Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new class of compounds, 9-[(2RS)-3-fluoro-2-phosphonylmethoxypropyl] [(RS)-FPMP] derivatives of purines, is described that has selective activity against a broad spectrum of retroviruses [including human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2)] but not other RNA or DNA viruses. This activity spectrum is completely different from that of the parental compounds, 9-[(2S)-3-hydroxy-2-phosphonylmethoxypropyl] [(S)-HPMP] derivatives of purines, which are active against a broad range of DNA viruses. The racemic (RS)-FPMP derivatives of adenine and 2,6-diaminopurine, termed (RS)-FPMPA and (RS)-FPMPDAP, respectively, are markedly more selective as in vitro antiretroviral agents than their 9-(2-phosphonylmethoxyethyl) (PME) counterparts, PMEA and PMEDAP. Also, (RS)-FPMPA and (RS)-FPMPDAP have a substantially higher therapeutic index in mice in inhibiting Moloney murine sarcoma virus-induced tumor formation and associated death and are markedly less inhibitory to human bone marrow cells than PMEA and PMEDAP. The diphosphate derivative of (RS)-FPMPA [(RS)-FPMPApp] is a potent and selective inhibitor of HIV-1 reverse transcriptase but not of HSV-1 DNA polymerase or DNA polymerase alpha. (RS)-FPMPApp, akin to PMEA diphosphate (PMEApp), acts as a DNA chain terminator. The DNA chain-terminating properties of PMEApp and (RS)-FPMPApp seem to be a prerequisite for acyclic nucleoside phosphonates to exhibit antiretrovirus (i.e., anti-HIV) activity.
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PMID:9-[(2RS)-3-fluoro-2-phosphonylmethoxypropyl] derivatives of purines: a class of highly selective antiretroviral agents in vitro and in vivo. 171 Dec 14

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) and 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) are selectively inhibitory to human immunodeficiency virus and other retroviruses. We have now investigated the effects of different PMEA and PMEDAP treatment schedules in newborn mice infected with Moloney murine sarcoma virus (MSV). Administration of a single dose of PMEA or PMEDAP on the day of MSV inoculation conferred a greater protective effect against MSV-induced tumor formation than when this dose was divided over two, four or seven injections per week. Also, the therapeutic index of PMEA and PMEDAP was increased if administered as a single dose. Furthermore, PMEA and PMEDAP afforded a marked antiviral protection if administered within one day before MSV infection. Thus, single doses of PMEA or PMEDAP, when administered shortly before or after MSV infection, appear to be effective in preventing the manifestations of the retroviral disease.
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PMID:Single-dose administration of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) in the prophylaxis of retrovirus infection in vivo. 177 76

The acyclic purine nucleoside analogue 9-(2-phosphonomethoxyethyl)adenine [PMEA; formerly referred to as 9-(2-phosphonylmethoxyethyl)adenine] is a potent and selective inhibitor of human immunodeficiency virus replication in vitro and of Moloney murine sarcoma virus-induced tumor formation in mice. In the latter system PMEA has stronger antiretroviral potency and selectivity than 3'-azido-3'-thymidine (AZT). We have now investigated the effect of the drug in cats infected with the feline immunodeficiency virus (FIV). In vitro, PMEA was found to efficiently block FIV replication in feline thymocytes (50% effective dose, 0.6 microM). When administered to cats at doses of 20, 5, or 2 mg/kg per day, PMEA caused a dose-dependent suppression of FIV replication and virus-specific antibody production. Seropositive field cats with signs of opportunistic infection (gingivitis, stomatitis, and diarrhea) showed clinical improvement during PMEA therapy (5 mg/kg per day) and recurrence of the disease after treatment was discontinued. Thus, FIV infection in cats is an excellent model to test the efficacy of selective anti-human immunodeficiency virus agents in vivo.
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PMID:Suppression of feline immunodeficiency virus infection in vivo by 9-(2-phosphonomethoxyethyl)adenine. 215 2

9-(2-Phosphonylmethoxyethyl)adenine (PMEA), a potent inhibitor of human immunodeficiency virus (HIV), caused a dose-dependent suppression of tumor formation, and mortality associated therewith, in 6-day-old NMRI mice inoculated intracerebrally with Moloney murine sarcoma virus (MSV). Even at a dose as low as 1 mg/kg/day, PMEA effected a significant delay in tumor formation. When evaluated in parallel with PMEA, 3'-azido-2',3'-dideoxythymidine (AZT) conferred a comparable tumor-inhibitory effect at a 5- to 10-fold higher dose than PMEA. Prolonged treatment of MSV-infected mice with PMEA resulted in long-term survivors without apparent signs of tumor development. In view of the propensity of HIV to spread to the central nervous system (CNS), the marked activity shown by PMEA against experimental retrovirus infection of the brain in mice points to its potential in the treatment of AIDS and other retrovirus infections of the CNS.
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PMID:Inhibitory effects of 9-(2-phosphonylmethoxyethyl)adenine and 3'-azido-2',3'-dideoxythymidine on tumor development in mice inoculated intracerebrally with Moloney murine sarcoma virus. 230 39

Phosphonylmethoxyalkylpurine analogues were evaluated for their antitumor activity in murine tumor models. Three compounds, (S)-9-[(3-hydroxy-2-phosphonylmethoxy)propyl]adenine (HPMPA), 9-[(2-phosphonylmethoxy)ethyl]adenine (PMEA), and 9-[(2-phosphonylmethoxy)ethyl]guanine (PMEG) were modestly active with treated versus control (T/C) values of 125%-175% versus intraperitoneal P388 leukemia, but were inactive versus intravenously implanted P388. The most active and most potent of the three was PMEG, which was also evaluated against subcutaneously (SC) implanted B16 melanoma. In confirmatory experiments, optimal therapy with PMEG yielded reproducible increases in life span (T/C values of 164%-170%) and delays in primary tumor growth (7.3- to 13.0-day T-C values). PMEG is representative of a new class of antitumor antimetabolites heretofore recognized only for their antiviral properties.
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PMID:In vivo antitumor activity of 9-[(2-phosphonylmethoxy)ethyl]-guanine and related phosphonate nucleotide analogues. 231 24

Different treatment schedules have been investigated when evaluating the inhibitory effect of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and 3'-azido-2',3'-dideoxythymidine (AZT) on the replication of human immunodeficiency virus type I (HIV-I) in MT-4 cells, transformation of C3H/3T3 cells by Moloney murine sarcoma virus (MSV), and MSV-induced tumor formation in newborn NMRI mice. Shortening the exposure time of HIV-I-infected MT-4 cells to PMEA or AZT led to an increase in the selectivity index of both compounds. PMEA proved markedly more efficient in suppressing MSV-induced tumor formation in mice when administered as a single dose on the day of infection than when these doses were spread over 2, 4 or 7 administrations within 1 week after the virus infection. This was not observed when the total dose of AZT was fractionated. While the infrequent dosage regimen increased the anti-retrovirus activity of PMEA, it did not increase its toxicity for the host. This unique property makes PMEA an attractive candidate for the treatment of retrovirus infections, including AIDS.
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PMID:Anti-retrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in vivo increases when it is less frequently administered. 238 80

9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) is a potent inhibitor of the replication of human immunodeficiency virus (HIV) in human T-lymphocyte MT-4 cells (50% effective dose: 2 microM). PMEDAP strongly inhibited Moloney murine sarcoma virus (MSV)-induced transformation of murine C3H/3T3 embryo fibroblasts and caused a dose-dependent suppression of tumor formation and mortality in newborn mice inoculated with MSV. Even at a dose as low as 0.25 mg/kg/day, PMEDAP effected a significant delay in tumor appearance and an enhancement of the survival rate of tumor-bearing mice. PMEDAP proved fivefold more efficacious as an anti-MSV agent than 9-(2-phosphonylmethoxyethyl)-adenine (PMEA), which has been previously shown to exhibit strong antiretroviral efficacy in vivo. However, PMEDAP was also more toxic, so that its therapeutic index was equivalent to that of PMEA.
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PMID:9-(2-Phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP): a novel agent with anti-human immunodeficiency virus activity in vitro and potent anti-Moloney murine sarcoma virus activity in vivo. 255 45

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is a potent and selective inhibitor of the replication of human immunodeficiency virus (HIV) in vitro in human T-lymphocyte MT-4, H9, and ATH8 cells. PMEA also inhibits Moloney murine sarcoma virus (Mo-MSV)-induced transformation of murine C3H embryo fibroblasts. Moreover, PMEA causes a dose-dependent suppression of tumor formation and associated mortality in mice inoculated with Mo-MSV. At a dose of 50 or 20 mg/kg per day PMEA effected a 90-100% protection of the mice against Mo-MSV-induced tumor formation and mortality. Even with a PMEA dose as low as 1 to 5 mg/kg per day, tumor formation was significantly delayed and the survival rate was significantly enhanced. In parallel experiments, azidothymidine exhibited a comparable inhibitory effect on Mo-MSV-induced tumor formation and associated death only at a 25-fold higher dose than PMEA. Because PMEA has stronger in vivo antiretrovirus potency and selectivity than azidothymidine and various other compounds currently being subjected to clinical trials, PMEA studies should be pursued to assess the potential of this compound in the treatment of acquired immunodeficiency syndrome (AIDS) and other retrovirus infections in humans.
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PMID:Marked in vivo antiretrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine, a selective anti-human immunodeficiency virus agent. 291 79

Although common in Japan, early gastric cancer (EGC = gastric adenocarcinoma confined to the mucosa and submucosa of the stomach, with or without regional lymph node metastases) is thought to be an infrequent occurrence in the United States. However, a review of all "curative" resections for carcinoma of the gastric body and antrum at the University of Virginia between 1974 and 1982 revealed EGC in five of 31 patients (16%). The purpose of the present study was to compare EGC to more advanced gastric cancer (ADV; n = 26) to determine whether any presenting historical, laboratory, x-ray, or endoscopic features distinguished the two groups before surgery and to ascertain whether postoperative survival in the United States mimicked the Japanese experience. All surviving patients were contacted, all charts were abstracted, all pathologic specimens were reexamined, and all radiographs were reviewed blindly by an experienced radiologist. Statistical evaluation was accomplished using Kaplan-Meier plots, chi square analysis, and unpaired "t" tests, as appropriate. At presentation, patients with EGC were younger (44 +/- 6 vs. 67 +/- 2 years, p less than 0.01) with higher admission albumin levels (4.1 +/- 0.2 vs. 3.7 +/- 0.1 mgm/dl, p less than 0.01). Although not significantly different, admission hemoglobin tended to be higher (41 +/- 2 vs. 35 +/- 2%), the incidence of weight loss tended to be less (40 vs. 65%), duration of symptoms tended to be longer (21 +/- 11 vs. 8 +/- 3 months), and tumor diameter tended to be smaller (1.7 +/- 0.6 vs. 5.8 +/- 0.7 cm) in EGC. No differences were apparent with respect to endoscopic or radiographic appearance, tumor location (greater than 70% antrum), presence of regional lymph node metastases (EGC = 2/5; ADV = 20/26), or type of resection (subtotal gastrectomy in 4/5 EGC, in 19/26 ADV). On median 5-year follow-up, however, survival with EGC has been 100%. In contrast, the Kaplan-Meier estimate of 5-year survival in ADV is 15% (42% with muscularis invasion, 0% with serosal invasion, 12% with extra-gastric spread; p less than 0.01 vs. EGC). One suture line recurrence in EGC was successfully treated by re-resection. No ADV patient with recurrence survives (p less than 0.01). Thus, EGC behaves similarly in the United States and Japan; for example, prognosis is excellent even in the presence of lymph node metastases. Inability to distinguish EGC from ADV before surgery justifies an aggressive surgical approach to all patients with resectable gastric neoplasms.
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PMID:Early gastric cancer. 672 9

9-(2-phosphonylmethoxyethyl)adenine (PMEA) is the prototype compound of a series of acyclic nucleoside phosphonate derivatives endowed with potent and selective anti-retroviral activity in vitro and in vivo. We have now found that PMEA is also a potent inducer of differentiation of a number of tumor cells, including human erythroleukemia K562 cells, rat choriocarcinoma RCHO cells and human acute promyelocytic leukemic HL-60 cells. At 10 microM PMEA, rat RCHO cell cultures could be almost fully differentiated, and at 50 microM PMEA, approximately 50% of the K562 cells could be triggered to produce hemoglobin. The differentiating activity of butyric acid was at least partially additive to that of PMEA when both drugs were combined in K562 cell cultures. PMEA needs to be present for at least 2 or 3 days in the K562 cell cultures to achieve optimal differentiating activity. This suggests that either a PMEA metabolite and/or its anti-metabolic effects may be responsible for differentiation of the tumor cells.
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PMID:The human immunodeficiency virus(HIV) inhibitor 9-(2-phosphonylmethoxyethyl)adenine (PMEA) is a strong inducer of differentiation of several tumor cell lines. 770 26


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