mercaptopurine and Leukemia-P388

Four new sapogenins, porrigenins A (2a) and B (3a), identified as (25R)-5 alpha-spirostan-2 beta,3 beta,6 beta-triol and (25R)-2-oxo-5 alpha-spirostan-3 beta,6 beta-diol, respectively, and neoporrigenins A (2b) and B (3b) were also isolated from Allium porrum. In addition, the known agigenin (1a) and its 25S epimer, neoagigenin (1b), were also identified. Their structure elucidation was provided by comprehensive spectroscopic analyses. Compounds 1a, 2a, and 3a exhibited cytotoxicity and high antiproliferative activity on four different tumor cell lines in vitro.

Topics: Allium; Animals; Antineoplastic Agents, Phytogenic; Carbohydrate Sequence; Cell Division; Drug Screening Assays, Antitumor; Humans; Leukemia P388; Magnetic Resonance Spectroscopy; Mass Spectrometry; Mice; Molecular Sequence Data; Sapogenins; Tumor Cells, Cultured

We have examined the therapeutic effects of combination therapy of pirarubicin ((2"R)-4'-O-tetrahydropyranyladriamycin, THP) with various antitumor agents against P388 murine leukemia. THP showed a high antitumor activity in combination with various antitumor drugs, especially with cyclophosphamide (CPM), cisplatin (CDDP), mitomycin C (MMC), enocitabine (BHAC), vindesine (VDS) or methotrexate (MTX). The effects of combination therapy depended on the order of administration of THP and combined drugs. THP-preceding treatment gave more synergistic effects in combination with 5-fluorouracil (5-FU) or MTX. THP-preceding or simultaneous treatment with etoposide (ETP) indicated the higher synergistic activity than ETP-preceding one. Moreover, THP showed much higher synergistic effects in any order of the combination with CPM, CDDP, MMC, BHAC, VDS or MTX. These results suggest that THP possesses a therapeutic usefulness clinically in combination with various antitumor drugs, if the selection of drugs combined with THP and the order of administration are suitable.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Screening Assays, Antitumor; Fluorouracil; Leukemia P388; Male; Mercaptopurine; Methotrexate; Mice; Mice, Inbred BALB C; Mitomycin; Peplomycin; Vindesine

The main purpose of the present investigation was to study the effect of cloturin on aerobic glycolysis, endogenous and exogenous respiration and the level of ATP in both Ehrlich ascites carcinoma (EAC) and P388 murine leukaemia cells incubated in vitro. Also its effect on the level of total (T-SH) and non-protein (NP-SH) thiol groups was investigated. A significant inhibition of aerobic glycolysis was found only in P388 cells after 60 min of cloturin action. Cloturin inhibited both endogenous and exogenous respiration of EAC with succinate as substrate. Cloturin decreased the level of ATP after 2 h incubation in both types of tumour cell. The level of NP-SH was decreased more than that of T-SH in both types of cell.

Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Energy Metabolism; Glucose; Glycolysis; Leukemia P388; Mercaptopurine; Mice; Mustard Compounds; Oxygen Consumption; Sulfhydryl Compounds; Tumor Cells, Cultured

Combined activity of 4-amino-1-beta-D-arabinofuranosyl-2(1H)-pyrimidinone 5'-(sodium octadecyl phosphate) monohydrate, YNK01, with other antitumor agents was studied with mouse P388 and L1210 leukemia in vivo. The two-drug combinations with doxorubicin, daunorubicin, mitomycin C, cisplatin or vincristine showed marked synergistic effects against P388 leukemia. However, YNK01 plus methotrexate showed additive or competitive effect. Among these combinations, the combination with doxorubicin showed greatest activity and the number of cured mice were observed in a wide dose range. In a three-drug combination with daunorubicin and 6-mercaptopurine against L1210 leukemia, the combined effect was more synergistic than two-drug combinations with each of the three drugs. From these results, YNK 01 is expected to be a useful agent in combination chemotherapy.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleotides; Cisplatin; Cytidine Monophosphate; Cytosine Nucleotides; Daunorubicin; Doxorubicin; Drug Synergism; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Mercaptopurine; Mice; Mice, Inbred DBA; Mitomycin; Mitomycins; Vincristine

Topics: Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Cell Line, Tumor; Cell Survival; Cytarabine; Leukemia P388; Mercaptopurine; Mice; Mustard Compounds

Combination effects of etoposide (ET) with each of 10 antitumor drugs were examined with P 388 leukemia cells in vitro and in vivo. Median effect analysis was applied for the evaluation of in vitro effect by the growth inhibition, and the in vivo effect by comparison of the increase of life span (ILS) in a combined group with the sum of ILS's in 2 single agent groups. Among 10 drugs combined with ET, cyclophosphamide (melphalan was used for in vitro study), cisplatin and 6-mercaptopurine exhibited a strong synergism both in vitro and in vivo. The combination of ET with mitomycin C, vincristine, vindesine or cytarabine produced additive or slightly synergistic effect in the both systems. However, methotrexate + ET combination showed an antagonistic effect. Although the combination of ET with doxorubicin or fluorouracil showed a slight synergism in vitro, it was antagonistic in vivo. Thus, the in vitro and in vivo combined effects were consistent in 8 of 10 drugs. The employed methods in the present studies could distinguish high efficacy of ET + cyclophosphamide and ET + cisplatin, which are clinically approved as effective combinations against lung cancer. The methods seem to be useful to assess the drug efficacy in experimental combination.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Drug Screening Assays, Antitumor; Drug Synergism; Etoposide; Leukemia P388; Mercaptopurine; Mice; Mice, Inbred DBA; Mice, Inbred Strains; Tumor Cells, Cultured

The effect of cloturin on biosynthesis of DNA, RNA and proteins in both P388 and Ehrlich ascites carcinoma (EAC) cells have been studied in vitro. Biosynthesis of macromolecules indicated by the incorporation rate of [14C]adenine (DNA, RNA), [14C]thymidine (DNA), [14C]uridine (RNA) and [14C]valine (proteins) were studied for concentration (75 to 600 mumol/l) and time dependence. Cloturin inhibits incorporation of all 14C-precursors into the TCA-insoluble fraction of both types of cells in proportion to its concentration. The complete inhibition of 14C-precursors was reached at the highest concentrations of cloturin (300 and 600 mumol/l). The fact that incorporation of four precursors is inhibited suggests that the effect of cloturin lies at an underlying level of energy generation or transfer, rather than at specific reactions in the biosynthesis of DNA and proteins. The rate of DNA synthesis is rapidly affected by the lowering of the level of any of the four deoxyribonucleotide triphosphates. Interference with the generation of high-energy phosphate bonds is one of the mechanisms available for induction of nucleotide deficiency. A depletion of nucleotide pools can serve as an efficient tool to inhibit cellular growth and to induce cell death under some circumstances.

Topics: Adenine; Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; DNA, Neoplasm; Kinetics; Leukemia P388; Mercaptopurine; Mice; Mustard Compounds; Neoplasm Proteins; Neoplasms, Experimental; RNA, Neoplasm; Thymidine; Tumor Cells, Cultured; Uridine

Combination chemotherapy using the water-soluble nitrosourea MCNU with various anti-cancer agents was studied using L1210 leukemia and P388 leukemia. In titration experiments MCNU showed remarkable antitumor effects at doses from 5 mg/kg to 80 mg/kg, producing numbers of 60-day survivors with L1210 leukemia. In L1210 leukemia, respective combinations of MCNU with the antimetabolites, MTX, 6-MP, 6-TG, MCNU, 5-FU and Cyclo-C showed enhanced antitumor effects. MCNU combined with each of ADR, MMC and CPM also showed marked anti-tumor effects with 60-day survivors. In P388 leukemia MCNU combined with each of ADR, MMC, VDS and CPM produced strong anti-tumor effects with numbers of 60-day survivors. In the results of these combinations, especially the combinations of MCNU + 5-FU in L1210 leukemia and MCNU + CPM in both L1210 and P388 leukemia, a significant increase in mean survival time was achieved. These combinations also produced many 60-day survivors which were considered to be due to the synergistic antitumor effects of the combined drugs.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Doxorubicin; Female; Fluorouracil; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Mercaptopurine; Methotrexate; Mice; Mice, Inbred DBA; Mitomycin; Mitomycins; Nitrosourea Compounds; Thioguanine

Combinations of retinol palmitate (RP) and six different anticancer agents were examined to determine their effects on the life-span of mice bearing ascites sarcoma 180 or P388 leukemia. With ascites sarcoma 180, administration of a fixed dose of RP (3.3 mg/kg) considerably enhanced the antitumor effects of 5-fluorouracil (5-FU) (5 mg/kg, or 20 mg/kg), methotrexate (MTX) (0.5 mg/kg, or 1 mg/kg) and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) (12.5 mg/kg), when given by intraperitoneal injection. However RP failed to potentiate the antitumor effects of adriamycin (ADM) and 6-mercaptopurine (6-MP) against sarcoma 180. With P388 leukemia, RP (167 mg/kg, or 333 mg/kg) enhanced the antitumor effects of 6-MP (25 mg/kg, or 50 mg/kg), MTX (1 mg/kg, or 2 mg/kg), ADM (0.2 mg/kg), ACNU (5 mg/kg) and cis-dichlorodiammine-platinum (CDDP) (1 mg/kg) to a considerable extent, but it did not potentiate the antitumor effect of 5-FU. The combination of RP with ACNU or CDDP was particularly effective against P388 leukemia.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Diterpenes; Doxorubicin; Drug Evaluation, Preclinical; Drug Synergism; Fluorouracil; Leukemia P388; Male; Mercaptopurine; Methotrexate; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Neoplasms, Experimental; Nimustine; Nitrosourea Compounds; Retinyl Esters; Sarcoma 180; Vitamin A

While the combination of L1210 murine leukemia cell vaccine (L1210 vaccine) with 6-mercaptopurine (6-MP) or 6-thioguanine produces a therapeutic response greater than that induced by either of these agents alone, its combination with cyclophosphamide, N4-behenoyl-1-beta-D-arabinofuranosylcytosine, or 5-fluorouracil does not produce such a response. The administration of cyclophosphamide, N4-behenoyl-1-beta-D-arabinofuranosylcytosine, or 5-fluorouracil alone resulted in a response as great as, or greater than, that induced by 6-MP alone. This and the finding that the 6-MP-induced response was more pronounced upon its delayed rather than its early administration indicate that 6-MP-induced reduction of the tumor burden does not explain this augmentation. The combination of 6-MP and L1210 vaccine was not effective in mice bearing 6-MP-resistant L1210 leukemia; however, an augmented response occurred when the tumor burden was reduced by N4-behenoyl-1-beta-D-arabinofuranosylcytosine, indicating that reduction of the tumor burden by 6-MP was only partially associated with augmentation of the therapeutic response. Augmentation was associated with vaccine-induced antitumor immunity because it was induced by the combination of 6-MP and concanavalin A-bound, but not concanavalin A-free L1210 vaccine. This augmentation was dependent on the timing of the L1210 vaccine administration. The combination was not effective in mice bearing P388 leukemia, indicating the tumor specificity of the augmentation. These results show that 6-MP not only reduced the tumor burden but also potentiated the vaccine-dependent antitumor immunity, resulting in the induction of an augmented therapeutic response.

Topics: Animals; Concanavalin A; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; Immunotherapy; Leukemia; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Male; Mercaptopurine; Mice; Thioguanine

A series of novel aziridinyl-substituted 1(2)H-indazole-4,7-diones and related 1(2)H-indazole-4,7-diones was synthesized and tested against Ehrlich ascites carcinoma growth in male CF1 mice. Ten of the test compounds, including two aziridinyl-substituted 1(2)H-indazole-4,7-diones, were found to be significantly active (inhibition of tumor growth greater than 80%) in the Ehrlich ascites carcinoma screen. Several structure-activity relationships were indicated for antitumor activity in this screen. An aziridinyl-substituted derivative, 5-aziridinyl-6-chloro-1H-indazole-4,7-dione (8a), also exhibited significant activity against the growth of P-388 lymphocytic leukemia cells in male BDF1 mice (% T/C = 145; % T/C greater than 125 is considered significant).

Topics: Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Cell Division; Indazoles; Leukemia P388; Male; Mice; Pyrazoles

Two new purine antagonists, 5-carbamoyl-1H-imidazol-4-yl piperonylate (SL-1250) and 4-carbamoylimidazolium 5-olate (SM-108), were investigated for their antitumor activities against 6-mercaptopurine (6-MP)-resistant sublines of P388 and L1210 leukemia. It was found that both resistant sublines exhibited collateral sensitivity instead of cross-resistance to these new antipurine drugs. Since more potent cytotoxic activities of these drugs against 6-MP-resistant cells were observed even in vivo cell culture systems, this collateral sensitivity was proved on a cellular basis. Biochemical studies revealed that 6-MP-resistant sublines of both P388 and L1210 leukemia are deficient in hypoxanthine-guanine phosphoribosyltransferase activity. In these cells, not only the activation of 6-MP to its nucleotide but also the synthesis of guanosine 5'-monophosphate via the salvage pathway seems to be severely restricted. However, SL-1250 and SM-108 can be activated to their nucleotide even in these 6-MP-resistant cells because the activation of these compounds is proceeded by adenine phosphoribosyltransferase. In conclusion, suppression of de novo purine synthesis with SL-1250 and SM-108 seems to be a very efficient means of killing these 6-MP-resistant cells, which lack a salvage pathway for guanosine 5'-monophosphate.

Topics: Animals; Antineoplastic Agents; Biotransformation; Cells, Cultured; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Guanosine Monophosphate; Hypoxanthine Phosphoribosyltransferase; Imidazoles; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Mercaptopurine; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Purines

A series of novel substituted thiochromones and thiochroman-4-ones was synthesized. Compounds were designed as analogues of naphthoquinone and as potential "bioreductive alkylating agents" and were tested for antitumor activity. The lead compound, 3-(chloromethyl)thiochromone 1,1-dioxide (4), inhibited Ehrlich ascites tumor growth by 100% in CF1 male mice at 10 (mg/kg)/day ip. Similarly, 18 of the 29 related compounds demonstrated good activity in this tumor screen. Few definitive structure-activity correlations were evident regarding the nature of the 3-substituent. However, the 2,3 double bond and a sulfone or sulfoxide were required for activity. Four of the compounds synthesized showed marginal but significant activity against P-388 lymphocytic leukemia.

Topics: Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Chemical Phenomena; Chemistry; Cyclic S-Oxides; Leukemia P388; Male; Mice

Diazomethyl ketone and chloromethyl ketone analogues prepared from N-tosyl amino acids have been synthesized and tested for antitumor activity in Ehrlich ascites carcinoma and P-388 lymphocytic leukemia screens in mice. The N-tosyl chloromethyl ketone analogues prepared from glycine, L-alanine, beta-alanine, L-valine, and 6-(N-tosyl-amino)caproic acid were the most potent antineoplastic agents in the Ehrlich ascites carcinoma screen. The N-tosyl diazomethyl ketone analogues synthesized from glycine, L-leucine, and L-proline were the most active of this series in the Ehrlich ascites screen, along with 5-keto-1-tosyl-2-(diazoacetyl)pyrrolidine and the diazomethyl ketone analogues prepared from 6-(N-tosylamino)caproic acid. In the P-388 lymphocytic leukemia screen, the N-tosyl chloromethyl ketone prepared from glycine and the compound 5-keto-1-tosyl-2-(diazoacetyl)pyrrolidine were the most active.

Topics: Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Diazomethane; Ketones; Leukemia P388; Male; Mice; Mice, Inbred DBA; Structure-Activity Relationship; Tosyl Compounds

A series of N-protected cyanomethyl esters of various amino acids was synthesized and tested for antineoplastic and antiinflammatory activity in rodents. Utilizing the L-phenylalanine cyanomethyl ester and varying the N-protecting moiety demonstrated that the N-tosyl and the N-Cbz analogues were the most active against Ehrlich ascites cell proliferation. The N-(carbobenzyloxy)- and N-benzoyl-L-phenylalanine cyanomethyl esters were the most active against carrageenan-induced inflammation. In the N-benzoyl series of cyanomethyl esters, L-alanine, DL-valine, and L-leucine amino acid analogues were the most active against Ehrlich ascites cell proliferation. The glycine and L-alanine analogues possessed the best inhibitor activity in the antiinflammatory screen. The cyanomethyl esters also demonstrated immunosuppressive activity and the ability to suppress the writhing reflex which is associated with inflammatory pain. However, no antipyretic or narcotic analgesic activity was demonstrated by these agents.

Topics: Acetonitriles; Amino Acids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Body Temperature; Carcinoma, Ehrlich Tumor; Carrageenan; Esters; Immunosuppressive Agents; Lethal Dose 50; Leukemia P388; Male; Mice; Mice, Inbred DBA; Rats; Reaction Time; Structure-Activity Relationship

Topics: Animals; Antimetabolites, Antineoplastic; Drug Resistance; Female; Fluorouracil; Leukemia P388; Leukemia, Experimental; Mercaptopurine; Methotrexate; Mice; Neoplasm Transplantation