and the C8-ethyl analogue (7) showed a remarkable inhibitory activity against TS (IC50=0.017 microM).


Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Thymidylate Synthase/antagonists & inhibitors , Amino Acid Sequence , Animals , Drug Design , Humans , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Models, Molecular , Molecular Sequence Data , Spectrophotometry, Infrared
2.
Chem Pharm Bull (Tokyo) ; 48(9): 1270-80, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10993224

ABSTRACT

The glutamic acid moiety of N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-g lutamic acid (1b, TNP-351) and the related compound (1a), was replaced with various N(omega)-acyl-, sulfonyl-, carbamoyl- and aryl-2,omega-diaminoalkanoic acids, and the inhibitory effects of the resulting products (9, 11, 14, 18, 21, 23, 25, 30, 36) on dihydrofolate reductase (DHFR), the growth of murine fibrosarcoma Meth A cells, and methotrexate-resistant human CCRF-CEM cells, were examined. Compounds (9a-f) acylated with a hemiphthaloyl group were efficiently synthesized by coupling pyrrolo[2,3-d]pyrimidine carboxylic acids (7a,b) and N(omega)-phthaloyl 2,omega-diaminoalkanoic acid methyl esters (6a-c) and subsequent hydrolysis. The other N(omega)-acyl- and sulfonyl-ornithine analogs (21, 23, 25) were synthesized by acylation of free amino intermediates (19a,b) derived from tert-butoxycarbonyl-ornithine analogs (17a,b). A free ornithine analog (18) did not strongly inhibit Meth A cell growth, whereas all N(omega)-acyl-, sulfonyl-, carbamoyl- and aryl-ornithine analogs (9, 11, 21, 23, 25, 30, 36) exhibited much more potent inhibitory activities against both DHFR and Meth A cell growth. In particular, compounds 9c, 21k and 36a also showed remarkable growth-inhibitory activities against methotrexate-resistant CCRF-CEM cells. These results demonstrate that the potent inhibitory activities of N(omega)-masked ornithine analogs against the growth of Meth A cells and methotrexate-resistant CCRF-CEM cells, results from effective uptake via reduced folate carrier and their potent DHFR inhibition.


Subject(s)
Folic Acid Antagonists/chemical synthesis , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , Cell Division/drug effects , Drug Resistance, Neoplasm , Folic Acid Antagonists/pharmacology , Humans , Magnetic Resonance Spectroscopy , Methotrexate/pharmacology , Pyrimidines/pharmacology , Pyrroles/pharmacology , Spectrophotometry, Infrared , Tetrahydrofolate Dehydrogenase/metabolism , Tumor Cells, Cultured
3.
Jpn J Cancer Res ; 88(3): 306-15, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9140116

ABSTRACT

The antitumor activity of recombinant human interleukin 2 (rIL-2) in combination with 5'-deoxy-5-fluorouridine (doxifluridine; 5'-DFUR) against marine colon carcinoma 26 (Colon 26) was studied. BALB/c mice were treated daily for 15 days with 5'-DFUR, rIL-2 or both, beginning on day 7 after subcutaneous transplantation of Colon 26. While mice treated with 5'-DFUR or rIL-2 alone died of tumor growth with pulmonary metastases within 9 weeks posttransplantation, the survival time was significantly prolonged in mice treated with both 5'-DFUR and rIL-2. Most of the combination-treated animals showed the regression of local tumors and the inhibition of pulmonary metastasis. Histopathologically, many tumor cells were degenerated and necrotized, with marked infiltration of mononuclear cells including large granular lymphocytes (LGLs) with periodic acid-Schiff-positive cytoplasmic granules. The cells were positive for CD3 epsilon, asialo GM1 and NK1.1. Spleen cells from the combination-treated mice showed high activities of natural killer (NK) cytotoxicity as well as growth inhibition of Colon 26 and Meth A fibrosarcoma in mice. The results suggest that the combination therapy of 5'-DFUR plus rIL-2 enhanced non-specific cytotoxicity of LGL/NK cells for Colon 26 in tumor-bearing mice and was effective in the inhibition of tumor growth.


Subject(s)
Antineoplastic Agents/therapeutic use , Colonic Neoplasms/therapy , Floxuridine/therapeutic use , Interleukin-2/therapeutic use , Animals , Cell Division/drug effects , Cell Line , Colonic Neoplasms/pathology , Drug Therapy, Combination , Female , Humans , Isomerism , Mice , Mice, Inbred BALB C , Recombinant Proteins/therapeutic use
4.
Chem Pharm Bull (Tokyo) ; 44(8): 1498-509, 1996 Aug.
Article in English | MEDLINE | ID: mdl-8795269

ABSTRACT

The glutamic acid moiety of N-[4-[3-(2,4-diamino-7H-pyrrolo[2, 3-d]pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid (1b, TNP-351) and related compounds was replaced with some N5-substituted glutamines. Antifolates (4A-S) were effectively prepared by coupling pyrrolo[2,3-d]pyrimidine carboxylic acids (11a, b) with some properly protected N5-substituted glutamine derivatives (10A-S), which were prepared by coupling Boc-Glu-OMe (7) with various amines (8A-S) using a suitable condensing reagent, followed by hydrolysis. The inhibitory effects of the resulting products on dihydrofolate reductase (DHFR), thymidylate synthetase (TS) and the growth of murine fibrosarcoma Meth A cells in culture were examined. All N5-substituted glutamine analogs (4A-S) inhibited DHFR much more strongly than TNP-351 and some analogs exhibited the same potent growth inhibition of Meth A cells as TNP-351. Some typical analogs (4Bb, 4Db, 4F, 4Oa) were also examined for inhibitory effects on the growth of methotrexate (MTX)-resistant human CCRF-CEM cells in culture and for in vivo antitumor activities against murine leukemia and solid tumors. MTX-resistant cells, with a defect in transport and decreased polyglutamylation activity, showed little cross resistance to the analog (4Oa) having a tetrazole moiety as a substituent of glutamine, which exhibited potent antitumor activities. These results demonstrate that the antifolate analogs (4) with N5-substituted glutamine in place of glutamic acid are novel potent DHFR inhibitors with activity against MTX-resistant tumors. The potent antitumor activity of these analogs (4) may result from their effective uptake via reduced folate carrier in combination with their potent inhibition of DHFR.


Subject(s)
Folic Acid Antagonists/chemical synthesis , Pyrimidines/chemical synthesis , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cells, Cultured , Drug Resistance , Drug Screening Assays, Antitumor , Folic Acid Antagonists/pharmacology , Humans , Methotrexate/pharmacology , Mice , Mice, Inbred BALB C , Pyrimidines/pharmacology , Structure-Activity Relationship , Thymidylate Synthase/antagonists & inhibitors , Tumor Cells, Cultured
5.
Chem Pharm Bull (Tokyo) ; 43(2): 230-5, 1995 Feb.
Article in English | MEDLINE | ID: mdl-7728929

ABSTRACT

Either the alpha- or gamma-carboxyl group of the glutamic acid moiety of N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5- yl)propyl]benzoyl]-L-glutamic acid (1b, TNP-351) and its related compound (1a) was replaced with a 1H-tetrazole ring, and the inhibitory effects of the resulting compounds on dihydrofolate reductase (DHFR) and the growth of murine fibrosarcoma Meth A cells were examined. The gamma-tetrazole analogs (2) were found to be much more potent DHFR inhibitors than TNP-351, and strongly inhibited the growth of Meth A cells. On the other hand, the alpha-tetrazole analogs (3) were much less active against Meth A cells, even though their DHFR-inhibitory activity was comparable to that of TNP-351. These findings suggest that the alpha-carboxyl group plays an important role in effective uptake via the reduced folate carrier, and a novel DHFR inhibitor could be obtained by chemically modifying the gamma-carboxyl moiety while leaving the alpha-carboxyl group intact.


Subject(s)
Antineoplastic Agents/pharmacology , Folic Acid Antagonists/pharmacology , Glutamic Acid/chemistry , Methotrexate/analogs & derivatives , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Cell Division/drug effects , Fibrosarcoma/pathology , Folic Acid Antagonists/chemistry , Folic Acid Antagonists/metabolism , Magnetic Resonance Spectroscopy , Methotrexate/chemistry , Methotrexate/metabolism , Methotrexate/pharmacology , Mice , Structure-Activity Relationship , Tetrazoles/chemistry , Tumor Cells, Cultured
6.
Chem Pharm Bull (Tokyo) ; 43(2): 256-61, 1995 Feb.
Article in English | MEDLINE | ID: mdl-7728932

ABSTRACT

Novel pyrrolo[2,3-d]pyrimidine antifolates (1a, b and 2a, b) with a nitrogen atom in the bridge chain between the 2,4-diaminopyrrolo[2,3-d]pyrimidine and phenylene rings were designed and efficiently synthesized. These compounds exhibited more potent inhibitory activities than methotrexate (MTX) against the proliferation of human epidermoid carcinoma KB cells and human non-small cell lung carcinoma A549 cells despite their modest dihydrofolate reductase (DHFR)-inhibitory potency.


Subject(s)
Antineoplastic Agents/chemical synthesis , Folic Acid Antagonists/chemical synthesis , Pyrimidines/chemistry , Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/pathology , Cell Division/drug effects , Folic Acid Antagonists/pharmacology , Humans , Lung Neoplasms/pathology , Magnetic Resonance Spectroscopy , Methotrexate/analogs & derivatives , Methotrexate/chemistry , Microcomputers , Nitrogen , Pyrimidines/pharmacology , Structure-Activity Relationship , Tumor Cells, Cultured
7.
Biol Pharm Bull ; 17(8): 1101-5, 1994 Aug.
Article in English | MEDLINE | ID: mdl-7820116

ABSTRACT

We have investigated the biological properties of an immune complex composed of recombinant interleukin-2 (rIL-2) and an F(ab')2 fragment of a monoclonal antibody against rIL-2 in mice for the induction of killer cells and anti-tumor activity, as well as the pharmacokinetic properties of the immune complex injected subcutaneously into mice. The immune complex demonstrated sustained serum rIL-2 levels, with a 2.4-times longer "mean-residence-time" than free rIL-2. A more significant portion of rIL-2 was detected in lymph nodes after the subcutaneous injection of the immune complex than with rIL-2 alone. Splenic lymphocytes from mice given the immune complex showed higher killer cell activity against YAC-1 and P815 cells than those from mice given rIL-2 alone. The immune complex also exerted a more significant anti-tumor effect in a dose-dependent manner in Meth-A fibrosarcoma-bearing mice than dit rIL-2 alone.


Subject(s)
Antibodies, Monoclonal/immunology , Antineoplastic Agents/pharmacology , Immunoglobulin Fab Fragments/pharmacology , Interleukin-2/pharmacology , Animals , Cell Division/drug effects , Cell Survival/drug effects , Enzyme-Linked Immunosorbent Assay , Female , Fibrosarcoma/drug therapy , Immunoglobulin G/immunology , Killer Cells, Lymphokine-Activated/drug effects , Mice , Mice, Inbred BALB C , Recombinant Proteins/pharmacology , Tumor Cells, Cultured
8.
Biotherapy ; 6(3): 225-31, 1993.
Article in English | MEDLINE | ID: mdl-8292462

ABSTRACT

We have investigated biological properties of an immune complex of recombinant interleukin-2 (rIL-2) and a monoclonal antibody against rIL-2 in mice for induction of killer cells and for anti-tumor activity. We have also examined the clearance of subcutaneously-injected immune complex in mice and compared it with that of rIL-2 alone. Plasma rIL-2 levels were sustained longer in mice given the immune complex than in mice given rIL-2 alone at a dose of 10 micrograms/mouse, and they were detectable even at 24 hours after the administration of the immune complex, while they fell to undetectable levels by 6 hours after the administration of rIL-2 alone. A more significant portion of rIL-2 was detected in lymph nodes after subcutaneous injection of the immune complex than that of rIL-2 alone. Splenic lymphocytes from mice given the immune complex demonstrated a higher killer cell activity against YAC-1 cells than those from mice given rIL-2 alone. The immune complex also exerted more significant anti-tumor effect in a dose-dependent manner in Meth-A fibrosarcoma-bearing mice than rIL-2 alone. Our results indicate that immunocomplexing of rIL-2 with an antibody against rIL-2 provides a useful tool as the drug delivery system for cancer therapy using rIL-2.


Subject(s)
Antibodies, Monoclonal/pharmacology , Antigen-Antibody Complex/immunology , Antineoplastic Agents/pharmacology , Interleukin-2/pharmacology , Animals , Antibodies, Monoclonal/immunology , Antineoplastic Agents/immunology , Antineoplastic Agents/pharmacokinetics , Female , Immunotoxins/pharmacology , Interleukin-2/immunology , Interleukin-2/pharmacokinetics , Mice , Recombinant Proteins , Tumor Cells, Cultured
9.
Jpn J Cancer Res ; 82(8): 950-7, 1991 Aug.
Article in English | MEDLINE | ID: mdl-1910031

ABSTRACT

The antitumor effect of recombinant human interleukin-2 (rIL-2) on murine hemangioendothelioma D14 (D14) in female BALB/c-nu/nu mice was examined histologically. D14 cells which had been maintained in vitro were transplanted subcutaneously into nude mice on day 0 (1 x 10(7) cells/mouse). The mice with established tumor on day 28 received rIL-2 subcutaneously at a dose of 20 micrograms/mouse/day for 35 days. On day 63, the mice were killed, and the tumor, spleen and bone marrow were examined histologically. In the mice that had received rIL-2, tumor growth was significantly suppressed. Histologically, there was marked infiltration of large granular cells (about 15-30 microns in diameter) in the tumors. In the adjacent areas, there was a significant increase in the number of tumor cells showing karyorrhexis. The large granular cells (LGC) contained periodic acid Schiff-positive round granules in the cytoplasm and were stained positively for Thy-1.2 surface antigen. The LGC were also positive for asialo GM1 surface antigen but not for Lyt-1, Lyt-2 or IgG surface antigens. This evidence suggests that the LGC are lymphokine-activated killer-like cells which were derived from a natural killer cell lineage. The concomitant increases in the number of LGC and the number of cells showing karyorrhexis in the tumors of the mice treated with rIL-2 suggest that LGC play an important role in the destruction of tumor cells.


Subject(s)
Antineoplastic Agents/therapeutic use , Hemangioendothelioma/therapy , Interleukin-2/therapeutic use , Animals , Bone Marrow/pathology , Female , Hemangioendothelioma/immunology , Hemangioendothelioma/pathology , Immunohistochemistry , Killer Cells, Lymphokine-Activated/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Transplantation , Recombinant Proteins/therapeutic use , Spleen/pathology
10.
J Pharmacol Exp Ther ; 257(3): 1203-7, 1991 Jun.
Article in English | MEDLINE | ID: mdl-2046024

ABSTRACT

The antitumor effect of cisplatin-(CDDP)-encapsulated thermosensitive large unilamellar liposome (ThLip) administration with hyperthermia (HT) was examined in mice bearing Meth A fibrosarcoma. The tumor Pt levels after ThLip administration were increased in response to HT. The targeting index was approximately 3. The antitumor activity of ThLip + HT, as measured by tumor growth delay or tumor weight inhibition, was larger than that of ThLip without HT or a solution with or without HT. The CDDP dose in ThLip + HT to give equivalent tumor growth delay in solution (40 micrograms/mouse) + HT was about 10 micrograms/mouse, and therefore the targeted drug delivery enhancement ratio was about 4. The ratio correlates with the targeting index. The blood urea nitrogen level, as an indicator of CDDP nephrotoxicity, was increased 7 days after the administration of ThLip (40 micrograms CDDP/mouse) with HT. However, this blood urea nitrogen level rise was independent of the activity enhancement by the liposome. These findings suggest that the HT combined CDDP delivery system using ThLip can decrease the effective CDDP dose, thereby increasing its therapeutic index.


Subject(s)
Cisplatin/administration & dosage , Hyperthermia, Induced , Animals , Cisplatin/pharmacokinetics , Combined Modality Therapy , Dose-Response Relationship, Drug , Drug Carriers , Female , Fibrosarcoma/metabolism , Fibrosarcoma/therapy , Hot Temperature , Liposomes , Mice , Mice, Inbred BALB C , Neoplasm Transplantation , Platinum/pharmacokinetics , Tissue Distribution
11.
Jpn J Cancer Res ; 80(9): 895-903, 1989 Sep.
Article in English | MEDLINE | ID: mdl-2513305

ABSTRACT

The antitumor effects of recombinant human interleukin-2 (rIL-2), in combination with recombinant human interferon-alpha A/D hybrid (rIFN-alpha A/D) on colon carcinoma 26 (colon 26) in mice were examined histologically. Colon 26 was transplanted subcutaneously into female BALB/c mice on day 0. The mice bearing the tumor received intramuscular injections of rIL-2, rIFN-alpha A/D or the combination of rIL-2 and rIFN-alpha A/D for 2-10 consecutive days starting on day 7. Mice were killed on days 9, 13, 17 and 21. After day 13, growth of the tumor was significantly suppressed in the mice treated with rIL-2 or rIFN-alpha A/D alone and was stopped in the mice treated with rIL-2 in combination with rIFN-alpha A/D. Histologically, tumor necrosis developed in all treated groups, though the degree was the most severe in the group receiving combination treatment. Many large cells (about 15-30 microns in diameter) infiltrated into the tumor, and they had Thy-1 surface antigen and many periodic acid-Schiff-positive round granules in the cytoplasm. The incidence of these large granular cells was correlated well with the reduction in tumor weight. The ultrastructural features of the large granular cells were very similar to those of murine large granular lymphocyte-like cells maintained in vitro in an IL-2-containing medium. The present large granular cells appear to be a kind of activated lymphoid cells.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colonic Neoplasms/drug therapy , Animals , Cell Line , Colonic Neoplasms/pathology , Colonic Neoplasms/ultrastructure , Female , Immunohistochemistry , Interferon Type I/administration & dosage , Interferon Type I/therapeutic use , Interleukin-2/administration & dosage , Interleukin-2/therapeutic use , Mice , Mice, Inbred BALB C , Microscopy, Electron , Necrosis/pathology , Recombinant Proteins/therapeutic use
12.
Clin Exp Immunol ; 76(2): 278-83, 1989 May.
Article in English | MEDLINE | ID: mdl-2788049

ABSTRACT

When Meth-A fibrosarcoma-bearing BALB/c mice were injected subcutaneously with 10 micrograms of recombinant human interleukin 2(rIL-2) once a day for 10 days, tumour growth inhibition was in the range of 22-31% of that of the control animals. Anti-tumour effector cells against Meth-A were detected in the spleen cells of the tumour-bearing BALB/c mice injected with rIL-2, using a modified Winn-type neutralization assay with the auxiliary injection of rIL-2. To induce the strongest anti-tumour activity in this assay system, the following were necessary: 1) the effector cells were derived from tumour-bearing BALB/c mice; 2) the donors of the effector cells were injected with rIL-2; 3) the recipient mice in the Winn assay were auxiliarily injected with rIL-2 (a modified Winn assay). The anti-tumour effector activity detected in the modified Winn assay was inhibited by treatment with anti-CD8 or anti-asialo GM1 antibodies plus complement (C), but not completely. We supposed that at least two kinds of anti-Meth-A effector cells with different surface antigens, positive for CD8 and asialo GM1 antigens, were induced in the Meth-A-bearing BALB/c mice injected with rIL-2; these populations seemed to function independently and at least partly as anti-tumour effector cells in this tumour-host system. These spleen cells showed in vitro cytotoxicity against Meth-A cells, which are resistant to NK cells, if the activity was measured in a 24 h 51Cr-release assay in the presence of rIL-2.


Subject(s)
Fibrosarcoma/immunology , Interleukin-2/pharmacology , Killer Cells, Natural/immunology , Animals , Female , Fibrosarcoma/chemically induced , Killer Cells, Natural/drug effects , Methylcholanthrene , Mice , Mice, Inbred BALB C , Recombinant Proteins/pharmacology
13.
Cancer Immunol Immunother ; 30(2): 71-80, 1989.
Article in English | MEDLINE | ID: mdl-2598180

ABSTRACT

The potential for a recombinant human interleukin-2 (rIL-2, TGP-3) alone, in combination with cyclophosphamide, and in combination with cyclophosphamide and normal immunocompetent cells to manifest biological activity in vivo was tested using allogeneic, semi-syngeneic, and syngeneic tumor-host systems in mice. The biological activity of rIL-2 was evaluated by the inhibition of the growth of tumors and the inhibition of metastases in short-term assays and, in long-term assays, the prolongation of the survival time of mice bearing subcutaneously (s.c.) or intradermally transplanted tumors. rIL-2 was injected s.c. daily continuously for up to 40 days or intermittently two to four times into mice bearing established tumors. In the short-term assays, the dose and schedule dependence of activity of rIL-2 alone was significantly manifested against sarcoma 180 in ICR mice (allogeneic) by the regression of the tumor, and was confirmed against Meth-A fibrosarcoma in BALB/c mice (syngeneic) by retarding the growth of the tumor. When assessed using these tumor, it was found that the antitumor activity of rIL-2 was schedule-dependent: the growth of tumors was more significantly suppressed when rIL-2 was injected every day for 10 days, starting on the 7th day after tumor transplantation, than when rIL-2 was injected five times every other day or twice every 5th day, even if the total amounts of rIL-2 injected were same. The continuous injection for 10 days was considered to be a standard regimen and the daily effective doses of rIL-2 were 5, 10, and 25 micrograms/mouse. Using the standard regimen and the effective doses, the activity of rIL-2 alone was also observed against two other syngeneic tumors: Colon carcinoma 26 in BALB/c mice, by retarding the growth of the tumor, and Lewis lung carcinoma in C57BL/6 mice by reducing the formation of lung metastases. When assessed using M5076 reticulum cell sarcoma, in a long-term assay, the activity of rIL-2 alone was not manifested in C57BL/6 mice (syngeneic) even when rIL-2 was injected for a long period (20 days) but it was observed in BDF1 (semi-syngeneic) mice. On the other hand, it was found that rIL-2 was effective in combination with cyclophosphamide in prolonging the survival time of C57BL/6 mice bearing the tumor.(ABSTRACT TRUNCATED AT 400 WORDS)


Subject(s)
Cyclophosphamide/therapeutic use , Interleukin-2/therapeutic use , Lymphocyte Transfusion , Neoplasms, Experimental/therapy , Animals , Combined Modality Therapy , Female , Immunotherapy , Lymphocytes/immunology , Mice , Mice, Inbred Strains , Recombinant Proteins/therapeutic use
14.
Gan To Kagaku Ryoho ; 14(8): 2502-8, 1987 Aug.
Article in Japanese | MEDLINE | ID: mdl-3304169

ABSTRACT

The effects of recombinant human interferon-alpha A/D (rIFN-alpha A/D, a subtype of recombinant human leukocyte interferon with biological activities against murine tumor cells) on the growth of murine tumors were studied. rIFN-alpha A/D significantly inhibited the growth of mouse M5076 reticulum cell sarcoma, MOPC-104E myeloma, colon carcinoma 26 and Meth A fibrosarcoma by dose-dependent fashion. rIFN-alpha A/D also inhibited the metastases and growth of Lewis lung carcinoma and showed a synergistic effect with combination of cyclophosphamide. The antitumor activity of rIFN-alpha A/D was observed by intra-muscular, intravenous, subcutaneous, intraperitoneal injections or by the injection at the site of the tumors.


Subject(s)
Interferon Type I/therapeutic use , Neoplasms, Experimental/therapy , Animals , Female , Fibrosarcoma/therapy , Lymphoma, Large B-Cell, Diffuse/therapy , Mice , Mice, Inbred Strains , Neoplasms, Experimental/pathology , Recombinant Proteins/therapeutic use
15.
Immunology ; 60(2): 173-9, 1987 Feb.
Article in English | MEDLINE | ID: mdl-3493209

ABSTRACT

Recombinant human interleukin-2 (rIL-2) suppressed metastatic tumour colony formation in the lungs of C57BL/6 mice bearing Lewis lung carcinoma (3LL). In tumour-bearing mice given rIL-2, non-specific killer cells that were cytotoxic not only against natural killer-sensitive YAC-1 cells but also against 3LL cells in an in vitro 51Cr-release assay were concomitantly induced as tumour metastasis was suppressed. These non-specific killer cells were mostly removed by treatment with anti-Thy 1.2 or anti-asialo GM1 antibody plus complement (C) in vitro but not with anti-Lyt 1.2 or anti-Lyt 2.2 plus C, indicating that they were positive for Thy 1 and asialo GM1 but not for Lyt 1 and Lyt 2. In order to explore the mechanism by which rIL-2 suppressed tumour metastasis, we examined the clearance of intravenously injected 51Cr-labelled 3LL cells in the lungs of mice given rIL-2. The rate of tumour cell clearance was increased. This enhanced clearance was almost completely removed by injecting anti-asialo GM1 antibody. In addition, the injection of anti-asialo GM1 antibody also depleted most of the non-specific killer cells induced by administering rIL-2. These results indicate that asialo GM1-positive cells are not only cytotoxic in vitro but also play a critical role in the clearance of 3LL cells in the lungs in vivo. Our results indicate that asialo GM1-positive cells play an important role as anti-metastatic effector cells in suppressing the metastasis of 3LL cells in mice given rIL-2.


Subject(s)
G(M1) Ganglioside , Interleukin-2/therapeutic use , Killer Cells, Natural/immunology , Lung Neoplasms/secondary , Animals , Antigens, Surface/analysis , Female , Glycosphingolipids/immunology , Lung Neoplasms/pathology , Lung Neoplasms/prevention & control , Mice , Mice, Inbred C57BL , Recombinant Proteins/therapeutic use , Spleen/immunology
18.
Gan ; 73(6): 938-44, 1982 Dec.
Article in English | MEDLINE | ID: mdl-6186564

ABSTRACT

Macbecin I showed marked antitumor activity against intraperitoneally (ip) inoculated leukemia P388, melanoma B16, and Ehrlich carcinoma in mice on ip administration. The maximum effect measured in terms of ILS% (increase of life span) was 97 at a daily dose level of 10 mg/kg for leukemia P388, 103 at 5 mg/kg for melanoma B16, and 206 at 10 mg/kg for Ehrlich carcinoma. The effect of macbecin I on leukemia L1210 was slight (39 ILS%) and no activity was observed against leukemia L5178Y or P388/P-3 (a line of P388 resistant to ansamitocin P-3), or MOPC-104E myloma. Three to six hours after administration of 0.5 mg/kg or more of macbecin I to mice bearing ascites leukemia P388 cells, typical karyorrhexis followed by cytolysis in P388 cells was observed. Cytocidal changes induced by macbecin I were also observed in cells which were temporarily prevented from entering mitosis by treatment with known antitumor agents such as 5-fluorouracil, cyclophosphamide, and neocarzinostatin, whereas such cytolysis was not observed in cells which were arrested in metaphase by treatment with ansamitocin P-3. Cytotoxicity of macbecin I to cultured KB cells was observed at doses of 10(-1) micrograms/ml and more. Reverse transcriptase and terminal deoxynucleotidyl transferase activities were not inhibited by macbecin I.


Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Neoplasms, Experimental/drug therapy , Animals , Benzoquinones , Cell Line , Cell Survival/drug effects , Chromomycin A3/therapeutic use , DNA Nucleotidylexotransferase/metabolism , Female , Lactams, Macrocyclic , Maytansine/analogs & derivatives , Maytansine/therapeutic use , Mice , Mice, Inbred Strains , Mitomycin , Mitomycins/therapeutic use , Neoplasm Transplantation , Neoplasms, Experimental/pathology , Prognosis , Quinones/therapeutic use , RNA-Directed DNA Polymerase/metabolism
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