nogalamycin and Leukemia-P388

We estimated antitumor activity of TUT-7 following p.o. administration using animal tumor models and human tumor xenografts. In mouse L 1210 leukemia system, antitumor activity of TUT-7 administered orally was as good as that by i.v. administration. Treatment involving schedules of every 4-days or daily administration was much more effective than single treatment. Therapiotic indices of this compound administered both p.o. or i.v. routes, were better than that of adriamycin administered i.v.. TUT-7 showed antitumor activities against various mouse tumors (L 1210 leukemia, P 388 leukemia, colon 38 adenocarcinoma, B 16 melanoma), LX-1 human tumor xenografts, and Yoshida sarcoma in rat. Base on above results, we concluded that oral administration is one of the useful route of TUT-7 administration.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Colonic Neoplasms; Daunorubicin; Doxorubicin; Humans; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Lung Neoplasms; Menogaril; Mice; Nogalamycin; Rats; Sarcoma, Yoshida

Menogaril is an anthracycline presently in Phase II clinical trials. Menogaril-resistant mouse leukaemia P388 cells were developed in vitro by 4 months of exposure to step-wise increasing concentrations of menogaril after which resistant cells (P388/MEN) were cloned in 320 ng ml-1 menogaril. P388/MEN cells were 40-fold more resistant to menogaril in vitro compared to P388/O and were also resistant in vivo. Resistance to menogaril was stable for at least 2 months in the absence of the drug. The results indicate that P388/MEN, although resistant to an anthracycline, did not display the typical multidrug resistant phenotype. It was not cross-resistant to several structurally unrelated drugs such as actinomycin D, cisplatin, or vinblastine, but it was cross-resistant to the anthracycline, adriamycin. Uptake and efflux of menogaril was similar in sensitive and resistant cell lines. Also, resistance was not reversed by verapamil. No major karyotypic difference was noted between P388/O and P388/MEN. There was no significant amplification or overexpression of the mdr gene in P388/MEN compared to P388/O. In contrast to P388/MEN, P388 cells resistant to adriamycin displayed the typical multidrug resistant phenotype. Glutathione content of P388/MEN cells was similar to that of P388/O and depletion of glutathione did not potentiate menogaril cytotoxicity. Therefore, we conclude that glutathione is not likely to be involved in menogaril resistance to P388/MEN cells.

Topics: Animals; Antineoplastic Agents; Cell Division; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance; Drug Synergism; Glutathione; In Vitro Techniques; Leukemia P388; Menogaril; Mice; Nogalamycin; Verapamil

Menogaril is an antitumor agent of the anthracycline type which is less cardiotoxic than doxorubicin in a chronic rabbit model and is active in experimental tumor systems when given by p.o. or parenteral routes. It is currently undergoing i.v. and p.o. Phase II clinical evaluation. We report here the results of pharmacokinetic and systemic bioavailability studies of menogaril in three species (mouse, dog, and monkey). Upon i.v. administration, menogaril plasma concentration-time curves declined in a biexponential (dog) or triexponential (mouse and monkey) manner, with the terminal disposition half-life (t1/2) being considerably shorter in the dog (2.86 +/- 0.47 h) than in the mouse and monkey (21.6 and 19.0 +/- 3.7 h, respectively). The systemic clearance (CL, in liters/h/kg) was highest in mouse (6.2), followed by dog (2.9) and then monkey (1.4). The drug was extensively distributed in all three species, with steady state volumes of distribution being 88.5, 9.8, and 27.9 liters/kg in the mouse, dog, and monkey, respectively. One, two, and three metabolites were detected in the plasma of mice, monkeys, and dogs, respectively, using reverse phase high performance liquid chromatography. The major fluorescent metabolite in all species coeluted with authentic N-demethyl-menogaril; the other two metabolites were present at low concentrations relative to unchanged menogaril and its putative N-demethylated metabolite. One of these metabolites, which was found in both the dog and monkey, eluted with authentic (7R)-nogarol. Mean maximum plasma concentrations of the putative N-demethylmenogaril metabolite were approximately one-tenth those of menogaril in all three species following i.v. drug administration. Upon p.o. treatment, first-pass metabolism or incomplete absorption reduced the systemic bioavailability to 12% in the dog and 33% in the mouse and monkey. N-Demethylmenogaril was the major fluorescent metabolite observed in the plasma of p.o. treated animals. Interspecies comparison of menogaril pharmacokinetic parameters in mice, dogs, monkeys, and humans using allometric techniques indicated that the parameters for mice, monkeys, and humans were highly correlated; in each of these species presystemic metabolism of p.o. administered menogaril reduced its systemic bioavailability to an equivalent extent (30-35%). To determine if metabolically formed N-demethylmenogaril might contribute to the overall antitumor activity of menogaril, we determined the effect of

Topics: Administration, Oral; Animals; Antineoplastic Agents; Biological Availability; Daunorubicin; Dogs; Female; Injections, Intravenous; Leukemia P388; Macaca mulatta; Menogaril; Mice; Mice, Inbred Strains; Nogalamycin; Species Specificity

Mice bearing the P388/S or P388/ADR (doxorubicin-resistant) leukemia were treated with menogaril or mitoxantrone. Both drugs were highly effective against P388/S but were ineffective against the doxorubicin-resistant subline, indicating cross-resistance. These observations may be of use in the design of clinical trials with these drugs.

Topics: Animals; Antineoplastic Agents; Body Weight; Cell Line; Daunorubicin; Doxorubicin; Drug Resistance; Leukemia P388; Life Expectancy; Menogaril; Mice; Mice, Inbred Strains; Mitoxantrone; Nogalamycin

The cytotoxic effect of (7S)- and (7R)-O-epoxyalkyl derivatives of daunomycinone on leukemia P388 cells was followed in in vitro tests and their mutagenicity was determined by means of the bacterial SOS chromotest. The biological effects of the substances were compared with those of daunomycin, carminomycin and nogalamycin. The most efficient derivative proved to be the (7S)-9-acetyl-4-methoxy 7-O-(2,3-epoxypropyl)-7,8,9,10-tetrahydro-6,9,11-trihydroxy-5, 12-naphthacenequinone 10 which inhibited the DNA and RNA synthesis and proliferation of P388 cells on the level of daunomycin or carminomycin. The cytotoxic and mutagenic action of 7-O-epoxyalkyl derivatives of daunomycinone was affected by the length of alkyl and its configuration.

Topics: Animals; Carubicin; Cell Survival; Daunorubicin; DNA Replication; Leukemia P388; Mice; Mutagenicity Tests; Naphthacenes; Nogalamycin; RNA; Structure-Activity Relationship

Doxorubicin-resistant P388 mouse leukemia cells are cross-resistant to anthracycline and non-anthracycline DNA intercalators as well as to natural and semisynthetic anthracyclines which bind weakly or not at all to DNA. In the presence of a non-lethal concentration of 5 microM trifluoperazine cytotoxic effects of the strong DNA binding drugs actinomycin-D, mitoxantrone and m-AMSA were enhanced less than 2 fold in doxorubicin-sensitive cells and up to 50 fold in doxorubicin-resistant cells. Additionally, trifluoperazine induced a greater than 2-fold enhancement in the cytotoxic effects (but not accumulation and retention) of the strong DNA binder N,N-dimethyladriamycin-14-valerate only in doxorubicin resistant cells. In contrast, cell kill, drug accumulation and retention in P388/S and P388/DOX cells treated with the weak DNA binders N-benzyl-adriamycin-14-valerate and 7(R)-O-methylnogarol, and DNA-nonbinding N,N-dibenzyldaunorubicin was similar with or without trifluoperazine treatment. The study demonstrates that the calmodulin inhibitor trifluoperazine induces a specific and marked enhancement in the cytotoxic effects of strong vs weak DNA binding antitumor drugs in doxorubicin-resistant cells.

Topics: Aminoacridines; Amsacrine; Animals; Anthraquinones; Antibiotics, Antineoplastic; Antineoplastic Agents; Cell Line; Dactinomycin; Daunorubicin; DNA; Doxorubicin; Drug Interactions; Drug Resistance; Leukemia P388; Leukemia, Experimental; Menogaril; Mice; Mitoxantrone; Naphthacenes; Nogalamycin; Trifluoperazine

Nogalamycin (1) has been modified by changes at C-10 and C-7 and in the dimethylamino group to prepare an extensive series of analogues. The chemistry involved in the modifications and structure--activity relationships among these nogalamycin analogues are discussed, as well as comparisons with previously reported compounds 1, 7-con-O-methylnogarol (2), and disnogamycin (11).

Topics: Animals; Body Weight; Chemical Phenomena; Chemistry; Daunorubicin; Leukemia L1210; Leukemia P388; Mice; Nogalamycin; Structure-Activity Relationship