title: Correlation of the in vitro cytotoxicity of ethyldeshydroxysparsomycin and cisplatin with the in vivo antitumour activity in murine L1210 leukaemia and two resistant L1210 subclones.
abstract: The cultured murine leukaemia L1210 cell populations used in the present study were derived from L1210 cells that had been grown in vivo. Subclones resistant to sparsomycin (L1210/Sm) or cisplatin (L1210/CDDP) were also developed in vivo. The doubling times of the cultured cell populations were identical. Fractions surviving after drug treatment in vitro were determined by colony formation in soft agar. The results, based on the differential sensitivity of the cell populations to ethyldeshydroxysparsomycin (EdSm) and CDDP, indicated that after a short exposure, cultured L1210/CDDP cells were cross-resistant to EdSm. L1210/Sm cells, however, were not cross-resistant to CDDP. The results obtained in cultured cell populations were confirmed in vivo. CD2f1 mice bearing i.p. implants of 1 x 10(5) tumour cells were given EdSm or CDDP and a combination of the two agents. Drugs were given once daily every 4 days for 3 doses starting at 24 h after tumour implantation. Treatment of mice bearing L1210/wt leukaemia with combined EdSm and CDDP caused strongly synergistic antitumour activity. In animals bearing the two resistant subclones, however, combined drug treatment did not improve the antitumour activity. The corresponding median survival of mice receiving combined drug treatment was 60 days in each group containing 6 mice bearing L1210/wt, with 4-6 cures being noted; 19 days in animals harbouring L1210/Sm, with 2 cures being recorded among 6 mice; and 11 days in mice bearing L1210/CDDP, with no cure being obtained. The results of this study indicate that the synergism resulting from combined treatment with CDDP and EdSm is a function of the cellular properties of the target tumour-cell populations and is independent of host factors.
authors.affiliation: Department of Internal Medicine, Nijmegen University Hospital, The Netherlands.
authors.forename: H P
authors.initials: HP
authors.lastname: Hofs
authors.forename: D J
authors.initials: DJ
authors.lastname: Wagener
authors.forename: V
authors.initials: V
authors.lastname: de Valk-Bakker
authors.forename: H
authors.initials: H
authors.lastname: van Rennes
authors.forename: A J
authors.initials: AJ
authors.lastname: van Zeist
authors.forename: L A
authors.initials: LA
authors.lastname: van den Broek
authors.forename: H C
authors.initials: HC
authors.lastname: Ottenheijm
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002460:Cell Line; D002945:Cisplatin / Q000008:administration & dosage; D002999:Clone Cells; D004357:Drug Synergism; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000401:mortality; D051379:Mice; D013033:Sparsomycin / Q000008:administration & dosage / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C074101:ethyldeshydroxysparsomycin; D013033:Sparsomycin; D002945:Cisplatin