ABSTRACT
A new type of antitumor platinum complex has been prepared and examined for antitumor activity against L1210 leukemia both in vitro and in vivo. The coordination environment of platinum in these complexes consists of three anionic chloride ions and a positively charged amine. The positive charge is introduced by monoprotonation or monoalkylation of a diamine. Platinum(IV) derivatives have been prepared for several of the complexes, and a water-soluble sulfate derivative has been prepared for one of them. Several of these complexes exhibit significant in vitro activity, and trichloro(3-aminoquinuclidinium)platinum(II) (QTP) exhibits significant in vivo activity as well. An increase in life span of approximately 40% has been observed using QTP. QTP is toxic at doses slightly in excess of effective doses.
Subject(s)
Antineoplastic Agents/chemical synthesis , Organoplatinum Compounds/chemical synthesis , Animals , Cell Line , Chemical Phenomena , Chemistry , Leukemia L1210/drug therapy , Male , Mice , Organoplatinum Compounds/pharmacologyABSTRACT
A new pyrimidine nucleoside, 2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil, previously has been shown to be active against the herpes group of viruses in vitro and in vivo. It is also active against mouse and human leukemic cells in culture and against mouse leukemias L1210, P388, and P815 in vivo. In contrast to other 1-beta-D-arabinofuranosylcytosine (ara-C) derivatives, 2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil, when given either i.p. or p.o., is highly active against lines of leukemias P815 and L1210 made resistant to ara-C. Against P815/ara-C and L1210/araC, it is more effective than is 5-azacytidine, a drug which has shown definite effectiveness in patients with acute leukemia whose disease has become resistant to ara-C. For these reasons, 2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil would seem to merit clinical trial in patients with acute nonlymphocytic leukemia whose disease has become resistant to ara-C.
Subject(s)
Cytarabine/therapeutic use , Leukemia, Experimental/drug therapy , Pyrimidine Nucleosides/therapeutic use , Animals , Arabinofuranosyluracil/analogs & derivatives , Arabinofuranosyluracil/therapeutic use , Cells, Cultured , Cytarabine/analogs & derivatives , Humans , Leukemia L1210/drug therapy , Leukemia P388/drug therapy , Leukemia, Experimental/mortality , MiceABSTRACT
There is a great need for clinical trial of new second-generation platinum coordination compounds that might demonstrate greater clinical activity in a broader spectrum of tumors, decreased renal toxicity and emesis, improved solubility, synergism in combination therapy, and lack of cross-resistance to cis-dichlorodiammineplatinum(II) (cis-platinum). Lack of cross-resistance to cis-platinum is shown by certain 1,2-diamino-saturated cyclic platinum derivatives which also have a high degree of activity against transplanted mouse leukemias. cis-Platinum and these cyclic compounds combine synergistically with derivatives of cytosine arabinoside, VP-16-213, and Adriamycin. These 1,2-diamino cyclic compounds appear to have less renal toxicity than cis-platinum. The toxic and therapeutic effects of both cis-platinum and the diamino cyclic compounds can be blocked by massive doses of thiourea. Varying doses and time intervals of thiourea rescue are being studied in the hope of improving the therapeutic index of the platinum derivatives.