The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Giuseppe Rainaldi - One of the best experts on this subject based on the ideXlab platform.
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The Sensitivity of MCF10A Breast Epithelial Cells to Alkylating Drugs is Enhanced by the Inhibition of O^6-Methylguanine-DNA Methyltransferase Transcription with a Synthetic Double Strand DNA Oligonucleotide
Breast Cancer Research and Treatment, 2002Co-Authors: Laura Mariani, Lorenzo Citti, Antonella Piccirilli, Maria Giovanna Colombo, Laura Poliseno, Giuseppe RainaldiAbstract:Cytoxicity of alkylating chemotherapeutic drugs is affected by the cellular content of the enzyme O^6-methylguanine-DNA methyl transferase (MGMT). Since high levels of the enzyme confer the efficient repair of DNA alkylation, the chemotherapeutic potential of alkylating chemicals can be maintained either increasing drug dosage or reducing the amount of endogenous MGMT. This study strives to the latter end by competing away a transcriptional activator of the MGMT gene from its native enhancer sequence using a synthetic double strand DNA oligonucleotide (MEBP-ODN). MEBP-ODN was administered in culture medium to MCF10A human breast ep-ithelial cells expressing high level of MGMT. Reverse transcription-polymerase chain reaction and western blotting analyses showed decrease in both MGMT mRNA and protein content. Concomitantly, MEBP-ODN exposed cells were more sensitive to the alkylating drug Mitozolomide than their controls, which were not exposed to MEBP- ODN. These results indicate that the cis -acting MEBP-ODN can efficiently deplete MGMT protein by working as decoy binding site for the transcriptional activator MEBP. This approach represents a successful strategy to counteract the protective role of MGMT repair enzyme during an alkylating drug based chemotherapeutic regimen.
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The sensitivity of MCF10A breast epithelial cells to alkylating drugs is enhanced by the inhibition of O6-methylguanine-DNA methyltransferase transcription with a synthetic double strand DNA oligonucleotide.
Breast cancer research and treatment, 2002Co-Authors: Laura Mariani, Lorenzo Citti, Antonella Piccirilli, Maria Giovanna Colombo, Laura Poliseno, Giuseppe RainaldiAbstract:Cytoxicity of alkylating chemotherapeutic drugs is affected by the cellular content of the enzyme O6-methylguanine-DNA methyl transferase (MGMT). Since high levels of the enzyme confer the efficient repair of DNA alkylation, the chemotherapeutic potential of alkylating chemicals can be maintained either increasing drug dosage or reducing the amount of endogenous MGMT. This study strives to the latter end by competing away a transcriptional activator of the MGMT gene from its native enhancer sequence using a synthetic double strand DNA oligonucleotide (MEBP-ODN). MEBP-ODN was administered in culture medium to MCF10A human breast ep-ithelial cells expressing high level of MGMT. Reverse transcription-polymerase chain reaction and western blotting analyses showed decrease in both MGMT mRNA and protein content. Concomitantly, MEBP-ODN exposed cells were more sensitive to the alkylating drug Mitozolomide than their controls, which were not exposed to MEBP- ODN. These results indicate that the cis-acting MEBP-ODN can efficiently deplete MGMT protein by working as decoy binding site for the transcriptional activator MEBP. This approach represents a successful strategy to counteract the protective role of MGMT repair enzyme during an alkylating drug based chemotherapeutic regimen.
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Ribozyme and free alkylated base: a dual approach for sensitizing Mex^+ cells to the alkylating antineoplastic drug
Cancer Gene Therapy, 2000Co-Authors: Laura Mariani, Lorenzo Citti, Silvio Nevischi, Fritz Eckstein, Giuseppe RainaldiAbstract:N -alkyl-nitrosoureas and alkyl-triazenes are alkylating antineoplastic drugs, the efficacy of which is strongly affected by the level of expression of the DNA-repair enzyme O^6-methylguanine-DNA methyltransferase (MGMT). In tumors, MGMT activity reduces the chemotherapeutic potential of alkylating drugs; therefore, efforts have been made to down-regulate the protein. A partial sensitization of Mex^+ cells to alkylating drugs has been obtained using either free alkylated bases or oligonucleotides targeted against MGMT mRNA. In the present work, O^6-methylguanine and a chemically modified ribozyme, without a cationic liposome as a carrier, were coadministered to CHO47 cells, which express a high level of human MGMT protein. The reduction of MGMT mRNA and protein enhanced the genotoxicity of the alkylating drug Mitozolomide. Furthermore, the sensitivity of CHO47 cells is the same as that of CHO5 cells, which lack MGMT protein. These data indicate that a strategy in which both mRNA and protein are degradation targets can be successfully applied to down-regulate the MGMT gene.
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Transient transfection of a synthetic hammerhead ribozyme targeted against human MGMT gene to cells in culture potentiates the genotoxicity of the alkylation damage induced by Mitozolomide.
Antisense & nucleic acid drug development, 1999Co-Authors: Lorenzo Citti, Laura Mariani, Fritz Eckstein, B. Capecchi, S. Nevischi, A. Poggi, Giuseppe RainaldiAbstract:Unmodified and chemically modified forms of a synthetic hammerhead ribozyme with the mRNA of methylguanine-DNA methyltransferase (MGMT) gene as substrate were characterized for their in vitro and i...
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The sensitization of cells treated with O6-methylguanine to alkylation damage is affected by the number of O6-methylguanine-DNA methyltransferase molecules escaped from inactivation.
Mutation research, 1998Co-Authors: Lorenzo Citti, Laura Mariani, Barbara Capecchi, Antonio Piras, Rosanna Leuzzi, Giuseppe RainaldiAbstract:O6-Methylguanine (MeG) can bind to the active site of O6-methylguanine-DNA methyltransferase (MGMT) as a free base. The subsequent methyl transfer reaction inactivates the repair protein. Hence, MeG is used to deplete the active MGMT pools in Chinese hamster cell lines (CHO) transfected to express varying amounts of human MGMT. After treatment with the free base, a residual population of active protein molecules remains localized mostly in the cytoplasm. Depleted cells are then challenged with the alkylating drug Mitozolomide. Genotoxicity of this agent varied among the cell lines, and the compound sensitivity seemed to be regulated by a steady state equilibrium of residual MGMT molecules between nucleus and cytoplasm.
Laura Mariani - One of the best experts on this subject based on the ideXlab platform.
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The Sensitivity of MCF10A Breast Epithelial Cells to Alkylating Drugs is Enhanced by the Inhibition of O^6-Methylguanine-DNA Methyltransferase Transcription with a Synthetic Double Strand DNA Oligonucleotide
Breast Cancer Research and Treatment, 2002Co-Authors: Laura Mariani, Lorenzo Citti, Antonella Piccirilli, Maria Giovanna Colombo, Laura Poliseno, Giuseppe RainaldiAbstract:Cytoxicity of alkylating chemotherapeutic drugs is affected by the cellular content of the enzyme O^6-methylguanine-DNA methyl transferase (MGMT). Since high levels of the enzyme confer the efficient repair of DNA alkylation, the chemotherapeutic potential of alkylating chemicals can be maintained either increasing drug dosage or reducing the amount of endogenous MGMT. This study strives to the latter end by competing away a transcriptional activator of the MGMT gene from its native enhancer sequence using a synthetic double strand DNA oligonucleotide (MEBP-ODN). MEBP-ODN was administered in culture medium to MCF10A human breast ep-ithelial cells expressing high level of MGMT. Reverse transcription-polymerase chain reaction and western blotting analyses showed decrease in both MGMT mRNA and protein content. Concomitantly, MEBP-ODN exposed cells were more sensitive to the alkylating drug Mitozolomide than their controls, which were not exposed to MEBP- ODN. These results indicate that the cis -acting MEBP-ODN can efficiently deplete MGMT protein by working as decoy binding site for the transcriptional activator MEBP. This approach represents a successful strategy to counteract the protective role of MGMT repair enzyme during an alkylating drug based chemotherapeutic regimen.
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The sensitivity of MCF10A breast epithelial cells to alkylating drugs is enhanced by the inhibition of O6-methylguanine-DNA methyltransferase transcription with a synthetic double strand DNA oligonucleotide.
Breast cancer research and treatment, 2002Co-Authors: Laura Mariani, Lorenzo Citti, Antonella Piccirilli, Maria Giovanna Colombo, Laura Poliseno, Giuseppe RainaldiAbstract:Cytoxicity of alkylating chemotherapeutic drugs is affected by the cellular content of the enzyme O6-methylguanine-DNA methyl transferase (MGMT). Since high levels of the enzyme confer the efficient repair of DNA alkylation, the chemotherapeutic potential of alkylating chemicals can be maintained either increasing drug dosage or reducing the amount of endogenous MGMT. This study strives to the latter end by competing away a transcriptional activator of the MGMT gene from its native enhancer sequence using a synthetic double strand DNA oligonucleotide (MEBP-ODN). MEBP-ODN was administered in culture medium to MCF10A human breast ep-ithelial cells expressing high level of MGMT. Reverse transcription-polymerase chain reaction and western blotting analyses showed decrease in both MGMT mRNA and protein content. Concomitantly, MEBP-ODN exposed cells were more sensitive to the alkylating drug Mitozolomide than their controls, which were not exposed to MEBP- ODN. These results indicate that the cis-acting MEBP-ODN can efficiently deplete MGMT protein by working as decoy binding site for the transcriptional activator MEBP. This approach represents a successful strategy to counteract the protective role of MGMT repair enzyme during an alkylating drug based chemotherapeutic regimen.
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Ribozyme and free alkylated base: a dual approach for sensitizing Mex^+ cells to the alkylating antineoplastic drug
Cancer Gene Therapy, 2000Co-Authors: Laura Mariani, Lorenzo Citti, Silvio Nevischi, Fritz Eckstein, Giuseppe RainaldiAbstract:N -alkyl-nitrosoureas and alkyl-triazenes are alkylating antineoplastic drugs, the efficacy of which is strongly affected by the level of expression of the DNA-repair enzyme O^6-methylguanine-DNA methyltransferase (MGMT). In tumors, MGMT activity reduces the chemotherapeutic potential of alkylating drugs; therefore, efforts have been made to down-regulate the protein. A partial sensitization of Mex^+ cells to alkylating drugs has been obtained using either free alkylated bases or oligonucleotides targeted against MGMT mRNA. In the present work, O^6-methylguanine and a chemically modified ribozyme, without a cationic liposome as a carrier, were coadministered to CHO47 cells, which express a high level of human MGMT protein. The reduction of MGMT mRNA and protein enhanced the genotoxicity of the alkylating drug Mitozolomide. Furthermore, the sensitivity of CHO47 cells is the same as that of CHO5 cells, which lack MGMT protein. These data indicate that a strategy in which both mRNA and protein are degradation targets can be successfully applied to down-regulate the MGMT gene.
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Transient transfection of a synthetic hammerhead ribozyme targeted against human MGMT gene to cells in culture potentiates the genotoxicity of the alkylation damage induced by Mitozolomide.
Antisense & nucleic acid drug development, 1999Co-Authors: Lorenzo Citti, Laura Mariani, Fritz Eckstein, B. Capecchi, S. Nevischi, A. Poggi, Giuseppe RainaldiAbstract:Unmodified and chemically modified forms of a synthetic hammerhead ribozyme with the mRNA of methylguanine-DNA methyltransferase (MGMT) gene as substrate were characterized for their in vitro and i...
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The sensitization of cells treated with O6-methylguanine to alkylation damage is affected by the number of O6-methylguanine-DNA methyltransferase molecules escaped from inactivation.
Mutation research, 1998Co-Authors: Lorenzo Citti, Laura Mariani, Barbara Capecchi, Antonio Piras, Rosanna Leuzzi, Giuseppe RainaldiAbstract:O6-Methylguanine (MeG) can bind to the active site of O6-methylguanine-DNA methyltransferase (MGMT) as a free base. The subsequent methyl transfer reaction inactivates the repair protein. Hence, MeG is used to deplete the active MGMT pools in Chinese hamster cell lines (CHO) transfected to express varying amounts of human MGMT. After treatment with the free base, a residual population of active protein molecules remains localized mostly in the cytoplasm. Depleted cells are then challenged with the alkylating drug Mitozolomide. Genotoxicity of this agent varied among the cell lines, and the compound sensitivity seemed to be regulated by a steady state equilibrium of residual MGMT molecules between nucleus and cytoplasm.
Zbigniew Zylicz - One of the best experts on this subject based on the ideXlab platform.
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In vitro and in vivo anticancer activity of Mitozolomide and sparsomycin in human tumor xenografts, murine tumors and human bone marrow
Journal of Cancer Research and Clinical Oncology, 1990Co-Authors: Heinz H. Fiebig, D. P. Berger, Karin Köpping, Harry C. J. Ottenheijm, Zbigniew ZyliczAbstract:The colony formation in agar of human tumor xenografts, of murine tumors and of human bone marrow was used as a test system to determine the in vitro activity of the two novel cytostatic agents, Mitozolomide and sparsomycin. Mitozolomide was additionally studied in vivo in nine human tumor xenografts. The comparison of in vitro/in vivo activity allows an assessment of the relevant in vitro dose based on in vivo pharmacological behavior of a compound. Both compounds showed clear dose/response effects in vitro. A dose of 3 μg/ml Mitozolomide, given by continuous exposure, was active (colony number of test
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In vitro and in vivo anticancer activity of Mitozolomide and sparsomycin in human tumor xenografts, murine tumors and human bone marrow.
Journal of cancer research and clinical oncology, 1990Co-Authors: Heinz H. Fiebig, D. P. Berger, Karin Köpping, Harry C. J. Ottenheijm, Zbigniew ZyliczAbstract:The colony formation in agar of human tumor xenografts, of murine tumors and of human bone marrow was used as a test system to determine the in vitro activity of the two novel cytostatic agents, mitozolamide and sparsomycin. Mitozolomide was additionally studied in vivo in nine human tumor xenografts. The comparison of in vitro/in vivo activity allows an assessment of the relevant in vitro dose based on in vivo pharmacological behavior of a compound. Both compounds showed clear dose/response effects in vitro. A dose of 3 micrograms/ml Mitozolomide, given by continuous exposure, was active (colony number of test less than 30% of the control group) in 12/42 (29%) human tumor xenografts as well as in the four murine tumors, P388, L1210, B16 melanoma and colon carcinoma 38, whereas the two human bone marrows showed no significant suppression of the ability to form colonies in culture. The comparison of in vitro with in vivo activity suggests that the in vitro dose of 3 micrograms/ml corresponds best to the activity observed in animal experiments. The highest activity was observed in small-cell cancer of the lung (4/5), followed by melanomas (2/7) and non-small-cell cancer of the lung (2/9). Furthermore, activity was found in a cancer of the large bowel, stomach, breast and in one sarcoma. In the treatment of nine human tumor xenografts growing subcutaneously in nude mice, Mitozolomide effected a complete or partial remission in 6 out of 9 tumors. In comparison to standard drugs Mitozolomide is one of the most effective compounds in these tumors. These data indicate that Mitozolomide possesses potent broad-spectrum activity in human tumor xenografts. Sparsomycin (0.1 micrograms/ml, continuous exposure) was active in 11/46 (24%) human tumor xenografts and in 4/5 of the murine tumors, whereas the colony-forming capacity of four human bone-marrows showed no inhibition, suggesting that this dose level may be the relevant in vitro dose. However, the high in vitro activity in murine tumors is incompatible with the in vivo activity. In mice the only responsive tumor was leukemia P388, whereas the L1210, B16 melanoma and colon carcinoma 38 were resistant. At the dose level of 0.03 microgram/ml only 3/30 (10%) of the human tumor xenografts were sensitive. In an earlier clinical phase I study the dose-limiting adverse effect was eye toxicity and not bone-marrow suppression.(ABSTRACT TRUNCATED AT 400 WORDS)
Lorenzo Citti - One of the best experts on this subject based on the ideXlab platform.
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The Sensitivity of MCF10A Breast Epithelial Cells to Alkylating Drugs is Enhanced by the Inhibition of O^6-Methylguanine-DNA Methyltransferase Transcription with a Synthetic Double Strand DNA Oligonucleotide
Breast Cancer Research and Treatment, 2002Co-Authors: Laura Mariani, Lorenzo Citti, Antonella Piccirilli, Maria Giovanna Colombo, Laura Poliseno, Giuseppe RainaldiAbstract:Cytoxicity of alkylating chemotherapeutic drugs is affected by the cellular content of the enzyme O^6-methylguanine-DNA methyl transferase (MGMT). Since high levels of the enzyme confer the efficient repair of DNA alkylation, the chemotherapeutic potential of alkylating chemicals can be maintained either increasing drug dosage or reducing the amount of endogenous MGMT. This study strives to the latter end by competing away a transcriptional activator of the MGMT gene from its native enhancer sequence using a synthetic double strand DNA oligonucleotide (MEBP-ODN). MEBP-ODN was administered in culture medium to MCF10A human breast ep-ithelial cells expressing high level of MGMT. Reverse transcription-polymerase chain reaction and western blotting analyses showed decrease in both MGMT mRNA and protein content. Concomitantly, MEBP-ODN exposed cells were more sensitive to the alkylating drug Mitozolomide than their controls, which were not exposed to MEBP- ODN. These results indicate that the cis -acting MEBP-ODN can efficiently deplete MGMT protein by working as decoy binding site for the transcriptional activator MEBP. This approach represents a successful strategy to counteract the protective role of MGMT repair enzyme during an alkylating drug based chemotherapeutic regimen.
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The sensitivity of MCF10A breast epithelial cells to alkylating drugs is enhanced by the inhibition of O6-methylguanine-DNA methyltransferase transcription with a synthetic double strand DNA oligonucleotide.
Breast cancer research and treatment, 2002Co-Authors: Laura Mariani, Lorenzo Citti, Antonella Piccirilli, Maria Giovanna Colombo, Laura Poliseno, Giuseppe RainaldiAbstract:Cytoxicity of alkylating chemotherapeutic drugs is affected by the cellular content of the enzyme O6-methylguanine-DNA methyl transferase (MGMT). Since high levels of the enzyme confer the efficient repair of DNA alkylation, the chemotherapeutic potential of alkylating chemicals can be maintained either increasing drug dosage or reducing the amount of endogenous MGMT. This study strives to the latter end by competing away a transcriptional activator of the MGMT gene from its native enhancer sequence using a synthetic double strand DNA oligonucleotide (MEBP-ODN). MEBP-ODN was administered in culture medium to MCF10A human breast ep-ithelial cells expressing high level of MGMT. Reverse transcription-polymerase chain reaction and western blotting analyses showed decrease in both MGMT mRNA and protein content. Concomitantly, MEBP-ODN exposed cells were more sensitive to the alkylating drug Mitozolomide than their controls, which were not exposed to MEBP- ODN. These results indicate that the cis-acting MEBP-ODN can efficiently deplete MGMT protein by working as decoy binding site for the transcriptional activator MEBP. This approach represents a successful strategy to counteract the protective role of MGMT repair enzyme during an alkylating drug based chemotherapeutic regimen.
-
Ribozyme and free alkylated base: a dual approach for sensitizing Mex^+ cells to the alkylating antineoplastic drug
Cancer Gene Therapy, 2000Co-Authors: Laura Mariani, Lorenzo Citti, Silvio Nevischi, Fritz Eckstein, Giuseppe RainaldiAbstract:N -alkyl-nitrosoureas and alkyl-triazenes are alkylating antineoplastic drugs, the efficacy of which is strongly affected by the level of expression of the DNA-repair enzyme O^6-methylguanine-DNA methyltransferase (MGMT). In tumors, MGMT activity reduces the chemotherapeutic potential of alkylating drugs; therefore, efforts have been made to down-regulate the protein. A partial sensitization of Mex^+ cells to alkylating drugs has been obtained using either free alkylated bases or oligonucleotides targeted against MGMT mRNA. In the present work, O^6-methylguanine and a chemically modified ribozyme, without a cationic liposome as a carrier, were coadministered to CHO47 cells, which express a high level of human MGMT protein. The reduction of MGMT mRNA and protein enhanced the genotoxicity of the alkylating drug Mitozolomide. Furthermore, the sensitivity of CHO47 cells is the same as that of CHO5 cells, which lack MGMT protein. These data indicate that a strategy in which both mRNA and protein are degradation targets can be successfully applied to down-regulate the MGMT gene.
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Transient transfection of a synthetic hammerhead ribozyme targeted against human MGMT gene to cells in culture potentiates the genotoxicity of the alkylation damage induced by Mitozolomide.
Antisense & nucleic acid drug development, 1999Co-Authors: Lorenzo Citti, Laura Mariani, Fritz Eckstein, B. Capecchi, S. Nevischi, A. Poggi, Giuseppe RainaldiAbstract:Unmodified and chemically modified forms of a synthetic hammerhead ribozyme with the mRNA of methylguanine-DNA methyltransferase (MGMT) gene as substrate were characterized for their in vitro and i...
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The sensitization of cells treated with O6-methylguanine to alkylation damage is affected by the number of O6-methylguanine-DNA methyltransferase molecules escaped from inactivation.
Mutation research, 1998Co-Authors: Lorenzo Citti, Laura Mariani, Barbara Capecchi, Antonio Piras, Rosanna Leuzzi, Giuseppe RainaldiAbstract:O6-Methylguanine (MeG) can bind to the active site of O6-methylguanine-DNA methyltransferase (MGMT) as a free base. The subsequent methyl transfer reaction inactivates the repair protein. Hence, MeG is used to deplete the active MGMT pools in Chinese hamster cell lines (CHO) transfected to express varying amounts of human MGMT. After treatment with the free base, a residual population of active protein molecules remains localized mostly in the cytoplasm. Depleted cells are then challenged with the alkylating drug Mitozolomide. Genotoxicity of this agent varied among the cell lines, and the compound sensitivity seemed to be regulated by a steady state equilibrium of residual MGMT molecules between nucleus and cytoplasm.
Heinz H. Fiebig - One of the best experts on this subject based on the ideXlab platform.
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In vitro and in vivo anticancer activity of Mitozolomide and sparsomycin in human tumor xenografts, murine tumors and human bone marrow
Journal of Cancer Research and Clinical Oncology, 1990Co-Authors: Heinz H. Fiebig, D. P. Berger, Karin Köpping, Harry C. J. Ottenheijm, Zbigniew ZyliczAbstract:The colony formation in agar of human tumor xenografts, of murine tumors and of human bone marrow was used as a test system to determine the in vitro activity of the two novel cytostatic agents, Mitozolomide and sparsomycin. Mitozolomide was additionally studied in vivo in nine human tumor xenografts. The comparison of in vitro/in vivo activity allows an assessment of the relevant in vitro dose based on in vivo pharmacological behavior of a compound. Both compounds showed clear dose/response effects in vitro. A dose of 3 μg/ml Mitozolomide, given by continuous exposure, was active (colony number of test
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In vitro and in vivo anticancer activity of Mitozolomide and sparsomycin in human tumor xenografts, murine tumors and human bone marrow.
Journal of cancer research and clinical oncology, 1990Co-Authors: Heinz H. Fiebig, D. P. Berger, Karin Köpping, Harry C. J. Ottenheijm, Zbigniew ZyliczAbstract:The colony formation in agar of human tumor xenografts, of murine tumors and of human bone marrow was used as a test system to determine the in vitro activity of the two novel cytostatic agents, mitozolamide and sparsomycin. Mitozolomide was additionally studied in vivo in nine human tumor xenografts. The comparison of in vitro/in vivo activity allows an assessment of the relevant in vitro dose based on in vivo pharmacological behavior of a compound. Both compounds showed clear dose/response effects in vitro. A dose of 3 micrograms/ml Mitozolomide, given by continuous exposure, was active (colony number of test less than 30% of the control group) in 12/42 (29%) human tumor xenografts as well as in the four murine tumors, P388, L1210, B16 melanoma and colon carcinoma 38, whereas the two human bone marrows showed no significant suppression of the ability to form colonies in culture. The comparison of in vitro with in vivo activity suggests that the in vitro dose of 3 micrograms/ml corresponds best to the activity observed in animal experiments. The highest activity was observed in small-cell cancer of the lung (4/5), followed by melanomas (2/7) and non-small-cell cancer of the lung (2/9). Furthermore, activity was found in a cancer of the large bowel, stomach, breast and in one sarcoma. In the treatment of nine human tumor xenografts growing subcutaneously in nude mice, Mitozolomide effected a complete or partial remission in 6 out of 9 tumors. In comparison to standard drugs Mitozolomide is one of the most effective compounds in these tumors. These data indicate that Mitozolomide possesses potent broad-spectrum activity in human tumor xenografts. Sparsomycin (0.1 micrograms/ml, continuous exposure) was active in 11/46 (24%) human tumor xenografts and in 4/5 of the murine tumors, whereas the colony-forming capacity of four human bone-marrows showed no inhibition, suggesting that this dose level may be the relevant in vitro dose. However, the high in vitro activity in murine tumors is incompatible with the in vivo activity. In mice the only responsive tumor was leukemia P388, whereas the L1210, B16 melanoma and colon carcinoma 38 were resistant. At the dose level of 0.03 microgram/ml only 3/30 (10%) of the human tumor xenografts were sensitive. In an earlier clinical phase I study the dose-limiting adverse effect was eye toxicity and not bone-marrow suppression.(ABSTRACT TRUNCATED AT 400 WORDS)