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

These investigations were performed to clarify the molecular basis for the enhanced expression of cytosolic aldehyde dehydrogenase (ALDH-1) enzymatic activity in the cyclophosphamide-resistant L1210/CPA murine leukemia cell line, as compared to the parental L1210/O strain. Western immunoblot analysis was performed using a 15-fold greater quantity of cytosolic protein from the L1210/O as compared to the L1210/CPA cell line. Nevertheless, ALDH-1 immunoreactive protein could be detected only in the L1210/CPA cells. Northern analyses, performed using total cellular and polyadenylated RNA, again demonstrated ALDH-1-specific transcripts only in the L1210/CPA cell line. This transcript was identical in size to the ALDH-1 message expressed by normal murine hepatocytes. On Southern analysis, no evidence of gene amplification, gene rearrangement, or significant mutations of length was detected. These studies suggest that the ALDH-1 protein produced by the L1210/CPA cell line is structurally normal. Moreover, overexpression of the gene does not appear to have arisen as a result of an incremental process, such as gene amplification. Rather, a qualitative abnormality in the regulation of this gene appears to exist in the L1210/CPA cells, which distinguishes them from L1210/O cells and from normal murine lymphocytes.
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PMID:Structure and expression of the cytosolic aldehyde dehydrogenase gene in cyclophosphamide-resistant murine leukemia L1210 cells. 174 71

Cyclosporin A (CsA) is an effective modulator of multidrug resistance (MDR) in vitro and in murine tumour systems in vivo. We now report the production of immunity to L1210 leukaemia by the addition of CsA to VP-16 therapy of leukaemic BDF/1 mice. VP-16/cyclosporin A tumour immunity induction arises as a consequence of active therapy independently of immunisation with modified tumour cells. The addition of CsA to VP-16 prolongs survival of BDF/1 host mice bearing L1210 leukaemia beyond that produced by equivalent dose VP-16 alone. A subpopulation of 60-day surviving mice after combined VP-16/CsA are immune to rechallenge with the same leukaemia inoculum to which they were originally exposed. Spleen cells from immune mice adoptively transfer anti-L1210 leukaemia immunity to untreated BDF/1 mice in a dose dependent, statistically significant manner. Adoptive transfer experiments additionally suggest active recruitment of immunologic response in recipient animals: (1) We have been able to perpetuate leukaemia immunity in four sequential cohorts of naive recipient mice. This propogation of adoptive immunity is accomplished by use of spleen cells harvested from each preceeding passively-protected animal cohort; (2) Cyclophosphamide pretreatment of adoptive transfer recipient mice abrogates the ability of their splenocytes to perpetuate passive protection in sequential adoptive transfer experiments.
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PMID:Development of cyclosporin A mediated immunity in L1210 leukaemia. 176 73

Lymphoblasts from 11 patients with acute lymphoblastic leukaemia (ALL) of precursor-B type were exposed to the cyclophosphamide derivative mafosfamide (ASTA-Z-7654), and examined for growth inhibition using an in vitro colony assay. Leukaemic clonogenic cells were significantly more resistant to this cytotoxic drug (mean IC50 29.2 micrograms/ml, IC90 64.8 micrograms/ml) compared with myeloid progenitors from seven normal bone marrow samples (mean IC50 9.0, IC90 19.9) (p less than 0.0001). This effect was most pronounced in the four previously treated cases examined (mean IC90 84.4 micrograms/ml). The implications of these findings for bone marrow purging with ASTA-Z in patients with ALL for autologous marrow transplantation are discussed.
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PMID:Effect of mafosfamide (ASTA-Z-7654) on the clonogenic cells in precursor-B acute lymphoblastic leukaemia: significance for ex vivo purging of bone marrow for autologous transplantation. 176 69

The anti-tumour effects of methoxyphenyl maleamic acid (MPMA) and cytotoxic drugs, in combination were investigated on P388 leukaemia and S180 (ascites) tumours. Simultaneous administration of MPMA with CTX or HN2 resulted in enhancement of anti-tumour activity. The increased activity was observed against P388 leukaemia, whereas S180 (ascites) tumour was not responsive to the combined treatment. The possible mechanism (s) of action, responsible for the modulation of activity of CTX and HN2 against P388 tumour have been postulated.
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PMID:Methoxyphenyl maleamic acid augments the activity of cytotoxic drugs against murine tumours. 176 80

We previously reported that cimetidine but not ranitidine significantly enhances cyclophosphamide-induced bone marrow toxic effects and the appearance of cyclophosphamide alkylating species in a murine leukemia mouse model, and we advised caution in the use of cimetidine with microsomally metabolized anticancer drugs. Both drugs have been used for the treatment of gastric complications of chemotherapy. Using a randomized, double-blind, crossover study design, we have now evaluated the potential interaction of ranitidine with cyclophosphamide in seven cancer patients, who received two courses of cyclophosphamide, one with ranitidine and one with placebo. Four patients received ranitidine in the first course, and three received placebo. Ranitidine or placebo was started 3 days before a single dose of cyclophosphamide and given for 17 consecutive days. Ranitidine or placebo was given orally (300 mg/d), and cyclophosphamide (600 mg/m2) was given intravenously with [3H]cyclophosphamide (1000 muCi). Cyclophosphamide treatment was repeated at 4 weeks plus or minus 4 days. Blood samples were collected at intervals from 5 minutes to 24 hours after cyclophosphamide treatment and analyzed by thin-layer chromatography and radioassay for the drug and its metabolites. On days 0, 7, 14, and 21 after cyclophosphamide administration, complete blood cell counts, white blood cell differential counts, platelet counts, and SMA-17 were determined. The differences in mean nadir white blood cell counts, granulocyte counts, hemoglobin levels, and hematocrit values during ranitidine versus placebo treatment were not statistically significant. In a statistical but not a clinical sense, mean nadir platelet counts were significantly lower with ranitidine. There was a statistically significant increase in area under the curve for drug concentration in plasma x time (AUC) with ranitidine as well as a statistically significant decrease in the total-body clearance rate of the cyclophosphamide molecule. However, the effect on AUC for the major oncolytic metabolites 4-hydroxycyclophosphamide and phosphoramide mustard was not statistically significant. The lack of toxicologic or metabolic interaction between ranitidine and cyclophosphamide suggests that ranitidine can be used safely with cyclophosphamide.
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PMID:Lack of ranitidine effects on cyclophosphamide bone marrow toxicity or metabolism: a placebo-controlled clinical trial. 177 May 53

2(R,S)-D-ribo-(1',2',3',4'-Tetrahydroxybutyl)-thiazolidine-4(R)-ca rboxylic acid (RibCys) is a prodrug of L-cysteine that releases the sulfhydryl amino acid after nonenzymatic ring opening and hydrolysis. The L-cysteine then elevates glutathione (GSH) levels by stimulating its biosynthesis. RibCys was investigated for its ability to protect CDF1 mice from the potent urotoxicity of cyclophosphamide (CTX) without compromising the therapeutic utility of the drug. RibCys induced a significant reduction in weight loss of the animals and in bladder inflammation at 48 h after CTX administration; however, bladder tissue remained inflamed as compared with that in controls. Bladder histology also showed some pathological changes in the presence of RibCys. In contrast, all parameters of toxicity (body weight loss, bladder inflammation, and pathological abnormalities) had been virtually reversed by day 21 after administration. In tests against L1210 leukemia, RibCys did not interfere with CTX anticancer activity. From these preliminary studies, RibCys appears to be a likely candidate for protecting against long-term CTX toxicity, perhaps reversing the original damage caused by a very high dose, without compromising the therapeutic utility of the alkylating agent.
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PMID:L-cysteine prodrug protects against cyclophosphamide urotoxicity without compromising therapeutic activity. 185 73

The B-cell leukemia line, DL811, established in DDD mice, has been characterized by strong immunogenicity leading to occasional spontaneous cure with tumor dormancy. Cyclophosphamide (CY) is an available chemo-immunotherapeutic agent. The effects of CY on the cure and dormancy of DL811 leukemias were investigated. Simultaneous injection of DL811 cells and CY into athymic nude mice revealed that DL811 cells were sensitive to CY doses of 0.5 mg and more per mouse in a dose-related manner. A single dose of 1 mg CY on day 7 after DL811 cell inoculation was most curative of disseminated leukemias (cure rate: 50-80%) as compared with other single CY doses at different times. Cured mice were strongly immune to DL811 leukemias. This therapeutic modality had no curative effect in athymic nude mice. Relapses occurred occasionally in CY-cured mice and most relapsed tumors had the same surface phenotype as that of the DL811 leukemia. In comparison with DL811 leukemias, however, relapsed tumors were less sensitive to rejection by cured mice and less frequently cured by a single dose of 1 mg CY on day 7 of inoculation, implying that they changed in antigenicity and drug sensitivity. Whole-body irradiation of 400 rad gamma-rays to cured mice raised the incidence of relapses from 22.9 to 44.7% and that of deaths from relapses from 8.6 to 26.3%. Thus, leukemic cells may survive against host immune surveillance in a dormant state and relapse after changing their immunologic and chemotherapeutic natures. Lyt-2+, L3T4- T cells appeared to mediate host anti-tumor immunity to eradicate leukemic cells and maintain dormant state.
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PMID:Survival of leukemic cells in a dormant state following cyclophosphamide-induced cure of strongly immunogenic mouse leukemia (DL811). 187 74

HO-221, N-[4-(5-bromo-2-pyrimidinyloxy)-3-chlorophenyl]-N'-(2- nitrobenzoyl) urea is a new benzoylphenylurea derivative. The compound exhibits significant antitumor effects against various animal tumors, and was especially effective against the solid tumors implanted subcutaneously. HO-221 inhibits DNA polymerase alpha activity strongly in vitro. In this study, we examined the cross-resistance of HO-221 to various antitumor agents using sublines of mouse leukemia. HO-221 showed antitumor effects in mice bearing L 1210 or P 388 leukemia resistant to 10 antitumor agents, DM (daunomycin), MMC (mitomycin C), CDDP (cisplatin), 5-FU (5-fluorouracil), Ara-C (cytosine arabinoside), MTX (methotrexate), CPA (cyclophosphamide), CQ (carboquone), ADM (adriamycin) and VCR (vincristine), respectively. These antitumor agents were also effective in P 388 leukemia resistant to HO-221 (P 388/HO-221). Furthermore, CDDP- and MMC-resistant sublines showed a collateral sensitivity to HO-221 in vivo. The grow the inhibitory effects were also noted in vitro in ADM-, CDDP- and MMC-resistant cells by HO-221. However, the in vitro experiments didn't show such collateral sensitivity on the resistant sublines. These results suggest that there is no cross-resistance between HO-221 and other known antitumor agents, and that HO-221 seemed to be worth for evaluating clinical usefulness.
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PMID:[Cross-resistance of HO-221 and various antitumor agents in sublines of mouse leukemia]. 189 47

Cyclophosphamide (Cy), an alkylating agent widely used in chemotherapy of leukemia and cancer, causes a well-documented toxicity on hematopoietic and lymphoid cells. Neutropenia is thought to be the main factor involved in infectious complications following antimitotic chemotherapy. Little is known on the effects of these therapies on the mucosal associated lymphoid system which is one of the main barriers against environmental pathogenic agents. The present study examined the effects of a single administration of Cy (200 mg/kg) on murine T and B cell populations of Peyer's patches (PPs), IgA secretion in the proximal part of the small intestine, and plasma cells of the lamina propria. Cy induced in mice a transient decrease in the T and B cell populations of the PPs with a drastic fall of B cell counts and a profound decrease of intestinal IgA secretion due to a reduction of lamina propria plasma cells. This transient secretory IgA deficiency may contribute to the infectious complications following antimitotic chemotherapy.
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PMID:Transient secretory IgA deficiency in mice after cyclophosphamide treatment. 195 41

To explain the sequence-dependent in vitro cytotoxic synergism between 4-hydroperoxycyclophosphamide (4-HC) and cisplatin in the K-562 human leukemia cell line, we have hypothesized that 4-HC decreases cellular glutathione (GSH) levels and that the resulting diminution of the cellular protective effect of GSH leads to the increased cytotoxicity of cisplatin. Exposure of K-562 cells to 4-HC resulted in a concentration- and time-dependent depletion of cellular GSH. To determine the effect of modulation of GSH levels on the toxicity of cisplatin, K-562 cells were exposed to buthionine sulfoximine (BSO) and/or GSH ethyl esters. Depletion of GSH to approximately 10% of control values by BSO potentiated the cytotoxicity of cisplatin, while rapid replenishment of GSH to within normal levels by GSH esters abolished the potentiation of BSO. Doubling cellular GSH by incubation with GSH esters protected against cisplatin cytotoxicity. Of importance, pretreatment of K-562 cells with BSO, in addition to increasing the cytotoxicity of 4-HC and cisplatin, abolished the synergism between the two drugs. The working hypothesis was also tested in two other cell lines in which the cytotoxic synergism between 4-HC and cisplatin was exhibited: the Raji cell line, a human lymphoblastic cell line, and the L1210-CPA cell line, a subclone of the murine L1210 leukemia with resistance to 4-HC. GSH levels in these two cell lines were not altered by incubation with concentrations of 4-HC at which the synergism was observed. In conclusion, the data for the K-562 cell line, indicating that (a) 4-HC depletes cellular GSH levels, (b) the lowering of cellular GSH levels enhances the toxicity of cisplatin, and (c) intact GSH stores are required for the synergism, strongly support the postulate that the cytotoxic synergism between 4-HC and cisplatin is modulated by GSH levels in this cell line. However, the lack of 4-HC-mediated depletion of GSH at concentrations of 4-HC resulting in cytotoxic synergism in the Raji and L1210-CPA cell line indicates that mechanisms other than modulation of GSH levels by 4-HC are responsible for the synergism in these cells.
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PMID:Role of glutathione in the in vitro synergism between 4-hydroperoxy-cyclophosphamide and cisplatin in leukemia cell lines. 202 33


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