UMLS:C0023418 - FACTA Search

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Query: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The therapeutic efficacy of 5-fluorouracil (FUra) and cis-dichlorodiamine-platinum (cis-DDP) in mice bearing transplantable leukemia and solid tumors was evaluated using different sequences of combination of these agents. The optimal sequence was cis-DDP administered 24 h after FUra. The administration of FUra at its maximally tolerated dose (MTD) followed 24 h later by low doses of cis-DDP yielded less toxicity and higher response rate against L1210 and colon 26 than the administration of these two agents in the opposite sequence or concurrently at the MTD. The sequence of administration of these two agents was not therapeutically important when the antitumor activity was evaluated against mice bearing lymphoma P388. These results indicate that the importance of sequencing of FUra and cis-DDP varies among different tumors. The biochemical basis for the therapeutic importance of sequencing in treatments with cis-DDP and FUra was investigated in mice bearing leukemia L1210 cells. While cis-DDP has no significant effects on the activity of thymidylate synthase (dTMP-S), the target enzyme for FUra action, recovery of dTMP-S inhibition following pretreatment with FUra was significantly delayed when cis-DDP was administered 12-24 h after the initial dose of FUra.
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PMID:The role of drug sequence in therapeutic selectivity of the combination of 5-fluorouracil and cis-platin. 262 82

Accumulating evidence has shown that thymic stromal-lymphoid interactions play a major role in the development of AKR thymic leukemia. A normal thymic stromal cell (TSC) line B6TE-A, which has been shown to support the in vitro growth of AKR leukemic T cells by forming multicellular complexes with them, was used to raise monoclonal antibodies. Three of these mAb, MTS 31, 32 and 38, in addition to 2 other MTS mAb, are abnormally expressed in the preleukemic and/or leukemic stages in AKR mice. These 5 MTS mAb, which detect antigens on both subpopulations of TSC and T cells, show some reduced cortical reactivity from the pre-leukemic period (MTS 32 and 35) to markedly depressed reactivity in the leukemic period (MTS 31, 32, 33, 35 and 38). While it appears that the major reduction is due to the loss of antigens from the cortical thymocytes, there is some indication that the stromal elements may be affected also. In addition, MTS 29, which was also produced in this study, while only reacting with rare thymic medullary cells in situ was densely distributed on cultured stromal cells from both normal and leukemic thymuses. In this report, the value of these MTS mAb for documenting various stages of AKR leukemogenesis has been clearly demonstrated: their possible modulatory effects on in vitro T cell leukemia growth is currently being investigated.
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PMID:Antigens shared by thymic stromal cells and T lymphocytes are abnormally expressed in AKR thymuses. 262 44

cis-Diamminedichloroplatinum(II) (cis-DDP) has a broad clinical application as an effective anticancer drug. However, development of resistance to the cytotoxic effects is a limiting factor. In an attempt to understand the mechanism of resistance, we have employed a host cell reactivation assay of DNA repair using a cis-DDP-damaged plasmid vector. The efficiency of DNA repair was assayed by measuring the activity of an enzyme coded for by the plasmid vector. The plasmid expression vector pRSVcat contains the bacterial gene coding for chloramphenicol acetyltransferase (CAT) in a configuration which permits expression in mammalian cells. The plasmid was transfected into repair-proficient and -deficient Chinese hamster ovary cells, and CAT activity was subsequently measured in cell lysates. In the repair-deficient cells, one cis-DDP adduct per cat gene was sufficient to eliminate expression. An equivalent inhibition of CAT expression in the repair-proficient cells did not occur until about 8 times the amount of damage was introduced into the plasmid. These results implicate DNA intrastrand cross-links as the lesions responsible for the inhibition of CAT expression. This assay was used to investigate the potential role of DNA repair in mediating cis-DDP resistance in murine leukemia L1210 cells. The parent cell line L1210/0 resembled repair-deficient cells in that about one adduct per cat gene eliminated expression. In three resistant L1210 cell lines, 3-6-fold higher levels of damage were required to produce an equivalent inhibition. This did not correlate with the degree of resistance as these cells varied from 10- to 100-fold resistant.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:DNA repair in cells sensitive and resistant to cis-diamminedichloroplatinum(II): host cell reactivation of damaged plasmid DNA. 274 29

Antitumor activity of a new platinum complex, oxalato (trans-l-1,2-diaminocyclohexane) platinum (II) (l-OHP), was studied. This water-soluble platinum complex showed a more prominent life-prolonging effect on a mouse leukemia L1210 than cisplatin (DDP). By an intermittent treatment schedule cured mice were observed at the optimal dose. In addition, a subline of L1210 having a 40-fold resistance to DDP (L1210/DDP) showed lack of cross-resistance to l-OHP both in vivo and in vitro. Especially in vivo l-OHP was more active against L1210/DDP than against the original L1210, and all mice were cured at doses of 6.25 and 3.12 mg/kg. l-OHP was also effective against several mouse tumors such as P388 leukemia, B16 melanoma, Lewis lung carcinoma, colon 26 and colon 38 adenocarcinomas, and M5076 fibrosarcoma, though its antitumor spectrum was somewhat different from that of DDP. The synthesis of both DNA and RNA in L1210 cells was inhibited by about 50% with exposure to 10 microM of l-OHP for 1 h, followed by postincubation in drug-free medium for 6-24 h, while only the inhibition of DNA synthesis was observed by DDP in the same experiment. If severe toxicity is not observed in preclinical study, l-OHP expected to be a new clinically active Pt complex.
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PMID:Antitumor activity of a new platinum complex, oxalato (trans-l-1,2-diaminocyclohexane)platinum (II): new experimental data. 279 Jan 45

Diethyldithiocarbamate (DDTC) has been shown to inhibit nephrotoxicity induced by cis-platinum (DDP) without inhibition of tumor response in the rat. We report here that DDTC at doses of 25-300 mg/kg inhibits DDP-induced nephrotoxicity and bone marrow toxicity in C57BL/6 X DBA/2F1 (hereafter called B6D2F1) mice, F344 rats, and beagle dogs and is also antiemetic in the dog. DDTC doses which afford excellent protection do not decrease median survival time following DDP treatment in L1210 and P388 leukemias, B16 melanoma, and Lewis lung and colon 26 carcinomas in B6D2F1 mice when DDTC is given 2 h after DDP. Preliminary experiments indicate that DDTC does not alter median survival time after treatment of P388 leukemia with the platinum analogues diammine(1,1-cyclobutanedicarboxylato)platinum(II) and cis-diisopropylamine-cis-dichloro-trans-dihydroxyplatinum(IV ). Maximum blood urea nitrogen levels after DDP treatment are reduced significantly by DDTC in all species; blood urea nitrogen elevation, total kidney platinum, weight loss, and leukopenia correlate with DDP-DDTC interval in the rat and indicate optimum protection at 2 h, the shortest interval examined. Bone marrow toxicity was assessed by peripheral white blood cell counts in all species and by marrow cellularity in the mouse. White blood cell nadirs were higher and bone marrow recovered more rapidly after DDTC compared with DDP given alone. DDP reduced marrow cellularity 50-60% in the mouse; administration of DDTC 2 h after DDP afforded no protection to the lymphocytes in the marrow but maintained the granulocyte + precursor population near control levels. DDTC plasma pharmacokinetic values have been determined after s.c., i.p., and i.v. administration in the mouse, rat, and dog. Peak plasma levels of 0.3-1.2 mM are observed after a 250-mg/kg dose, with a plasma half-life of 10-20 min. Our data indicate that DDTC may provide protection against most clinically significant toxicities arising from cis-platinum at doses which do not inhibit tumor response.
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PMID:Selective protection against cis-diamminedichloroplatinum(II)-induced toxicity in kidney, gut, and bone marrow by diethyldithiocarbamate. 300

In an attempt to find how much the low therapeutic effectiveness of antitumor drugs against so-called chemotherapy-refractory tumors such as colon carcinoma depends on drug sensitivity at the cellular level, sensitivity of five carcinoma cell lines (three colorectal, one pancreatic, and one renal) to nine typical anticancer agents was compared in vitro with that of four generally chemotherapy-susceptible leukemia cell lines. Sensitivity was assessed in terms of the percentage cell growth in control cultures, which was determined by exposing exponentially growing cells for 48 h to the following antitumor drugs: 1-(4-amino-2-methylpyridine-5-yl)-methyl-3-(2-chloroethyl)3-nitrosourea hydrochloride (ACNU), adriamycin (ADM), bleomycin (BLM), cisplatin (DDP), etoposide (VP-16), 5-fluorouracil (5FU), mitomycin C (MMC), methotrexate (MTX), and vinblastine (VLB). As expected, 10-fold or greater differences in sensitivity were scarcely ever observed between the two kinds of cell lines. Thus, we recorded a result of more (or less) sensitivity when there was a difference of 3-fold or more; and compared the drug sensitivity in every pair of carcinoma and leukemia cell lines (20 pairs for each drug). We found that carcinoma cell lines were less sensitive to VP-16, ADM, DDP, and MTX than leukemia cell lines in 18, 15, 12, and 10 of 20 pairs, respectively; only one opposite case was observed, with DDP. On the other hand, no such tendency between the two groups was observed with BLM, 5FU, or MMC. Overall, significantly different sensitivities were observed between them in 91 out of 180 pairs (i.e., 9 antitumor drugs x 5 carcinomas x 4 leukemias), and carcinoma cell lines were less sensitive than leukemia cell lines in 79 of these 91 pairs. These results suggest that the refractoriness of colon carcinoma, etc. to chemotherapy is, at least in part, due to low drug sensitivity of the tumor cell itself.
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PMID:Comparison of cellular basis of drug sensitivity of human colon, pancreatic, and renal carcinoma cell lines with that of leukemia cell lines. 316 59

DNA has been implicated as the critical intracellular target for cis-diamminedichloroplatinum(II) (cis-DDP) action. Inhibition of DNA synthesis is a consequence of platination and has become accepted as the critical step in cis-DDP-induced toxicity. We have previously demonstrated that, following incubation with cis-DDP, murine leukemia L1210 cells progress through synthesis only to arrest in the G2 phase of the cell cycle. The G2 arrest was transient at low drug concentrations and was persistent at higher concentrations with a concomitant loss of viability. Chinese hamster ovary cell lines both proficient and deficient for DNA excision repair have been used to analyze the relationship between inhibition of DNA synthesis and toxicity and to determine whether DNA repair is necessary for cell cycle progression. Two repair-deficient cell lines were hypersensitive to cis-DDP and demonstrated a marked arrest in the G2 phase. The arrest was transient over only a small range of concentrations. At higher concentrations, the arrest was persistent and the cells subsequently died. Incorporation of [3H]thymidine into macromolecules demonstrated no inhibition of DNA synthesis while these cells progressed through the S phase. In contrast, at higher, but nontoxic, concentrations of cis-DDP, the repair-proficient cells exhibited inhibition of DNA synthesis while in S. At toxic concentrations, these cells also arrested in G2. Therefore, direct inhibition of DNA synthesis correlated only with the concentration of drug and not with the different sensitivities of the cell lines. Arrest of cells in G2 did correlate with toxicity. In every cell line, the appearance of G2-arrested cells preceded cell disintegration. It is proposed that the G2-arrested cells preceded cell disintegration. It is proposed that the G2 arrest results from the inability of the cells to transcribe genes required for passage into mitosis. Cells proficient in DNA repair can circumvent this arrest by repairing the damaged DNA and permitting transcription to proceed. These results support the hypothesis that inhibition of DNA synthesis is not the critical step in cis-DDP-induced cytotoxicity.
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PMID:Influence of cis-diamminedichloroplatinum(II) on DNA synthesis and cell cycle progression in excision repair proficient and deficient Chinese hamster ovary cells. 318 81

DNA has been implicated as the critical target for cis-diamminedichloroplatinum(II) (cis-DDP)-induced cytotoxicity. In vitro, DNA-platinum adducts inhibit DNA synthesis. An assessment of the inhibition of DNA synthesis in murine leukemia L1210 cells demonstrated that, although cell division was halted, DNA replication continued for a period of time. The DNA underwent almost a complete doubling even in cells that did not divide. Flow cytometric analysis demonstrated a slowed synthetic phase which progressed to a block in the G2 phase of the cell cycle. The duration of the G2 block was proportional to the concentration of cis-DDP. Low concentrations of cis-DDP caused the cells to be transiently blocked in the G2 phase for 24 to 48 h. Higher concentrations of cis-DDP resulted in a G2 arrest that was not reversed by 96 h. After this time, the arrested cells appeared to disintegrate, rather than recover. Cell survival and trypan blue exclusion studies indicated that, at low drug concentrations, cells which had transiently arrested in the G2 phase survived, while at higher concentrations only a limited number of survivors were responsible for the observed recovery of growth. Analysis of DNA double-strand breaks showed that significant numbers of breaks only occurred at concentrations of cis-DDP that subsequently led to debris detectable on the flow cytometer and to loss of trypan blue exclusion. The formation of these breaks appeared to be the first detectable change that was indicative of cell death. It is proposed that cells arrest in the G2 phase because they are unable to transcribe damaged DNA and make mRNA essential for passage into mitosis. DNA repair probably overcomes this arrest. Cell death may therefore be a consequence of the inability to adequately recover transcription.
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PMID:Mechanism of cis-diamminedichloroplatinum(II)-induced cytotoxicity: role of G2 arrest and DNA double-strand breaks. 339 99

We used in parallel, to study the kinetics of cis-DDP cellular binding and distribution, a cL cell culture line established from L1210 murine leukemia ascites and its cLP derivative which acquired a 30-fold (ID50) resistance to cis-diamminedichloroplatinum(II). Cell cultures were incubated with 0.9 microgram/ml (3 microM) of the drug and after various incubation times up to 24 hr, the amount of platinum associated to whole cells, to isolated nuclei and to purified DNA was determined using atomic absorption spectrophotometry. For the first hours of incubation no significant difference in the rate of platinum association was observed between the two cell lines. After the first hours of incubation the amount of platinum associated to whole cells and to isolated nuclei was significantly higher in the drug sensitive cells. However, the rates of platinum association to the respective DNAs were quite similar in the two cell lines. Our study failed to demonstrate any significant quantitative modification of the overall drug-DNA association between the resistant and sensitive cell lines.
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PMID:Interaction of cis-diamminedichloroplatinum(II) with sensitive and resistant L1210 cell lines. Drug binding to nuclei and DNA. 342 97

A series of water-soluble N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes (IDP) were synthesized and tested for chemical stability, antitumor activity, and toxicity. The results obtained suggest that these complexes are relatively stable for more than 48 h when dissolved in water or phosphate buffer. All complexes had good in vitro cytotoxicity and were not cross-resistant with cis-dichloro-diammineplatinum(II) (DDP) in a DDP-resistant cell line in vitro. When the complexes were administered as a single i.p. injection to C57BL/6 X DBA/2F1 (hereafter called B6D2F1) mice inoculated with L1210 leukemia cells, a significant increase in mean survival time was observed, but there were few long-term survivors. When the complexes were administered on Days 1, 5, and 9 after tumor inoculation, however, cure rates of 50 to 85% were obtained. The oncolytic activity of the IDP complexes against L1210 ascites appeared much greater than that of DDP. The IDP complexes also had good antitumor activity when administered i.p. on Days 1, 5, and 9 following i.p. inoculation of B16 melanoma to B6D2F1 mice. Five of the six IDP complexes had no significant nephrotoxicity (as evidenced by lack of elevated blood urea nitrogen levels). N-Benzyl-iminodiacetato(1,2-diaminocyclohexane)-platinum(II) resolved into three distinct peaks of UV-absorbing material that corresponded with three distinct peaks of platinum-containing material. The exact chemical identity of the active component of this mixture is currently under investigation. The results obtained to date, however, suggest that the N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes are good candidates for further developmental studies.
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PMID:Water-soluble N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes as potential antitumor agents. 377 45

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