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Kr Harrap - One of the best experts on this subject based on the ideXlab platform.

  • lack of nephrotoxicity of oral Ammine amine platinum iv dicarboxylate complexes in rodents
    British Journal of Cancer, 1993
    Co-Authors: Mark J Mckeage, Sarah E Morgan, F E Boxall, Barry A Murrer, G C Hard, Kr Harrap
    Abstract:

    The comparative nephrotoxicity of i.v. cisplatin, i.v. carboplatin and six p.o. Ammine/amine Pt(IV) dicarboxylates was studied in rodents following single MTD treatments. In mice, i.v. cisplatin caused proteinuria (1 g l-1), glycosuria (16.7 mM) and decreased GFR at 4 days, and histological kidney damage with onset at 6 days. In contrast, mice treated with i.v. carboplatin or p.o. Ammine/amine Pt(IV) dicarboxylates had urinary glucose, urinary protein, GFR and kidney histology within the control range. In rats, i.v. cisplatin caused 5-fold elevations in plasma creatinine (188 +/- 33 microM) and urea (30.4 +/- 8.9 mM), a 10-fold fall in creatinine clearance (0.54 +/- 0.31 ml min-1 kg-1), a 25-fold elevation in urine/plasma glucose concentration ratio (3.28 +/- 0.17), a 20% increase in kidney weight (7.9 +/- 0.56 mg gm-1 body weight) and extensive histological damage 4 days after treatment. In contrast, i.v. carboplatin and p.o. JM216 (the lead compound of this series) caused neither abnormalities in renal function nor histological damage in rats. The nephrotoxicity of single MTD treatments of p.o. Ammine/amine Pt(IV) dicarboxylate complexes appears less than i.v. cisplatin and comparable to i.v. carboplatin.

  • mechanism related circumvention of acquired cis diAmminedichloroplatinum ii resistance using two pairs of human ovarian carcinoma cell lines by Ammine amine platinum iv dicarboxylates
    Cancer Research, 1992
    Co-Authors: Lloyd R Kelland, Barry A Murrer, Prakash Mistry, George Abel, Swee Y Loh, C F Oneill, Kr Harrap
    Abstract:

    Abstract Acquired resistance to cisplatin has been generated in vitro in two human ovarian carcinoma cell lines: 41M, established from a previously untreated patient; and CH1, from a patient previously treated with cisplatin and cis-diAmmine-1,1-cyclobutane dicarboxylatoplatinum(II) (carboplatin). In neither cell line with acquired resistance did intracellular detoxification (via increased glutathione or metallothioneins) appear to be a major determinant of resistance. Resistance in 41McisR (resistance factor of 4.7) appeared to be due predominantly to a reduced platinum accumulation (levels were only 23.8% in 41McisR versus 41M). This was also reflected at the DNA level by a similar level of reduced DNA interstrand cross-links and total platinum-DNA adducts measured immediately after a 2-h exposure to cisplatin in 41McisR versus 41M. Conversely, for CH1cisR (resistance factor of 6.5), platinum accumulation, and initial numbers of DNA-interstrand cross-links and total DNA-platinum adducts were not significantly different from the parent CH1 line. This is suggestive of a resistance mechanism involving increased DNA repair or tolerance to platinum-DNA adducts operating in the CH1cisR/CH1 pair of lines. Cross-resistance to carboplatin and partial cross-resistance to the 1,2-diaminocyclohexane-containing agent, (trans-d,l)-1,2-diaminocyclohexane tetrachloroplatinum(IV) (tetraplatin), was observed in both pairs. However, two novel platinum(IV) Ammine/amine dicarboxylates, Ammine dibutyratodichloro(cyclohexylamine)platinum(IV) (JM221) and Ammine dibenzoatodichloro(propylamine)platinum(IV) (JM244), completely circumvented resistance in 41McisR to produce some collateral sensitivity (resistance factors of 0.67 and 0.54, respectively) but showed cross-resistance in CH1cisR (resistance factors of 3.7 and 4.6). In contrast to the data for cisplatin, intracellular platinum levels were not significantly different between the 41M and 41McisR pair of cell lines after exposure to JM244. These results suggest that the Ammine/amine platinum(IV) dicarboxylates, which show considerably greater in vitro cytotoxicity than cisplatin, are capable of circumventing acquired cisplatin resistance which is due to decreased intracellular accumulation but are not able to overcome resistance at the level of DNA platination and removal.

  • Ammine amine platinum iv dicarboxylates a novel class of platinum complex exhibiting selective cytotoxicity to intrinsically cisplatin resistant human ovarian carcinoma cell lines
    Cancer Research, 1992
    Co-Authors: Lloyd R Kelland, Barry A Murrer, Prakash Mistry, George Abel, Christen M Giandomenico, Kr Harrap
    Abstract:

    Abstract Using a panel of six human ovarian carcinoma cell lines varying by two orders of magnitude in terms of cisplatin cytotoxicity, we have investigated the in vitro antitumor activity of a series of novel alkylamine Ammine dicarboxylatodichloroplatinum(IV) complexes of the general formula c, t, c -[PtC] 2 (OCO R 1 ) 2 NH 3 ( R NH 2 )]. A clear relationship existed between increasing the number of carbons in the R 1 substitutent and increasing cytotoxicity up to R 1 = C 5 H 11 . In terms of changing the R group, maximum cytotoxic effects were conferred by alicyclic substituents. Furthermore, increasing the alicyclic ring size from cyclobutane through to cycloheptane resulted in increasing cytotoxicity. The agents with longer axial chains ( e.g. , JM300, R = cyclohexyl, R 1 = C 6 H 13 ) were significantly more cytotoxic than cisplatin and, moreover, exhibited a selective cytotoxic effect against the most intrinsically cisplatin-resistant cell lines ( e.g. , for HX/62, cisplatin 50% inhibitory concentration, 12.6 µm; SKOV-3, cisplatin 50% inhibitory concentration, 4.4 µm and 41 m; cisplatin 50% inhibitory concentration, 0.23 µm; JM300 was 840-, 440-, and only 34-fold more active, respectively). The dicarboxylates JM221 ( R = cyclohexyl, R 1 = C 3 H 7 ) and JM244 ( R = n -propyl, R 1 = C 6 H 5 ) also retained activity against a 4-fold cisplatin-acquired resistant variant of the 41 M cell line. At least part of the increased cytotoxicity of the dicarboxylate, JM221, over cisplatin appeared to be attributable to an increased intracellular accumulation. This novel class of platinum compound represents a valuable lead in the development of a “third-generation” agent capable of exhibiting activity against clinical disease currently resistant to cisplatin.

Barry A Murrer - One of the best experts on this subject based on the ideXlab platform.

  • lack of nephrotoxicity of oral Ammine amine platinum iv dicarboxylate complexes in rodents
    British Journal of Cancer, 1993
    Co-Authors: Mark J Mckeage, Sarah E Morgan, F E Boxall, Barry A Murrer, G C Hard, Kr Harrap
    Abstract:

    The comparative nephrotoxicity of i.v. cisplatin, i.v. carboplatin and six p.o. Ammine/amine Pt(IV) dicarboxylates was studied in rodents following single MTD treatments. In mice, i.v. cisplatin caused proteinuria (1 g l-1), glycosuria (16.7 mM) and decreased GFR at 4 days, and histological kidney damage with onset at 6 days. In contrast, mice treated with i.v. carboplatin or p.o. Ammine/amine Pt(IV) dicarboxylates had urinary glucose, urinary protein, GFR and kidney histology within the control range. In rats, i.v. cisplatin caused 5-fold elevations in plasma creatinine (188 +/- 33 microM) and urea (30.4 +/- 8.9 mM), a 10-fold fall in creatinine clearance (0.54 +/- 0.31 ml min-1 kg-1), a 25-fold elevation in urine/plasma glucose concentration ratio (3.28 +/- 0.17), a 20% increase in kidney weight (7.9 +/- 0.56 mg gm-1 body weight) and extensive histological damage 4 days after treatment. In contrast, i.v. carboplatin and p.o. JM216 (the lead compound of this series) caused neither abnormalities in renal function nor histological damage in rats. The nephrotoxicity of single MTD treatments of p.o. Ammine/amine Pt(IV) dicarboxylate complexes appears less than i.v. cisplatin and comparable to i.v. carboplatin.

  • mechanism related circumvention of acquired cis diAmminedichloroplatinum ii resistance using two pairs of human ovarian carcinoma cell lines by Ammine amine platinum iv dicarboxylates
    Cancer Research, 1992
    Co-Authors: Lloyd R Kelland, Barry A Murrer, Prakash Mistry, George Abel, Swee Y Loh, C F Oneill, Kr Harrap
    Abstract:

    Abstract Acquired resistance to cisplatin has been generated in vitro in two human ovarian carcinoma cell lines: 41M, established from a previously untreated patient; and CH1, from a patient previously treated with cisplatin and cis-diAmmine-1,1-cyclobutane dicarboxylatoplatinum(II) (carboplatin). In neither cell line with acquired resistance did intracellular detoxification (via increased glutathione or metallothioneins) appear to be a major determinant of resistance. Resistance in 41McisR (resistance factor of 4.7) appeared to be due predominantly to a reduced platinum accumulation (levels were only 23.8% in 41McisR versus 41M). This was also reflected at the DNA level by a similar level of reduced DNA interstrand cross-links and total platinum-DNA adducts measured immediately after a 2-h exposure to cisplatin in 41McisR versus 41M. Conversely, for CH1cisR (resistance factor of 6.5), platinum accumulation, and initial numbers of DNA-interstrand cross-links and total DNA-platinum adducts were not significantly different from the parent CH1 line. This is suggestive of a resistance mechanism involving increased DNA repair or tolerance to platinum-DNA adducts operating in the CH1cisR/CH1 pair of lines. Cross-resistance to carboplatin and partial cross-resistance to the 1,2-diaminocyclohexane-containing agent, (trans-d,l)-1,2-diaminocyclohexane tetrachloroplatinum(IV) (tetraplatin), was observed in both pairs. However, two novel platinum(IV) Ammine/amine dicarboxylates, Ammine dibutyratodichloro(cyclohexylamine)platinum(IV) (JM221) and Ammine dibenzoatodichloro(propylamine)platinum(IV) (JM244), completely circumvented resistance in 41McisR to produce some collateral sensitivity (resistance factors of 0.67 and 0.54, respectively) but showed cross-resistance in CH1cisR (resistance factors of 3.7 and 4.6). In contrast to the data for cisplatin, intracellular platinum levels were not significantly different between the 41M and 41McisR pair of cell lines after exposure to JM244. These results suggest that the Ammine/amine platinum(IV) dicarboxylates, which show considerably greater in vitro cytotoxicity than cisplatin, are capable of circumventing acquired cisplatin resistance which is due to decreased intracellular accumulation but are not able to overcome resistance at the level of DNA platination and removal.

  • Ammine amine platinum iv dicarboxylates a novel class of platinum complex exhibiting selective cytotoxicity to intrinsically cisplatin resistant human ovarian carcinoma cell lines
    Cancer Research, 1992
    Co-Authors: Lloyd R Kelland, Barry A Murrer, Prakash Mistry, George Abel, Christen M Giandomenico, Kr Harrap
    Abstract:

    Abstract Using a panel of six human ovarian carcinoma cell lines varying by two orders of magnitude in terms of cisplatin cytotoxicity, we have investigated the in vitro antitumor activity of a series of novel alkylamine Ammine dicarboxylatodichloroplatinum(IV) complexes of the general formula c, t, c -[PtC] 2 (OCO R 1 ) 2 NH 3 ( R NH 2 )]. A clear relationship existed between increasing the number of carbons in the R 1 substitutent and increasing cytotoxicity up to R 1 = C 5 H 11 . In terms of changing the R group, maximum cytotoxic effects were conferred by alicyclic substituents. Furthermore, increasing the alicyclic ring size from cyclobutane through to cycloheptane resulted in increasing cytotoxicity. The agents with longer axial chains ( e.g. , JM300, R = cyclohexyl, R 1 = C 6 H 13 ) were significantly more cytotoxic than cisplatin and, moreover, exhibited a selective cytotoxic effect against the most intrinsically cisplatin-resistant cell lines ( e.g. , for HX/62, cisplatin 50% inhibitory concentration, 12.6 µm; SKOV-3, cisplatin 50% inhibitory concentration, 4.4 µm and 41 m; cisplatin 50% inhibitory concentration, 0.23 µm; JM300 was 840-, 440-, and only 34-fold more active, respectively). The dicarboxylates JM221 ( R = cyclohexyl, R 1 = C 3 H 7 ) and JM244 ( R = n -propyl, R 1 = C 6 H 5 ) also retained activity against a 4-fold cisplatin-acquired resistant variant of the 41 M cell line. At least part of the increased cytotoxicity of the dicarboxylate, JM221, over cisplatin appeared to be attributable to an increased intracellular accumulation. This novel class of platinum compound represents a valuable lead in the development of a “third-generation” agent capable of exhibiting activity against clinical disease currently resistant to cisplatin.

Lloyd R Kelland - One of the best experts on this subject based on the ideXlab platform.

  • mechanism related circumvention of acquired cis diAmminedichloroplatinum ii resistance using two pairs of human ovarian carcinoma cell lines by Ammine amine platinum iv dicarboxylates
    Cancer Research, 1992
    Co-Authors: Lloyd R Kelland, Barry A Murrer, Prakash Mistry, George Abel, Swee Y Loh, C F Oneill, Kr Harrap
    Abstract:

    Abstract Acquired resistance to cisplatin has been generated in vitro in two human ovarian carcinoma cell lines: 41M, established from a previously untreated patient; and CH1, from a patient previously treated with cisplatin and cis-diAmmine-1,1-cyclobutane dicarboxylatoplatinum(II) (carboplatin). In neither cell line with acquired resistance did intracellular detoxification (via increased glutathione or metallothioneins) appear to be a major determinant of resistance. Resistance in 41McisR (resistance factor of 4.7) appeared to be due predominantly to a reduced platinum accumulation (levels were only 23.8% in 41McisR versus 41M). This was also reflected at the DNA level by a similar level of reduced DNA interstrand cross-links and total platinum-DNA adducts measured immediately after a 2-h exposure to cisplatin in 41McisR versus 41M. Conversely, for CH1cisR (resistance factor of 6.5), platinum accumulation, and initial numbers of DNA-interstrand cross-links and total DNA-platinum adducts were not significantly different from the parent CH1 line. This is suggestive of a resistance mechanism involving increased DNA repair or tolerance to platinum-DNA adducts operating in the CH1cisR/CH1 pair of lines. Cross-resistance to carboplatin and partial cross-resistance to the 1,2-diaminocyclohexane-containing agent, (trans-d,l)-1,2-diaminocyclohexane tetrachloroplatinum(IV) (tetraplatin), was observed in both pairs. However, two novel platinum(IV) Ammine/amine dicarboxylates, Ammine dibutyratodichloro(cyclohexylamine)platinum(IV) (JM221) and Ammine dibenzoatodichloro(propylamine)platinum(IV) (JM244), completely circumvented resistance in 41McisR to produce some collateral sensitivity (resistance factors of 0.67 and 0.54, respectively) but showed cross-resistance in CH1cisR (resistance factors of 3.7 and 4.6). In contrast to the data for cisplatin, intracellular platinum levels were not significantly different between the 41M and 41McisR pair of cell lines after exposure to JM244. These results suggest that the Ammine/amine platinum(IV) dicarboxylates, which show considerably greater in vitro cytotoxicity than cisplatin, are capable of circumventing acquired cisplatin resistance which is due to decreased intracellular accumulation but are not able to overcome resistance at the level of DNA platination and removal.

  • Ammine amine platinum iv dicarboxylates a novel class of platinum complex exhibiting selective cytotoxicity to intrinsically cisplatin resistant human ovarian carcinoma cell lines
    Cancer Research, 1992
    Co-Authors: Lloyd R Kelland, Barry A Murrer, Prakash Mistry, George Abel, Christen M Giandomenico, Kr Harrap
    Abstract:

    Abstract Using a panel of six human ovarian carcinoma cell lines varying by two orders of magnitude in terms of cisplatin cytotoxicity, we have investigated the in vitro antitumor activity of a series of novel alkylamine Ammine dicarboxylatodichloroplatinum(IV) complexes of the general formula c, t, c -[PtC] 2 (OCO R 1 ) 2 NH 3 ( R NH 2 )]. A clear relationship existed between increasing the number of carbons in the R 1 substitutent and increasing cytotoxicity up to R 1 = C 5 H 11 . In terms of changing the R group, maximum cytotoxic effects were conferred by alicyclic substituents. Furthermore, increasing the alicyclic ring size from cyclobutane through to cycloheptane resulted in increasing cytotoxicity. The agents with longer axial chains ( e.g. , JM300, R = cyclohexyl, R 1 = C 6 H 13 ) were significantly more cytotoxic than cisplatin and, moreover, exhibited a selective cytotoxic effect against the most intrinsically cisplatin-resistant cell lines ( e.g. , for HX/62, cisplatin 50% inhibitory concentration, 12.6 µm; SKOV-3, cisplatin 50% inhibitory concentration, 4.4 µm and 41 m; cisplatin 50% inhibitory concentration, 0.23 µm; JM300 was 840-, 440-, and only 34-fold more active, respectively). The dicarboxylates JM221 ( R = cyclohexyl, R 1 = C 3 H 7 ) and JM244 ( R = n -propyl, R 1 = C 6 H 5 ) also retained activity against a 4-fold cisplatin-acquired resistant variant of the 41 M cell line. At least part of the increased cytotoxicity of the dicarboxylate, JM221, over cisplatin appeared to be attributable to an increased intracellular accumulation. This novel class of platinum compound represents a valuable lead in the development of a “third-generation” agent capable of exhibiting activity against clinical disease currently resistant to cisplatin.

Prakash Mistry - One of the best experts on this subject based on the ideXlab platform.

  • mechanism related circumvention of acquired cis diAmminedichloroplatinum ii resistance using two pairs of human ovarian carcinoma cell lines by Ammine amine platinum iv dicarboxylates
    Cancer Research, 1992
    Co-Authors: Lloyd R Kelland, Barry A Murrer, Prakash Mistry, George Abel, Swee Y Loh, C F Oneill, Kr Harrap
    Abstract:

    Abstract Acquired resistance to cisplatin has been generated in vitro in two human ovarian carcinoma cell lines: 41M, established from a previously untreated patient; and CH1, from a patient previously treated with cisplatin and cis-diAmmine-1,1-cyclobutane dicarboxylatoplatinum(II) (carboplatin). In neither cell line with acquired resistance did intracellular detoxification (via increased glutathione or metallothioneins) appear to be a major determinant of resistance. Resistance in 41McisR (resistance factor of 4.7) appeared to be due predominantly to a reduced platinum accumulation (levels were only 23.8% in 41McisR versus 41M). This was also reflected at the DNA level by a similar level of reduced DNA interstrand cross-links and total platinum-DNA adducts measured immediately after a 2-h exposure to cisplatin in 41McisR versus 41M. Conversely, for CH1cisR (resistance factor of 6.5), platinum accumulation, and initial numbers of DNA-interstrand cross-links and total DNA-platinum adducts were not significantly different from the parent CH1 line. This is suggestive of a resistance mechanism involving increased DNA repair or tolerance to platinum-DNA adducts operating in the CH1cisR/CH1 pair of lines. Cross-resistance to carboplatin and partial cross-resistance to the 1,2-diaminocyclohexane-containing agent, (trans-d,l)-1,2-diaminocyclohexane tetrachloroplatinum(IV) (tetraplatin), was observed in both pairs. However, two novel platinum(IV) Ammine/amine dicarboxylates, Ammine dibutyratodichloro(cyclohexylamine)platinum(IV) (JM221) and Ammine dibenzoatodichloro(propylamine)platinum(IV) (JM244), completely circumvented resistance in 41McisR to produce some collateral sensitivity (resistance factors of 0.67 and 0.54, respectively) but showed cross-resistance in CH1cisR (resistance factors of 3.7 and 4.6). In contrast to the data for cisplatin, intracellular platinum levels were not significantly different between the 41M and 41McisR pair of cell lines after exposure to JM244. These results suggest that the Ammine/amine platinum(IV) dicarboxylates, which show considerably greater in vitro cytotoxicity than cisplatin, are capable of circumventing acquired cisplatin resistance which is due to decreased intracellular accumulation but are not able to overcome resistance at the level of DNA platination and removal.

  • Ammine amine platinum iv dicarboxylates a novel class of platinum complex exhibiting selective cytotoxicity to intrinsically cisplatin resistant human ovarian carcinoma cell lines
    Cancer Research, 1992
    Co-Authors: Lloyd R Kelland, Barry A Murrer, Prakash Mistry, George Abel, Christen M Giandomenico, Kr Harrap
    Abstract:

    Abstract Using a panel of six human ovarian carcinoma cell lines varying by two orders of magnitude in terms of cisplatin cytotoxicity, we have investigated the in vitro antitumor activity of a series of novel alkylamine Ammine dicarboxylatodichloroplatinum(IV) complexes of the general formula c, t, c -[PtC] 2 (OCO R 1 ) 2 NH 3 ( R NH 2 )]. A clear relationship existed between increasing the number of carbons in the R 1 substitutent and increasing cytotoxicity up to R 1 = C 5 H 11 . In terms of changing the R group, maximum cytotoxic effects were conferred by alicyclic substituents. Furthermore, increasing the alicyclic ring size from cyclobutane through to cycloheptane resulted in increasing cytotoxicity. The agents with longer axial chains ( e.g. , JM300, R = cyclohexyl, R 1 = C 6 H 13 ) were significantly more cytotoxic than cisplatin and, moreover, exhibited a selective cytotoxic effect against the most intrinsically cisplatin-resistant cell lines ( e.g. , for HX/62, cisplatin 50% inhibitory concentration, 12.6 µm; SKOV-3, cisplatin 50% inhibitory concentration, 4.4 µm and 41 m; cisplatin 50% inhibitory concentration, 0.23 µm; JM300 was 840-, 440-, and only 34-fold more active, respectively). The dicarboxylates JM221 ( R = cyclohexyl, R 1 = C 3 H 7 ) and JM244 ( R = n -propyl, R 1 = C 6 H 5 ) also retained activity against a 4-fold cisplatin-acquired resistant variant of the 41 M cell line. At least part of the increased cytotoxicity of the dicarboxylate, JM221, over cisplatin appeared to be attributable to an increased intracellular accumulation. This novel class of platinum compound represents a valuable lead in the development of a “third-generation” agent capable of exhibiting activity against clinical disease currently resistant to cisplatin.

George Abel - One of the best experts on this subject based on the ideXlab platform.

  • mechanism related circumvention of acquired cis diAmminedichloroplatinum ii resistance using two pairs of human ovarian carcinoma cell lines by Ammine amine platinum iv dicarboxylates
    Cancer Research, 1992
    Co-Authors: Lloyd R Kelland, Barry A Murrer, Prakash Mistry, George Abel, Swee Y Loh, C F Oneill, Kr Harrap
    Abstract:

    Abstract Acquired resistance to cisplatin has been generated in vitro in two human ovarian carcinoma cell lines: 41M, established from a previously untreated patient; and CH1, from a patient previously treated with cisplatin and cis-diAmmine-1,1-cyclobutane dicarboxylatoplatinum(II) (carboplatin). In neither cell line with acquired resistance did intracellular detoxification (via increased glutathione or metallothioneins) appear to be a major determinant of resistance. Resistance in 41McisR (resistance factor of 4.7) appeared to be due predominantly to a reduced platinum accumulation (levels were only 23.8% in 41McisR versus 41M). This was also reflected at the DNA level by a similar level of reduced DNA interstrand cross-links and total platinum-DNA adducts measured immediately after a 2-h exposure to cisplatin in 41McisR versus 41M. Conversely, for CH1cisR (resistance factor of 6.5), platinum accumulation, and initial numbers of DNA-interstrand cross-links and total DNA-platinum adducts were not significantly different from the parent CH1 line. This is suggestive of a resistance mechanism involving increased DNA repair or tolerance to platinum-DNA adducts operating in the CH1cisR/CH1 pair of lines. Cross-resistance to carboplatin and partial cross-resistance to the 1,2-diaminocyclohexane-containing agent, (trans-d,l)-1,2-diaminocyclohexane tetrachloroplatinum(IV) (tetraplatin), was observed in both pairs. However, two novel platinum(IV) Ammine/amine dicarboxylates, Ammine dibutyratodichloro(cyclohexylamine)platinum(IV) (JM221) and Ammine dibenzoatodichloro(propylamine)platinum(IV) (JM244), completely circumvented resistance in 41McisR to produce some collateral sensitivity (resistance factors of 0.67 and 0.54, respectively) but showed cross-resistance in CH1cisR (resistance factors of 3.7 and 4.6). In contrast to the data for cisplatin, intracellular platinum levels were not significantly different between the 41M and 41McisR pair of cell lines after exposure to JM244. These results suggest that the Ammine/amine platinum(IV) dicarboxylates, which show considerably greater in vitro cytotoxicity than cisplatin, are capable of circumventing acquired cisplatin resistance which is due to decreased intracellular accumulation but are not able to overcome resistance at the level of DNA platination and removal.

  • Ammine amine platinum iv dicarboxylates a novel class of platinum complex exhibiting selective cytotoxicity to intrinsically cisplatin resistant human ovarian carcinoma cell lines
    Cancer Research, 1992
    Co-Authors: Lloyd R Kelland, Barry A Murrer, Prakash Mistry, George Abel, Christen M Giandomenico, Kr Harrap
    Abstract:

    Abstract Using a panel of six human ovarian carcinoma cell lines varying by two orders of magnitude in terms of cisplatin cytotoxicity, we have investigated the in vitro antitumor activity of a series of novel alkylamine Ammine dicarboxylatodichloroplatinum(IV) complexes of the general formula c, t, c -[PtC] 2 (OCO R 1 ) 2 NH 3 ( R NH 2 )]. A clear relationship existed between increasing the number of carbons in the R 1 substitutent and increasing cytotoxicity up to R 1 = C 5 H 11 . In terms of changing the R group, maximum cytotoxic effects were conferred by alicyclic substituents. Furthermore, increasing the alicyclic ring size from cyclobutane through to cycloheptane resulted in increasing cytotoxicity. The agents with longer axial chains ( e.g. , JM300, R = cyclohexyl, R 1 = C 6 H 13 ) were significantly more cytotoxic than cisplatin and, moreover, exhibited a selective cytotoxic effect against the most intrinsically cisplatin-resistant cell lines ( e.g. , for HX/62, cisplatin 50% inhibitory concentration, 12.6 µm; SKOV-3, cisplatin 50% inhibitory concentration, 4.4 µm and 41 m; cisplatin 50% inhibitory concentration, 0.23 µm; JM300 was 840-, 440-, and only 34-fold more active, respectively). The dicarboxylates JM221 ( R = cyclohexyl, R 1 = C 3 H 7 ) and JM244 ( R = n -propyl, R 1 = C 6 H 5 ) also retained activity against a 4-fold cisplatin-acquired resistant variant of the 41 M cell line. At least part of the increased cytotoxicity of the dicarboxylate, JM221, over cisplatin appeared to be attributable to an increased intracellular accumulation. This novel class of platinum compound represents a valuable lead in the development of a “third-generation” agent capable of exhibiting activity against clinical disease currently resistant to cisplatin.