pyrimidinones and Leukemia-P388

As part of a series of studies to discover new topoisomerase II inhibitors, novel pyrimidoacridones, pyrimidophenoxadines, and pyrimidocarbazoles were synthesized, and in vitro and in vivo antitumor activities and DNA-protein and/or DNA-topoisomerase II cross-linking activity as an indicator of topoisomerase II-DNA cleavable complex formation were evaluated. The pyrimidocarbazoles possessed high in vitro and in vivo potencies. Compound 26 (ER-37326), 8-acetyl-2-[2-(dimethylamino)ethyl]-1H-pyrimido[5,6,1-jk]carbazole-1,3(2H)-dione, showed in vitro growth inhibitory activity with respective IC(50) values of 0.049 microM and 0.35 microM against mouse leukemia P388 and human oral cancer KB. In vivo, this compound inhibited the tumor growth of mouse sarcoma M5076 implanted into mice with T/C values of 42% and 13% at 3.13 and 6.25 mg/kg/d respectively without significantly affecting the body weight. In addition, compound 26 (ER-37326) increased the formation of DNA-topoisomerase II cross-linking in P388 cells.

Topics: Acridines; Animals; Antineoplastic Agents; Carbazoles; Cell Line, Tumor; DNA Topoisomerases, Type II; Dose-Response Relationship, Drug; Humans; KB Cells; Leukemia P388; Mice; Molecular Structure; Pyrimidines; Pyrimidinones; Topoisomerase II Inhibitors

2(1H)-Pyrimidinone riboside (zebularine, 1b) and its 5-fluoro (6b) and 2'-ara-fluoro (7b) analogues have been synthesized and evaluated in vivo as antitumor agents. Zebularine provides increase in life span (ILS) values of ca. 70% against intraperitoneal (ip) murine B16 melanoma and 50% against P388 leukemia. This compound is active when administered either ip or orally against ip or subcutaneously implanted L1210 leukemia, producing ILS values of about 100% at an optimum dose of 400 mg/kg. 1b is also active (60% ILS) against ara-C-resistant L1210. The analogous unsubstituted purine riboside nebularine (2) has modest activity against P388 leukemia (60% ILS). While 2'-ara-fluorozebularine (7b) is only marginally active (40% ILS) at high doses against L1210 leukemia, 5-fluoro analogue 6b is more active than zebularine and is ca. 100 times more potent. Although the activity of 6b is about the same as that of 1b against P388 leukemia, greater potency also is realized in this model. Zebularine is a strong inhibitor of cytidine deaminase, but in contrast to tetrahydrouridine, 1b is acid-stable. In an attempt to use this property to advantage in oral administration, 1b and ara-C have been orally coadministered to mice with ip L1210 leukemia. When zebularine is given in divided doses, up to a 2-fold increase in activity is realized, relative to treatment with the same dose of ara-C alone.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Arabinonucleosides; Cytidine; Drug Screening Assays, Antitumor; Injections, Intraperitoneal; Injections, Subcutaneous; Leukemia L1210; Leukemia P388; Mice; Pyrimidine Nucleosides; Pyrimidinones; Structure-Activity Relationship

At least three marked differences were noted in the results compared from two parallel experiments using identical protocols with virus-free mice and mouse hepatitis virus (MHV) infected mice inoculated with P388 leukemia. First, the therapeutic effect of cyclophosphamide (CY), a cytotoxic antitumor drug, was apparently augmented in MHV-infected mice. A 162% increase of life span (ILS) was obtained in MHV-infected mice compared to a 100% ILS in uninfected mice. Second, the experimental error in terms of the range of animal survival time was much larger with MHV-infected mice than with uninfected mice. In MHV-infected mice, the therapeutic effect of the combination treatment with CY and pyrimidinone was not statistically different from that of the treatment with CY alone. In uninfected mice, the effects of the combination therapy at all doses of pyrimidinone were statistically more effective than that of CY treatment alone.

Topics: Animals; Antineoplastic Agents; Cyclophosphamide; Cytosine; Drug Therapy, Combination; Female; Hepatitis, Viral, Animal; Leukemia P388; Leukemia, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Murine hepatitis virus; Pyrimidinones

This study was undertaken in an attempt to evaluate the structure-activity relationship of pyrimidinones. Of 20 pyrimidinones tested, only those with a monohalogen substitution at the ortho- or meta-position of the phenyl moiety of the 2-amino-5-halo-6-phenyl-4(3H)-pyrimidinone and ABPP showed statistically significant synergism with cyclophosphamide (CY) against P388 leukemia. Therefore, ABMFPP, AIMFPP, and ABPP were selected for detailed therapeutic evaluation. The pyrimidinone alone had small but significant activity against B16 melanoma with slightly more than a 25% increase in lifespan (ILS); however, when used in combination with CY, ABPP or ABMFPP did not yield an effect greater than treatment with CY alone. Only AIMFPP appeared to produce a more or less additive effect with CY. Although none of these pyrimidinones alone had any significant activity against M5076 tumor, the combination with CY (100 mg/kg) produced a range of 102 to 123% ILS and six to nine of 10 mice per group survived greater than 45 days, whereas the treatment with CY alone yielded only a 48% ILS and none survived greater than 45 days. The synergism of the combination therapy was statistically significant (p less than 0.01). The combination used against L1210 leukemia also appeared to be superior to the treatment with CY alone and produced 25 to 50% long-term survivors (greater than 30 days). The significance of these findings is discussed in terms of its clinical implications.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Leukemia L1210; Leukemia P388; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Pyrimidinones; Sarcoma, Experimental; Species Specificity; Structure-Activity Relationship

Topics: Animals; Antineoplastic Agents; Cell Survival; Cyclophosphamide; Drug Therapy, Combination; Female; Killer Cells, Natural; Leukemia P388; Leukemia, Experimental; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Pyrimidinones