Cis-platinum (II) complexes of carboxymethyl-dextran as potential antitumor agents. II. In vitro and in vivo activity.
Cis-diamminedichloro platinum (II) (cis-DDP) and cis-diamminediaquo platinum (II) nitrate (cis-aq) were complexed to a macromolecular carrier carboxymethyl dextran (CM-dex). Two carriers were used in this study, one derived from dex-T-10 (Mr-10000) and the other from dex-T-40 (Mr-40000). The two platinum (II) drugs formed soluble complexes with both carriers. Uncomplexed and complexed drugs were tested and found to be cytotoxic in vitro against 5 murine and 2 human derived tumor cell lines. The two free platinum (II) drugs were cytotoxic against these cells to a similar extent. In comparison to the free drugs the complexes were somewhat less active, up to 3 fold, against murine 38C-13, L1210, EL-4 and RDM-4 leukemias, as well as against human HeLa and osteogenic sarcoma, and as active as the free drugs against murine F9 embryonal carcinoma. There were no major differences in the in vitro cytotoxic activity between CM-dex T-10 and CM-dex T-40 complexes. Differences due to the molecular size of the carrier were observed in vivo: The CM-dex T-10 complexes were significantly less toxic than the free drugs, whereas the reduction of toxicity by complexing to CM-dex T-40 was less profound. As for the efficacy, when tested in vivo against a cis-DDP sensitive tumor (F9) the T-40 complexes were equally or even more effective than the respective free drugs. The T-10 complexes were less effective than the free drugs at equal drug doses but their effectivity increased at increasing drug levels. These complexes were, however, very effective in inhibiting tumor growth upon repeated injections, leading to 100% survival.
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity*; D004261:DNA Replication / Q000187:drug effects; D003911:Dextrans / Q000627:therapeutic use / Q000633:toxicity*; D005260:Female; D006367:HeLa Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007942:Leukemia, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009363:Neoplasm Proteins / Q000096:biosynthesis; D012516:Osteosarcoma; D013329:Structure-Activity Relationship; D013724:Teratoma / Q000188:drug therapy
D000970:Antineoplastic Agents; D003911:Dextrans; D009363:Neoplasm Proteins; C034297:diamminediaqua platinum(II); C014392:carboxymethyl dextran; D002945:Cisplatin