Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The in vivo combination effect of navelbine (NVB, KW-2307) plus cisplatin was compared with that of vindesine (VDS) plus cisplatin in terms of antitumor activity and side effects. The antitumor activity of NVB or cisplatin against i.p. inoculated P388 leukemia was augmented by their combination on various schedules when the interval of administrations was within 24 h. Against i.v. inoculated P388 leukemia, the most significant combination effect was observed when cisplatin was administered 4 h after NVB injection (ILS(%) > 451) and three long-term survivors were observed. On this schedule, the combination of LD10 of each drug was achieved, indicating the lack of addition of toxicity. This was further proved by examination of body weight change, white blood cell count and platelet count. Interestingly, significant elevation of blood urea nitrogen concentration by cisplatin was prevented by the combination with NVB. The combination of maximum tolerated dose of NVB and cisplatin was also tolerable in nude mice, and their combination effect was observed against human lung large cell carcinoma Lu-65 and adenocarcinoma PC-12. The number of toxic death mice was more in VDS plus cisplatin-treated groups than in NVB plus cisplatin-treated groups, indicating that the combination chemotherapy of NVB plus cisplatin is a better regimen than that of VDS plus cisplatin in experimental tumor systems.
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PMID:Combination effect of navelbine (vinorelbine ditartrate) with cisplatin against murine P388 leukemia and human lung carcinoma xenografts in mice. 829 16

The novel cisplatin analogue D-17872 was studied for its anticancer activity using in vivo and in vitro preclinical models. The compound at the sublethal dose of 215 mg/kg (ca. 50% of the approximate LD50) induced no nephrotoxic effect strong enough to increase the blood urea level in rats. It had good in vivo antitumor efficacy against murine P388 (max. ILS: D-17872 132%, cisplatin 55%) and L1210 leukemia (max. ILS: D-17872 43%, cisplatin 38%), L5222 leukemia of the rat (max. ILS: D-17872 163%, cisplatin 163%) and murine B16 melanoma. Activity against P388 leukemia substantially exceeded that of cisplatin. Moreover, the M5076 reticulum cell sarcoma implanted into the subrenal capsule and the DMBA-induced mammary tumor of the rat were inhibited by D-17872 to a greater extent than by cisplatin (min. T/C: D-17872 -3%, cisplatin 11%). Using clonogenic microassays, D-17872 was active in vitro against a variety of human and rodent tumor cell lines, albeit at higher concentrations than cisplatin (IC50 values: D-17872 2.6-12.7 mumol/l, cisplatin 0.13-0.42 mumol/l). Apart from its cytotoxic action it was able to induce in vitro differentiation of the human HL-60 and K562 and of the murine M1-T22 cell lines, while cisplatin induced differentiation only in the HL-60 cell line. Thus D-17872 exhibited a pharmacological and toxicological profile different from that of the parent compound. The results suggest that induction of differentiation contributes to the antineoplastic efficacy of this novel cisplatin derivative.
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PMID:The antitumor activity of the platinum complex D-17872 is associated with tumor cell differentiation. 848 6

The antitumor effects of Behenoyl-ara-C (BH-AC) in combination with Idarubicin (IDA) on leukemia were studied. First, a combination of IDA with Ara-C, which is the main metabolite of BH-AC, was evaluated with regard to its in vitro cytotoxic activity on mouse P 388 leukemic cells. The effect of this combination proved to be additive according to isobologram analysis. Secondly, the antitumor activity of an intravenous bolus-administration of a combination of BH-AC and IDA was evaluated by the life span of P 388 bearing mice, and compared with the activity of the Ara-C and IDA combination. The antitumor activity of Ara-C administered alone was clearly dependent on the administration schedule and was most intense when Ara-C was administered with the most frequent injections (3 bolus injections/day x 3 days), whereas antitumor activity of BH-AC was less dependent on the schedule. IDA administered alone showed dose-dependency in its antitumor activity up to 3 mg/kg. The maximum effects of IDA were observed with amounts of 3 - 4 mg/kg. In the same leukemia model, the combination of frequent injections of BH-AC and a single injection of IDA (increased life span: ILS>300%; cure ratio: CR = 3/5) conferred a more potent effect compared to the results of BH-AC (ILS = 133%, CR = 0/5) or IDA (ILS = 67%, CR = 2/5) alone. The effect of BH-AC and IDA combination was comparable or superior to that of the Ara-C and IDA (ILS = 233%, CR = 2/5) combination. These results indicated the possibility of clinical usefulness with a combination therapy of BH-AC and IDA against leukemia.
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PMID:[Antitumor effects of Behenoyl-ara-C (BH-AC) in combination with Idarubicin (IDA) in P 388 leukemic cell bearing mice]. 871 21

Irinotecan (CPT-11) is a semi-synthetic derivative of camptothecin currently in clinical trials. In vitro, CPT-11 presented preferential cytotoxicity toward some solid tumor cells (mouse colon 38 and pancreas 03; human pancreas MIA PaCa-2) as compared to leukemia cells (L1210), whereas SN-38, a metabolite of CPT-11, was not solid tumor selective. In vivo, schedule of administration studies in P388 leukemia and mammary adenocarcinoma 16/C (MA16/C) showed that CPT-11 was not markedly schedule dependent. In order to determine its spectrum of anticancer activity, CPT-11 was evaluated against a variety of mouse and human tumors. The end points used were total log cell kill (Lck) for solid tumors and increase in life span (% ILS) for leukemia. Intravenous CPT-11 was found highly active against both early and advanced stage pancreatic ductal adenocarcinoma 03 (P03), with 60% long-term survivors and 100% complete regressions, respectively. Other responsive tumors included: colon adenocarcinomas 38 and 51 (both 1.0 Lck); MA16/C (3.4 Lck); MA13/C (1.0 Lck); human Calc18 breast adenocarcinoma (2.8 Lck); Glasgow osteogenic sarcoma (1.8 Lck); Lewis lung carcinoma (1.4 Lck); B16 melanoma (1.4 Lck); P388 leukemia (170% ILS) and L1210 leukemia (64% ILS). Of interest, CPT-11 was active against tumors with acquired resistance to vincristine (P388/Vcr), to doxorubicin (P388/Dox) and to docetaxel (Calc18/TXT). CPT-11 was also found highly active after oral administration in mice bearing P03 and MA16/C tumors. Pharmacokinetic evaluations performed i.v. at the highest non-toxic dosage in mice bearing P03 tumors revealed CPT-11 peak plasma concentrations (Cmax) of 8.9 micrograms/ml and a terminal half-life of 0.6 h. The metabolite SN-38 plasma concentrations presented a Cmax of 1.6 micrograms/ml and a terminal half-life of 7.4 h. Although the CPT-11 tumor levels were similar to the plasma concentrations for early time points, drug levels decreased more slowly in the tumor compared to plasma (half-life, 5.0 h). SN-38 tumor levels reached concentrations in the range of 0.32-0.34 micrograms/g and decayed with a half-life of 6.9 h. No significant difference in plasma or tumor pharmacokinetics of either CPT-11 or SN-38 were noted after one or five daily i.v. injections. Overall, these data show that CPT-11 has good activity in experimental models, when administered both by the i.v. and the oral routes. Compared to humans, a similar schedule of administration independence was observed and similar CPT-11 levels could be reached at efficacious dosages although metabolite SN-38 levels were found higher in mice.
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PMID:Experimental antitumor activity and pharmacokinetics of the camptothecin analog irinotecan (CPT-11) in mice. 882 13

Platinum complexes PtII(DAPO)X2 with diaminonitroxyl radical-trans-3,4-diamino-2,2,6,6-tetramethylpiperidine-1-oxyl (DAPO)-were synthesized by the direct reaction of DAPO with K2PtX4 (X = Cl, I) or by the replacement of chloro ligands in PtII(DAPO)Cl2 by bromo, nitrato, oxalato, malonato, and 1,1-cyclobutanedicarboxylato ligands. The complexes thus obtained were characterized by elemental analysis, infrared,electronic, electron paramagnetic resonance spectroscopic techniques, and high-performance liquid chromatography. The toxicity of compounds in terms of LD50 strongly depends on the nature of X-ligands, and varies between 11 mg/kg (X = NO3) and 400 mg/kg (X2 = 1,1-cyclobutanedicarboxylate). Up to 66% of mice bearing leukemia L1210 survive after the administration of these complexes. This effect is comparable to the effect of cisplatin (50% survive). An increase in the life span of the rest of the animals ranges from 158 to 383%. Complex PtII(DAPO)Cl2 appears to be more efficient than cisplatin against adenocarcinoma 755. Cisplatin, cis-diamminedichloroplatinum(II); CBDCA, 1,1-cyclobutanedicarboxylic acid; DAPO, trans-3,4-diamino-2,2,6,6-tetramethylpiperidine-1-oxyl; Mal, malonic acid; Ox, oxalic acid; IR, infrared; EPR, electron paramagnetic resonance; HPLC, high-performance liquid chromatography; Ca755, adenocarcinoma 755; LD50 and LD100, dose of compounds (mg/kg), causing a death of 50 or 100% or treated animals; ILS, increase in life span of mice.
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PMID:Synthesis and antitumor activity of platinum(II) complexes with trans-3,4-diamino-2,2,6,6-tetramethylpiperidine-1-oxyl. 883

The influence of 2-chlorodeoxyadenosine (2-CdA) and 2',2'-difluorodeoxycytidine (Gemcitabine, dFdC) on the survival time of mice bearing L1210 and P388 leukemias was investigated. Seventy-two male CD2F1 strain mice were used in the experiment. They were given 2-CdA (20 mg/kg) on days 1-5 after inoculation with leukemic cells (day 0) i.p. or dFdC (20 mg/kg) on days 1, 4, 7, and 10 i.p. The drugs were administered alone and in combination (sequential therapy) according to the following schedules: 2-CdA and dFdC at the same time at the doses given above; 2-CdA before dFdC, sequential therapy (2-CdA on days 1-5, then dFdC on days 6, 9, 12, 15); dFdC before 2-CdA, sequential therapy (dFdC on days 1, 4, 7, 10 and then 2-CdA on days 11-15). The animals were observed daily for survival for a minimum of 60 days. The efficacy of the therapy against leukemia (defined as the increase in lifespan, ILS) was assessed as the percentage of the median survival time (MST) of the treated group (T) to that of the control group (C): ILS = [(MSTc/MSTT-1] x 100. The survival time of mice bearing L1210 or P388 leukemia treated with dFdC before 2-CdA was significantly prolonged as compared with the animals receiving these agents separately. The prolongation of the survival time of the treated mice (ILS) compared with the untreated was 300% in case of L1210 and 241% in case of P388 leukemia. The combinations 2-CdA before dFdC and simultaneous injections of both drugs were not more effective than the treatment with dFdC alone. In case of L1210 leukemia, mice treated with these regimens showed a survival time similar to those treated with dFdC alone, although the survival time of mice bearing P388 leukemia treated with these regimens was shorter than that of mice given dFdC singly. Our study revealed that the most effective treatment schedule in both leukemias was dFdC given before 2-CdA. The results confirm the additive action of dFdC and 2-CdA.
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PMID:Additive action of gemcitabine (2',2'-difluorodeoxycytidine) and 2-chlorodeoxyadenosine on murine leukemias L1210 and P388. 1007 92

Combination of corticosteroids with new purine analogs such as cladribine 2-chlorodeoxyadenosine, (2-CdA) and fludarabine (FAMP) is controversial. The possibility of potentiation of antineoplastic activity of 2-CdA or FAMP by corticosteroids has not been documented so far. On the other hand, such combination may increase immunosuppression and the risk of infections. The aim of our study was to evaluate the influence of 2-CdA and dexamethasone (DEX) on the survival time of mice bearing lymphoid leukemias L1210 and P388. CD2F1 strain mice (132 male) were used in the experiment. The animals were injected i.p. on day 0 with 10(6) leukemic cells. The drugs were given on days 1-5 i.p. in the following concentrations: 2-CdA - 20 mg/kg, DEX 1.25 mg/kg, DEX 2.5 mg/kg, DEX 5 mg/kg, DEX 10 mg/kg, alone and in combination. The animals were observed daily for survival for a minimum of 30 days. The efficacy of the therapy against leukemia (defined as increase in lifespan - ILS) was assessed as the percentage of the median survival time (MST) of the treated group(t) to that of the control group(c): ILS(%) = (MSTt/MSTc) 100. The survival time of mice bearing L1210 or P388 leukemia treated with both drugs simultaneously was not longer than that of mice treated with either of drugs alone. Combination of 2-CdA and DEX in doses 5 and 10 mg/kg resulted in decrease of survival time of animals bearing P388 leukemia as compared with the control group without any treatment. Our study revealed that combination of 2-CdA with DEX in both leukemias is not more effective than 2-CdA alone. These results may indicate that routine addition of corticosteroids to purine analogs in the treatment of lymphoid malignancies is not warranted.
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PMID:Dexamethasone does not enhance antileukemic activity of cladribine in mice with leukemias L1210 and P388. 1104 40

We have used circular dichroism, hydrodynamic methods, absorbance, and fluorescence titration to study the interaction of 4-anilinopyrimido[4',5':4,5] selenolo (2,3-b)quinoline (APSQ) and 4-piperazinopyrimido[4',5':4,5] selenolo(2,3-b)quinoline (PPSQ) with DNA. The association constants of APSQ and PPSQ were of the order of 10(4)M(-1). The fluorescence properties at ionic strength 0.01M are best fit by the neighbor exclusion model, with K=0.58-9.2 x 10(4)M(-1) and an exclusion parameter of 0.9-6.4 bp. Binding to the GC-rich DNA of Micrococcus lysodeikticus was stronger than the binding to calf thymus DNA, suggest that drug binds preferentially to G+C pairs at low r. CD spectra indicate that stacking of these compounds with DNA induces a strong helicity in the usually disordered structure of this double strand. Viscosity experiments show with sonicated calf thymus DNA with PPSQ an twice increase in slope (m) as that with APSQ. PPSQ increases the T(m) for calf thymus DNA melting by approximately 10 degrees C as binding approaches saturation, with biphasic melting. The cytotoxicities of these compounds on leukemia HL-60, K-562, B16F10 melanoma and Colo-205 are quite similar and inhibition (IC(50)) was in the range of 0.39-9.80 microM. The anticancer efficacy against B16F10 melanoma has provided evidence of major anticancer activity for PPSQ. Single or multiple intraperitonial (i.p.) doses of drug proved high level activity against the subcutaneous (s.c.) grafted B16 melanoma, significantly increase in life span (ILS 139% and 170%). The aim of this study was to analyze the physiochemical properties of these compounds in an attempt to understand its superior biological activity.
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PMID:4-Anilinopyrimido[4',5':4,5]selenolo(2,3-b)quinoline and 4-piperazino pyrimido[4',5':4,5]selenolo(2,3-b)quinoline: new DNA intercalating chromophores with antiproliferative activity. 1618 98

Murine L1210 leukaemia cells expressing either the reduced folate carrier (RFC) or the membrane folate receptor (MFR) were studied in vitro and in vivo to assess the dynamics of membrane transport of two categories antifolates; folate-based inhibitors of dihydrofolate reductase (methotrexate, edatrexate, aminopterin, PT523, and PT644) and thymidylate synthase (TS) [CB3717, raltitrexed, plevitrexed (BGC9331), pemetrexed and GW1843]. The potency of in situ inhibition of TS was used as an endpoint to analyze the in vitro dynamics of RFC/MFR-membrane transport of these antifolates. Both for L1210-RFC and L1210-MFR cells, the potency of in situ TS inhibition was closely correlated with increasing affinities of these transporters for the antifolates (r = 0.64, P < 0.05 and r = -0.65, P < 0.05, respectively). Within the group of antifolates for which MFR had a low binding affinity, those that had the ability to become polyglutamylated, were more potent inhibitors of TS in situ activity than non-polyglutamatable antifolates. In vivo activity of methotrexate, edatrexate, raltitrexed and pemetrexed was assessed in L1210-RFC and L1210-MFR bearing mice that were fed either a standard or a folate-deficient chow. Dietary folate depletion significantly reduced the MTD for methotrexate (sevenfold), edatrexate (sevenfold), raltitrexed (50-fold) and pemetrexed (150-fold). Based on increased life spans, antitumor effects of methotrexate and edatrexate were markedly better in L1210-RFC bearing mice on the folate-deficient chow (ILS: 455 and 544%, respectively) than on standard chow (ILS: 213 and 263%, respectively). No therapeutic effects of methotrexate and edatrexate were observed for L1210-MFR bearing mice on either chow condition, which may be consistent with the low binding affinity for MFR. Irrespective of the folate diet status, pemetrexed and raltitrexed were inactive against both L1210-RFC and L1210-MFR bearing mice, which may be due to high circulating plasma thymidine levels. Collectively, this study underscores that modulation of dietary folate status can provide a basis within which the therapeutic effect of antifolates may be further improved.
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PMID:Dynamics of antifolate transport via the reduced folate carrier and the membrane folate receptor in murine leukaemia cells in vitro and in vivo. 1828 61

Nuclear distribution gene C (NudC) was first found in Aspergillus nidulans as an upstream regulator of NudF, whose mammalian homolog is Lissencephaly 1 (Lis1). NudC is conserved from fungi to mammals. Vertebrate NudC has three homologs: NudC, NudC-like protein (NudCL), and NudC-like protein 2 (NudCL2). All members of the NudC family share a conserved p23 domain, which possesses chaperone activity both in conjunction with and independently of heat shock protein 90 (Hsp90). Our group and the others found that NudC homologs were involved in cell cycle regulation by stabilizing the components of the LIS1/dynein complex. Additionally, NudC plays important roles in cell migration, ciliogenesis, thrombopoiesis, and the inflammatory response. It has been reported that NudCL is essential for the stability of the dynein intermediate chain and ciliogenesis via its interaction with the dynein 2 complex. Our data showed that NudCL2 regulates the LIS1/dynein pathway by stabilizing LIS1 with Hsp90 chaperone. The fourth distantly related member of the NudC family, CML66, a tumor-associated antigen in human leukemia, contains a p23 domain and appears to promote oncogenesis by regulating the IGF-1R-MAPK signaling pathway. In this review, we summarize our current knowledge of the NudC family and highlight its potential clinical relevance.
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PMID:Emerging roles of NudC family: from molecular regulation to clinical implications. 2696 24


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