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At least 19 recordsLinked to original sources
PubMed1985

Activity of a novel carotenoid analog, 4,4'-(3,7,12,16-tetramethyl-1,3,5,7,9,11,13,15,17-octadecanonaen -1,18- diyl) bis(1-ethylpyridinium) dibromide (Y-18598) on mouse leukemia P388.

4,4'-(3,7,12,16-Tetramethyl-1,3,5,7,9,11,13,15,17-octadecanonaen-1 ,18-diyl) bis (1-ethylpyridinium) dibromide (Y-18598), a novel carotenoid analog with 1-ethylpyridine rings as terminal groups, was found to be effective against P388 leukemia which was refractory to amphotericin B and retinoic acid used as representatives of polyene-containing drugs. The life span of leukemic mice was increased by 56% over the control following administration of 2.5 mg/kg on days 1-5. Among these polyene-containing compounds, Y-18598 was the most highly cytotoxic to P388 leukemia cells in vitro.

Amphotericin B↗
PubMed1989

[Sensitivity to chemotherapeutic preparations of anthracycline-resistant strains of murine leukemia P388].

P388 leukemia strains resistant to rubomycin and ruboxylnitroxyl derivative of rubomycin were studied for their drug sensitivity. The resistant strains exhibited cross resistance to anthracycline antibiotics, vinca alkaloids, actinomycin D, colchicine. The rubomycin-resistant strain gained significantly higher sensitivity (in comparison with the parent strain and the ruboxyl-resistant strain) to six drugs: cisplatin, sarcolisin, dopan, thiophosphamide, degranol, 6-mercaptopurine. The karyotype of the ruboxyl-resistant cells was characterized by the presence of chromosome with homogeneously straining region (HSR). The alteration of the HSR-location was accompanied by the increase of chemotherapeutical sensitivity of the ruboxylresistant strain to the alkylating agents.

Animals↗
PubMed1992

Phosphorus-containing metabolites in anthracycline-resistant murine leukemia P388 cells.

The method of 31P nuclear magnetic resonance was used to study in vivo the level of phosphorus-containing metabolites in P388 leukemia cells sensitive or resistant to rubomycin (daunomycin) and its nitroxyl analog-emoxyl. It was shown that decreased content of phosphomonoesters (PME) is characteristic of the resistant strains in comparison with the parent cells. Rubomycin and emoxyl were established not to affect practically the pool of phosphorus-containing metabolites in the cells of the resistant strains, but caused considerable increase of PME level in the cells of the parent strain.

Animals↗
PubMedDate not supplied

[The effect of thymalin on the count of large granular lymphocytes in the peripheral blood of mice with leukemia P388].

Effect of thymaline injections on peripheral blood natural killer cells in mice with p388 leukemia has been studied. The content of natural killers that have been identified as large granular lymphocytes decreased in blood of leukemia mice. Multiple thymaline injections (0.66 mg/kg) maintain the numbers of the lymphocytes at the level of control animals but did not increase the life span of leukemia mice.

Adjuvants, Immunologic↗
PubMed1993

[The cross resistance to cytostatics of leukemia P388 cells with induced resistance to doxorubicin].

Using BDF1 mice it has been shown that P388 leukemia tumor cells with induced resistance to doxorubicin (P388/DX) were cross-resistant to daunomycin, carminomycin, actinomycin D, vincristine and mitomycin C. It has been shown that P388/DX leukemia tumor cells were sensitive to bleocina, bleomycitina, cyclophosphamide, 5 fluorouracil. It has been discussed the ways of cross-resistance of P388/DX leukemia tumor cells to cytostatic drugs.

Animals↗
PubMed1982

Metabolism and therapeutic efficacy of 9-beta-D-arabinofuranosyl-2-fluoroadenine against murine leukemia P388.

The biochemical basis for the differential therapeutic activity of equally toxic doses of 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) administered on two schedules to tumor-bearing mice has been studied. A single dose (234 mg/kg) of F-ara-A in solution decreased the number of P388 leukemia cells by greater than 10(3), whereas a multiple-dose regimen (41 mg/kg every day for 5 days) of equal toxicity to the host was ineffective at reducing the tumor burden. No antitumor activity was seen when an equal dose of the relatively insoluble F-ara-A was injected as a suspension. The 5'-triphosphate of F-ara-A accumulated in P388 cells in levels proportional to the dose of the nucleoside and disappeared from these cells at an exponential rate with a half-life of 2.9 hr, which was independent of the cellular concentration of the nucleotide. The extent and duration of the inhibition of DNA synthesis of P388 cells was dependent on the dose of F-ara-A, but the rates of recovery were similar and in proportion to the cellular concentration of the analog triphosphate. The extent of the inhibition of DNA synthesis in host bone marrow and intestinal mucosa was also related to the dose of F-ara-A, but the recovery of these tissues proceeded to similar, incomplete levels (less than 60% of initial) 24 hr after F-ara-A injection of either 41 or 234 mg/kg. These results suggest that the equal toxicity of the two regimens of F-ara-A may be attributed to the similar extent of inhibition of host-tissue DNA synthesis evoked by each. In contrast, the greater extent and longer duration of inhibition of P388 cell DNA synthesis caused by the single dose of F-ara-A was responsible for its superior therapeutic activity. Measurements of F-ara-A triphosphate concentrations and the DNA-synthetic capacity of tumor and host tissues are determinants of the action of F-ara-A and may be used to predict optimal therapeutic dose schedules.

Animals↗
PubMed1987

Dihydrofolate reductase activity in adriamycin and methotrexate sensitive and resistant P388 leukemia cells.

P388 murine leukemia cells 18.4-fold more resistant to methotrexate (MTX) than the parent, drug susceptible line, were shown to possess a 1.5-fold higher dihydrofolate reductase (EC1.5.1.3) (DHFR) activity. This is in contrast to a MTX-resistant line, obtained from adriamycin-resistant cells, which is 27.9-fold more resistant to MTX and exhibits a 22.4-fold higher DHFR activity than that of the parent. The susceptibility of the enzyme to inhibition by MTX does not markedly change with the acquired drug resistance of the cell lines studied. Thus MTX-resistant cells obtained from an adriamycin-resistant line acquired resistance due to increased activity of the target enzyme, whereas other mechanisms are responsible for the resistance of cells derived from the adriamycin-sensitive parent.

Animals↗
PubMedDate not supplied

Antitumor activity of idarubicin, a derivative of daunorubicin, against drug sensitive and resistant P388 leukemia.

Idarubicin (IDA) possessed high antitumor activity against mouse P388 leukemia. When P388 leukemia bearing mice were administered an optimal dose of IDA intravenously, 200-250% of T/C and some cured mice were obtained. IDA showed a partial but significant effect against daunorubicin (DNR)-resistant P388 leukemia, whereas DNR, its parent drug, did not. Although IDA failed to show activity against doxorubicin (DX)- and aclarubicin (ACR)-resistant P388 leukemia in this study, IDA might have chemotherapeutic effects in patients in relapse and refractory to other anthracyclines. This assumption is supported by the results on the growth inhibition study in vitro. Among the metabolites, only idarubicinol showed cytotoxicity against P388 leukemia and idarubicinol showed 38% of the activity of IDA, indicating that the active components in animals could be IDA and idarubicinol. The combination of IDA and Ara-C induced some additive effect in P388 leukemia bearing mice as compared to the results with single drug usage.

Aclarubicin↗
PubMed1978

In vivo characteristics of resistance and cross-resistance of an adriamycin-resistant subline of P388 leukemia.

A subline of P388 leukemia resistant to adriamycin (P388/ADR) was developed by exposure to the drug in vivo. Resistance to adriamycin proved to be a stable characteristic of P388/ADR. There was no significant inhibition of nucleic acid synthesis in P388/ADR cells in vivo following a dose of 10 mg/kg of adriamycin in contrast to a prolonged and complete inhibition, particularly of DNA synthesis, observed in parental sensitive P388 leukemia cells. P388/ADR proved to be completely cross-resistant to a spectrum of anthracycline derivatives. Cross-resistance was observed to nonanthracycline DNA intercalating agents (with the exception of anthramycin), to agents which interfere with mitotic spindle function, and to antineoplastic inhibitors of protein biosynthesis (with the exception of bruceantin). P388/ADR was sensitive to antimetabolites and alkylating agents. Cross-resistance was also observed to several agents (ICRF-159, a terephthalanilide, taxol, lymphosarcin, bouvardin, and a crude extract of Ervatamia hyneana) whose mechanisms of action have not yet been clearly defined. This observation has proved useful in providing a lead for determination of mechanism of action of some of these drugs. The pattern of cross-resistance of a subline of P388 leukemia resistant to daunorubicin, though not studied extensively, appears to be similar to that of P388/ADR.

Animals↗
PubMed1977

Decreased retention of actinomycin D as the basis for cross-resistance in anthracycline-resistant sublines of P388 leukemia.

Sublines of P388 leukemia resistant to Adriamycin and daunorubicin were cross-resistant to actinomycin D in vivo and in vitro. The Adriamycin-resistant cell line was 1000-fold resistant to actinomycin D on 1-hr exposure in vitro and 370-fold resistant when exposed to the drug for 16 hr. The immediate binding of radioactive actinomycin D to sensitive and resistant cells was similar, and the uptake of the drug by the resistant cells was only about 27% less than the rate of uptake by sensitive cells. There was a dramatic difference in efflux of drug from sensitive and resistant sublines. Equivalent cytotoxicity of actinomycin D for the sensitive and resistant sublines was obtained at concentrations of the drug that resulted in approximately equivalent levels of net retention of actinomycin D (retained drug minus background levels of immediate binding of the drug to the cells). Incubation of cells in the presence of actinomycin D plus either Tween 80 or acridine orange incresed the rate of uptake and the percentage of actinomycin D retained by the resistant cells on short-term assays but did not reverse the resistance. It is concluded that these tumors must retain appreciable concentrations of actinomycin D for several hr in order to be killed. The anthracycline-resistant sublines are cross-resistant to actinomycin D by virtue of their inability to retain the drug.

Acridines↗
PubMed1999

Enhanced efficacy of 1-methyl-3-propyl-7-butylxanthine on the antitumor activity of doxorubicin against doxorubicin-resistant P388 leukemia.

The effects of 1-methyl-3-propyl-7-butylxanthine (MPBX), a xanthine derivative, on doxorubicin (DOX)-induced antitumor activity against DOX-sensitive P388 leukemia (P388) and DOX-resistant P388 leukemia (P388/DOX) have been examined. In P388-bearing mice, the combination of MPBX with DOX increased the antitumor activity of DOX 1.6-fold. In contrast, in P388/DOX-bearing mice, DOX alone did not decrease the tumor weight, whereas in combination with MPBX it significantly decreased the tumor weight in the control group by 50%. The increase in DOX-induced antitumor activity caused by MPBX was correlated with the DOX concentration in the tumors. The DOX concentration in the tumors of P388- and P388/DOX-bearing mice in the MPBX combination group increased by 1.3-fold and 2.2-fold, respectively, compared to the level in the DOX-alone group. On the other hand, there was no increase in the DOX concentration in the heart or liver in both types of tumor-bearing mice treated with MPBX. In vitro, the facilitated DOX influx and suppressed efflux by MPBX in both types of tumor cells were similar, suggesting that MPBX acts on the same site in both types of cells. P388/DOX overexpressed P-glycoprotein, i.e. the inhibitory order of DOX efflux caused by the inhibitor of P-glycoprotein was P388 < P388/DOX. However, the effect of MPBX was P388 > P388/DOX. Therefore, we expect that the site of attack by MPBX is not P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1980

Lymph node metastasis and effects of 1-beta-D-arabinofuranosylcytosine, 5-fluorouracil, and their lipophilic derivatives in an experimental model system using P388 leukemia.

Mouse P388 leukemic cells inoculated into the right forefootpad metastasized primarily to the right axillary lymph node. No significant metastasis to other lymph nodes or organs was detected on Day 12 after the inoculation of 10(6) P388 cells in the forefootpad, except that a lesser extent of metastasis was observed in some cases in the right inguinal lymph node, liver, and spleen. A quantitative estimation of metastasis in the axillary lymph node was accomplished by transferring the lymph node i.p. to the recipient mice (bioassay method). The metastasis of P388 cells to the axillary lymph node occurred linearly depending on the elapse of time after inoculation. In studying the chemotherapeutic effect on lymph node metastasis, two experimental models were established. Model 1, 10(6) P388 cells were inoculated into the right forefootpad, and drug was administered thereafter. The right axillary lymph node was removed on Day 8, and the extent of inhibition of lymph node metastasis was estimated by the bioassay method. In Model 2, P388 cells were inoculated, and the right forelimb including original tumor was amputated on Day 6 when the metastasis had already been established. The drug was given thereafter, and the extent of inhibition of metastasis was estimated on Day 12 by the bioassay method. In this experimental system, a lipophilic derivative N4-behenoyl-1-beta-D-arabinofuranosylcytosine was more effective than its parent compound 1-beta-D-arabinofuranosylcytosine; however, 5-fluorouracil was found to be more potent than its lipophilic derivative ftorafur for the inhibition of lymph node metastasis, suggesting an existence of various pharmacokinetic factors for the inhibition of lymph node metastasis.

Animals↗
PubMed1990

Inhibition of DNA biosynthesis by vincristine and pentoxifylline in murine P388 leukemia cells resistant to doxorubicin.

Pentoxifylline (PTX) is a methylxanthine used clinically in the treatment of intermittent claudication. It is an active hemorheological agent used for the treatment of defective microcirculation. The use of the anticancer agent vincristine is limited by its toxicity to normal body tissues. The data presented in the present paper show that it is possible to achieve greater cell-kill by using vincristine in combination with pentoxifylline. The effect of pentoxifylline alone and in combination with vincristine was studied using membrane filtration technique in P388 leukemia (P388) and its subline P388/DOX resistant to doxorubicin and cross-resistant to vincristine. Pentoxifylline (100 mumol/l) had minimal inhibitory effect on DNA biosynthesis in P388 leukemia cells. Vincristine, at the concentration employed in this study did not show significant inhibition of DNA biosynthesis confirming multidrug resistant nature of P388/DOX cells. Pentoxifylline had a dose-sparing effect, wherein it enhanced the antiproliferative activity of vincristine at a clinically achievable concentration. The studies on reversibility of inhibition of DNA biosynthesis in P388/DOX cells pretreated with vincristine and pentoxifylline showed the irreversible nature of the effect of combination of vincristine and pentoxifylline. This observation warrants the possible use of pentoxifylline as an adjuvant in cancer chemotherapy.

Animals↗
PubMedDate not supplied

Beta-adrenergic influences on doxorubicin-sensitive or -resistant P388 leukemia cells.

Taking into account the possible regulatory influences of the beta-adrenergic system on lymphocyte proliferation as well as the proposed role of cyclic 3'-5'-adenosine monophosphate (cAMP) in the modulation of multidrug resistance (MDR) in tumour cells, we have tried to assess the status of the interactions between the beta-adrenergic system and a mouse lymphocytic leukemia, the P388, both as a doxorubicin-sensitive (P388) and -resistant (MDR) variant (P388/DXR). P388 showed a low total number of high affinity 125I-pindolol binding sites (340 +/- 33/cell, Kd 108 pM) when compared with normal splenocytes (1221 +/- 67 sites/cell, Kd 97 pM). The number of beta-adrenergic receptors was even lower in P388/DXR cells (230 +/- 41 sites/cell, Kd 101 pM). In addition, these receptors were subnormally expressed on the cell surface: only 26% and 52% of the total receptors were surface receptors in P388 and P388/DXR, respectively, whereas it was 87% in normal splenocytes. Isoproterenol slightly (less than 1-fold) stimulated cAMP accumulation in P388 and P388/DXR; the stimulation observed in splenocytes was 2.5-fold. In addition, the basal levels of cAMP appeared to be low (0.48 +/- 0.05 pmoles/10(6) cells in P388 and 0.71 +/- 0.08 pmoles/10(6) cells in P388/DXR; 3.47 +/- 0.28 pmoles/10(6) cells in splenocytes) in the two leukemias and they were only slightly (less than 2-fold) increased by forskolin, which otherwise stimulated about 15-fold cAMP accumulation in splenocytes; thus, P388 and P388/DXR were probably also defective in their adenylate cyclase activity. It can be concluded that, owing to multifactorial mechanisms, the lymphocytic leukemia P388, also as an MDR variant, is minimally sensitive to the direct influences of the beta-adrenergic system, probably including any effect of this system on drug-sensitivity.

Animals↗
PubMed1990

Evaluation of quinidine effect on the antitumor activity of adriamycin and mitoxantrone in adriamycin-sensitive and -resistant P388 leukemia cells.

Utilizing the P388 murine leukemia cells sensitive (P388/S) and resistant (P388/ADR) to Adriamycin (ADR), we evaluated the effect of quinidine, an anti-arrhythmic agent, on the cytotoxic activity of ADR and Mitoxantrone (MITO), both in vitro as well as in vivo. Quinidine enhanced the cytotoxicity of both ADR and MITO in P388/S and P388/ADR cells, as assessed by the decrease in color intensity of formazan crystal in the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. A dose dependent inhibition of 3H-thymidine and 3H-uridine incorporation was observed when the P388/S and P388/ADR cells were exposed to quinidine alone. A non-toxic concentration of quinidine (5 microM) enhanced the DNA biosynthesis inhibition induced by ADR (55 to 65%) and MITO (37 to 44%) in P388/ADR cells, indicating reversal of resistance, while in P388/S cells only a minimal increase in DNA biosynthesis inhibition was observed. The combination of quinidine at doses of 50 to 100 mg/kg significantly potentiated the antitumor activity of ADR and MITO in P388/ADR bearing mice, whereas the potentiation of ADR and MITO antitumor response was lower in P388/S bearing mice. Quinidine increased the cellular levels of ADR by 53 to 126% in P388/ADR cells in vitro, but failed to indicate such elevated levels of cellular ADR in P388/S cells. This enhanced intracellular accumulation of ADR in P388/ADR cells, explains the therapeutic efficacy of ADR and MITO in P388/ADR, both in vitro as well as in vivo. Results suggest the efficacy of quinidine to ameliorate the antitumor effects of ADR and MITO in drug resistant tumor cells.

Animals↗
PubMed1987

[Characteristics of anthracycline-resistant strains of P388 leukemia].

Two strains of P388 murine leukemia with acquired resistance to rubomycin (P388/rm) and its nitroxyl derivative ruboxyl (P388/rx). The rubomycin resistance has been developed by the 14th generation and ruboxyl one-by the 8th generation. The growth kinetic patterns and the cell cycle time of the parent and resistant strains were similar. An increased tumourogenicity of both resistant strains cells was found. The resistance development was accompanied by the appearance of the additional chromosome materials, namely of homogeneously staining region (P388/rx) and of double chromatin bodies (P388/rm). The partial recovery of sensitivity to rubomycin occurred during 36 generations (1 year). Simultaneously the genetic markers have been lost. The recovery of sensitivity to ruboxyl in this period was not observed. The obtained resistant strains possessed the multidrug resistance: the cross resistance of P388/rm and P388/rx to actinomycin D, Vinca alkaloids and colchicine was shown.

Animals↗