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)

1-4-Amino-2-methylpyrimidin-5-yl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) is a water-soluble nitrosourea that has produced delayed hematological toxicity in man during Phase 1 clinical trials. ACNU has in vitro alkylating activy 40% less than that of 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose (chlorozotocin) but shares the property of negligible carbamoylating activity with the latter compounds. ACNU is highly active against murine L1210 leukemia. However, the maximum therapeutic dose, 30 mg/kg (a dose lethal to 10% of the animals), produced a 64% reduction in peripheral WBC and an 85% decrease in circulating neutrophils in normal mice. This was correlated with a 76% inhibition of normal mouse bone marrow DNA synthesis within 24 hr after treatment, followed by full recovery within 48 hr after treatment, followed by full recovery within 48 hr. In contrast, DNA synthesis in L1210 cells was suppressed to less than 10% of control for a minimum of 72 hr. While ACNU, a pyrimidine analog, possesses many of the chemical properties of chlorozotocin, it does not share with the latter compound its reduced myelotoxicity at therapeutic doses. The glucose carrier of the chlorozotocin molecule appears to impart the selective sparing of normal bone marrow.
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PMID:A comparison of the biological and biochemical properties of 1-(4-amino-2-methylpyrimidin-5-yl)methyl-3-(2-chloroethyl)-3-nitrosourea and 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose. 14 14

Antitumor activity of 6-thioguanine against L-1210 leukemia was studied in combination with various antitumor agents in clinical stages, such as mitomycin-C, carbazilquinone, cyclophosphamide, 3,3'-dimesyloxydipropylamine tosylate (864T), 4-hydroperoxyisophosphamide, and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chlorethyl)-1-nitrosourea hydrochloride (ACNU). The combination treatments with 6-thioguanine and each of six agents, especially with ACNU, showed a distinct therapeutic effect against the early L-1210 leukemia at dosage levels not producing any significant antitumor activity with each agent alone (ip-ip). The excellent antitumor activity of the combination of 6-thioguanine with ACNU was also proved in various sites of tumor inoculation and routes of drug administration systems, i.e., ip-iv, iv-ip, and iv-iv systems. Moreover, the effectiveness of the combination of these two drugs was clearly shown against advanced L-1210 leukemia which was refractory to each agent alone.
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PMID:Combination chemotherapy of 6-thioguanine with various antitumor agents against murine leukemia L-1210. 20 34

A transplantable mouse T cell leukemia, DL 812, is characterized by high sensitivity to 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-chloroethyl)-1-nitrosourea hydrochloride (ACNU) and intensive systemic infiltration. When subcutaneously inoculated, DL812 cells invade many organs and cause marked splenomegaly without forming local tumors. Disseminated DL812 leukemias are clinically completely cured by a single intraperitoneal injection of 1 mg ACNU, but more ACNU-resistant leukemias relapse immediately. A novel antitumor antibiotic, spergualin, is effective against various mouse leukemias. The effects of its analog with stronger anti-leukemia activity, 15-deoxyspergualin (DSG), on the relapse of DL812 leukemias after ACNU treatment were investigated. DDD mice were subcutaneously inoculated with 10(6) DL812 cells and intraperitoneally injected with 1 mg ACNU once on day 11 and with 100 micrograms DSG daily from day 12 on. The relapses were clinically completely suppressed for at least 30 days. Winn assays with spleen cells revealed that host immunity did not play a major role in maintenance of the clinical cure. Thus, when DSG treatment was discontinued after 15 or 30 daily injections, leukemias relapsed immediately. When it was extended to 50 daily injections, permanent cure was attained in 1 of 15 mice but relapses occurred under DSG treatment in the others. DSG is available for combined treatment of the leukemia. The current and previous results suggest that DL812 leukemias may serve as a model in study on immunochemotherapy of the disease.
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PMID:Spergualin treatment-dependent delayed relapse of mouse T cell leukemia (DL812) after chemotherapy. 179 66

Antitumor effect of CPT-11 in combination with cyclophosphamide (CY), nimustin hydrochloride (AC-NU), thio-TEPA (TESPA), methotrexate (MTX), 5-fluorouracil (5-FU), cytosine arabinoside (ara-C), thioinosine (6-MPR), adriamycin (ADM), bleomycin (BLM), mitomycin C (MMC), actinomycin D (ACT-D), vincristine sulfate (VCR), etoposide (VP-16) or cisplatin (CDDP) against L 1210 murine leukemia was investigated. The combination treatment of CPT-11 with CY, ACNU, ADM, CDDP, TESPA and ACT-D showed synergistic effects and significantly prolonged the survival time of L 1210-inoculated mice compared with CPT-11 alone or antitumor drug alone. Although the combination with 5-FU, 6-MPR, VP-16, MMC or VCR had synergistic effect for some schedules exceptionally with ara-C, MTX or BLM had slight synergistic effect against L 1210.
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PMID:[Combination therapy of CPT-11, a camptothecin derivative, with various antitumor drugs against L 1210 leukemia]. 190 Jun 84

Cytocidal effects of combined use of BH-AC and nitrosourea derivatives (MCNU, and ACNU) were evaluated in vitro against adriamycin-resistant human leukemia cell line (K-562/ADR-I). K-562/ADR-I cells were resistant to six kinds of agents (vindesine, mitoxantrone, aclacinomycin, cisplatin, MCNU, and BH-AC) of 14 agents tested and this cell line proved to be a multi-drug resistant line. Combined use of BH-AC and MCNU did not achieve additive effects on K-562, parent cell line and BH-AC and MCNU were less effective to K-562/ADR-I by single use. However, combination of BH-AC and MCNU showed additive effects. These results supported the evidence that combination of BH-AC with MCNU was effective in patients with multi-drug resistant malignant lymphomas.
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PMID:[In vitro effect of combined use of BH-AC and nitrosourea derivatives against adriamycin-resistant human leukemia cell line]. 195 59

Correlation between sensitivity to two cross-linking agents, 1-(4-amino-2-methylpyridine-5-yl)-methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) and cisplatin (DDP), and intracellular glutathione (GSH) level was investigated for two naturally drug-resistant human colon cancer cell lines in comparison with two drug-sensitive human leukemia cell lines. As a result, no appreciable correlation was observed between them. We also studied the possibility that DL-buthionine-S,R-sulfoximine (BSO), an inhibitor of GSH biosynthesis, can sensitize the cancer cells to these anticancer agents via depletion of intracellular GSH. It was found that BSO potentiated ACNU cytotoxicity against human leukemia K562 cells and DDP cytotoxicity against K562 and human colon cancer WiDr cells. It indicates that cancer cells with higher GSH level are more effectively sensitized by BSO regardless of degree of their intrinsic sensitivity to these anticancer agents. These results suggest that intracellular GSH level is not a common mechanism for natural resistance to cross-linking agents in human colon cancer cells but one of the determinants of sensitivity to these anticancer agents of GSH-rich cells.
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PMID:Intracellular glutathione levels in human colon cancer cells naturally resistant to cross-linking agents. 259 79

A case of malignant astrocytoma following radiotherapy for pituitary adenoma is presented in detail with a review of the literature. A 38 year-old housewife had developed a growth-hormone secreting pituitary adenoma, and received a total of 50 Gy at the pituitary region. Four years and six months later, she began suffering headache and vomiting. Computed tomography showed an extensive low density with ring enhancement in the right temporal region, corresponding to the previously irradiated field. A right frontotemporoparietal craniotomy was carried out, and a soft and reddish tumor was partially removed. The histological diagnosis was that of malignant astrocytoma. The patient was submitted to postoperative radiochemotherapy, receiving a total of 60 Gy, nimustine hydrochloride (ACNU), and tegafur (FT). Subsequently, after three months of clinical relief, she developed tumor regrowth, and died four months later. The present case fulfills the criteria for radiation-induced tumor established by Cahan et al.: A tumor location within irradiated area, no evidence of tumor prior to radiotherapy, a long latency period between radiation and tumor occurrence, and histological verification of the tumor. Thirty-nine cases of radiation-induced gliomas including the present case have been reported in the literature. It is noteworthy that the majority occur in the younger age bracket. Male preponderance is noted as it is in primary cerebral gliomas. The primary lesions for radiation frequently include leukemia and lymphoma. Craniopharyngioma, pituitary adenoma, and medulloblastoma etc are also included.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Malignant astrocytoma following radiotherapy in pituitary adenoma: case report]. 268 39

The combined effect of cisplatin (CDDP) with various types of antitumor drugs was examined in P 388 leukemia in vivo. Three representative drugs were chosen from every group of alkylating agents, antitumor antibiotics, antimetabolites, and plant originated drugs. According to their dependency on administration schedules, the dose-dependent and time-dependent drugs were administered once, and daily 5 times, respectively, before and after the single administration of CDDP. In addition to these sequential combinations, simultaneous treatment with CDDP was examined for the drugs which were singly administered. The combined effect was assessed by comparing ILS (increase in life span) in a combined group with the sum of ILS's of each of the 2 single-treatment groups. Synergistic effect was observed in the combination of CDDP with all drugs except MMC. Among them CYC, CQ, ACNU, ADR, PEP, ET, VCR, and VDS produced synergistic effect in any treatment schedules, irrespective of the combination sequences. In the cases of the combination with antimetabolites, the combined effect was depended on the treatment sequences; prior treatment of 5-FU, and posterior treatment of Ara-C and MTX to CDDP administration exhibited a synergistic effect, but the combination in reverse sequence remained almost additive.
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PMID:[Combined effect of CDDP with various types of antitumor drugs against P 388 leukemia]. 273 70

Seven transplantable leukemia lines were established from spontaneous leukemias and screened for 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(chloroethyl)-1-nitrosourea hydrochloride (ACNU) sensitivity in DDD mice. Three of them were classified as highly sensitive, two as sensitive and two as resistant to ACNU. A highly sensitive line, DL812, was extensively characterized from a therapeutic point of view. DL812 cells were so invasive as to produce enlargement of spleens and lymph nodes but not local tumors when injected s.c., markedly sensitive to in vitro ACNU exposure and moderately immunogenic. The invasion process of DL812 cells differed with the status of host immunity. Advanced DL812 leukemias were macroscopically completely cured with normalization of spleen and lymph node sizes 3-7 days after an i.p. injection of 0.5 mg ACNU, but more ACNU-resistant leukemias with splenomegaly and enlarged lymph nodes recurred thereafter. Recurring DL812 cells were approximately four times more resistant to in vitro ACNU exposure but maintained similar immunogenicity as compared to the original ones. Permanent cures of advanced leukemias were achieved by ACNU treatment plus subsequent adoptive transfer of immune splenocytes in 15% of diseased mice. The results suggest the importance of host antitumor immunity for permanent cures of highly drug-sensitive leukemias, overcoming drug resistance and relapse.
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PMID:Importance of antitumor immunity for complete cure of highly drug-sensitive leukemia in mice. 275 24

Previous studies have suggested that 1-(4-amino-2-methylpyrimidine-5-yl)-methyl-3-(2-chloroethyl) -3-nitrosoureahydrochloride (ACNU) and 1,(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) bind specifically to the nucleosomal DNA of murine bone marrow and L1210 leukaemia cells whereas the glucose nitrosoureas, 2-(3-(2-chloroethyl)-3-nitrosoureido)-2-deoxy-D-glucopyranose, (chlorozotocin, CLZ) and 1-(2-chloroethyl)-3-(-D-glucopyranosyl)-1-nitrosourea (GANU), bind preferentially to the linker DNA of bone marrow but not tumour cell chromatin. In order to provide an explanation for this differential, the DNA repeat and linker lengths in murine bone marrow and L1210 leukaemia cells were measured using electrophoresis of micrococcal nuclease-digested DNA. The linker length of bone marrow chromatin was approximately 22% longer than that in L1210 leukaemia cells from mouse ascites. The linker length of L1210 cells maintained in suspension culture was 27% less than in those from ascites fluid. The tissue-specific toxicity of sugar nitrosoureas and the differential binding of these drugs to chromatin does not appear to correlate quantitatively with differences in DNA linker length.
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PMID:DNA repeat length in chromatin from murine bone marrow and L1210 leukaemia cells. 293 Oct 97


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