Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ara-C, a phase-specific antitumor agent, is rapidly deactivated by the enzyme cytidine deaminase. A prolongation of the biological activity of ara-C can be achieved either by the concomitant use of a cytidine deaminase inhibitor or by the development of ara-C derivatives with increased resistance to deamination and a longer half-life in serum. Among such derivatives are cyclocytidine (cyclo-C), anhydro-ara-5-fluorocytidine (AAFC) and the N4-acyl-derivatives. AAFC has been recently shown to be active in human leukemias and in solid tumors of the digestive tract. The tolerance to AAFC is sufficient for clinical use, and AAFC does not produce parotid pains and hypotension, characteristic side effects of cyclo-C. The main toxicity consists of myelodepression, nausea and vomiting. The schedule dependence of AAFC is far less pronounced than for ara-C, so that a weekly application by rapid i.v. injection of 30-40 mg/kg (1,200-1,500 mg/m2) reaches the level of activity with acceptable toxicity. AAFC seems to be as active as ara-C in acute leukemias and is probably active too in malignant lymphomas. In a large phase II trial of the EORTC on selected solid tumor types, AAFC showed a significant activity in GI tract adenocarcinomas with 2 responses/3 evaluable in pancreas, 7/14 in stomach and 2/32 in colorectal tumors (4/30). Hints of activity were also detected in breast cancer (1/17) and anaplastic small cell carcinoma of the lung (1/9). No responses were obtained in 27 patients with epidermoid carcinoma of the lung. These results confirm that ara-C, or newer ara-C analogs, are potentially active in various solid tumor types, and suggest that an extensive further clinical study of such new derivatives is warranted.
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PMID:ARA-C analogs. 34 88

Carmethizole hydrochloride [1-methyl-2-methylthio-4,5-bis(hydroxymethyl)imidazole-4', 5'-bis(N-methylcarbamate)hydrochloride, NSC 602,668; hereafter called carmethizole] is a new antitumor drug that has shown relatively broad activity in initial evaluations against several murine tumors and human tumor xenografts in vivo. The present studies were designed to address questions about carmethizole's activity against established disease, its activity on different treatment schedules, and the extent of its cross-resistance with established drugs. Human MX-1 mammary carcinoma, human NCI-H82 small-cell lung carcinoma, and human LOX amelanotic melanoma xenografts in athymic mice were used to determine the drug's activity against established disease; the NCI-H82 lung-tumor xenograft in athymic mice was used to explore its schedule dependence; and a series of drug-resistant murine leukemias provided an in vivo cross-resistance profile. When injected i.p., carmethizole exhibited antitumor activity against advanced-stage s.c. MX-1 mammary, s.c. NCI-H82 lung, and i.p. LOX melanoma xenografts and was as effective against established disease (MX-1 and LOX) as it was against early-stage disease (no data are available for early-stage NCI-H82). The therapeutic effect of carmethizole was not route-dependent, as was evidenced by the similar delays observed in tumor growth following i.p. and i.v. administration. The use of a split-dose schedule on a single day instead of one bolus injection yielded an increase in the total dose delivered, resulting in an increased delay in tumor growth. Murine leukemias resistant to vincristine (VCR), amsacrine (AMSA), or methotrexate (MTX) were not cross-resistant to carmethizole. However, murine leukemias resistant to doxorubicin (ADR), melphalan (L-PAM), cisplatin (DDPt), 1-beta-D-ara-binofuranosylcytosine (ara-C), and 5-fluorouracil (5-FU) were cross-resistant to carmethizole, suggesting that patients who have previously been treated with any of these agents might be less likely to respond to carmethizole than those who have had no opportunity to develop resistance to any of these compounds. We anticipate that the information derived from these studies may be useful in the design of clinical trials of carmethizole and may stimulate additional basic research on the mechanism of action of this new agent.
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PMID:Antitumor activity and cross-resistance of carmethizole hydrochloride in preclinical models in mice. 132 3

The 1-beta-D-arabinofuranosylcytosine (ara-C) conjugates 1-O-alkyl (ether) and 1-S-alkyl (thioether) phospholipids, being analogues of ara-CDP-sn-1,2-O-dipalmitoylglycerol (1), showed significant antitumor activity against L1210 and P388 leukemia in vivo. The more active conjugates include the 1-O-alkyl analogues, ara-CDP-rac-1-O-hexadecyl-2-O-palmitoylglycerol (2) and ara-CDP-rac-1-O-octa-decyl-2-O-palmitoylglycerol (3), and the corresponding 1-S-alkyl analogues, ara-CDP-rac-1-S-hexadecyl-2-O-palmitoyl-1-thioglycerol (4) and ara-CDP-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (5, Cytoros). The conjugates were formulated by sonication, in which the conjugates existed as discs (size 0.01-0.04 microns). Among the conjugates of the three different phospholipids, the 1-S-alkyl analogues 4 and 5 displayed the strongest antitumor activity against L1210 leukemia in mice, followed by the 1-O-alkyl (2 and 3) and the 1-O-acyl (1) analogues. The 1-S-alkyl analogue 5 was considerably more effective than the 1-O-acyl analogue 1 against myelomonocytic WEHI-3B leukemia in mice. Conjugate 5 (Cytoros) showed a significant therapeutic activity in mice with colon 26 carcinoma, M5076 sarcoma, and C-1300 neuroblastoma. Furthermore, this agent inhibited liver metastases of M5076 sarcoma. Conjugates 3 and 5 also inhibited the metastasis of 3-Lewis lung carcinoma to the lungs of mice. Cytoros (5) and its analogues, with other ether and thioether phospholipids, appear to offer increased therapeutic benefit to mice with tumors.
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PMID:1-beta-D-arabinofuranosylcytosine conjugates of ether and thioether phospholipids. A new class of ara-C prodrug with improved antitumor activity. 181 47

HO-221, N-[4-(5-Bromo-2-pyrimidinyloxy)-3-chlorophenyl]-N'-(2-nitrobenzoyl ) urea is a novel benzoylphenylurea derivative. We had interested in various pharmacological actions of benzoylphenylurea compounds. Therefore, many compounds were synthetized and tested in various screening systems. In the process with these tests, we found HO-221 which showed an excellent antitumor activity. The antitumor activity of HO-221 was judged from the survival time and the tumor weight of experimented tumor-bearing animals. HO-221 preparation was orally administered. The compound exhibited significant effects against various animal tumors (P388, L1210, M5076, LLC, C38, S180, W256), and especially effective against the solid tumors. HO-221 was also markedly effective to MX-1 and LX-1 implanted into nude mice. However, the effect against mouse B16 melanoma was moderate. In addition, HO-221 showed a schedule dependency and once every 4 or 7 days treatments were most effective. The antitumor activities of the compound against advanced L1210 and Lewis lung tumors were examined. Tegafur and ara-C were used as reference drug for the study. Three agents showed the antitumor activities against L1210. Against Lewis lung carcinoma, HO-221 showed both the increase of life span and the tumor growth inhibition. On the other hand, tegafur and ara-C were ineffective for the increase of life span.
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PMID:[Antitumor effect of a benzoylphenylurea derivative HO-221]. 226 Aug 71

1-beta-D-Arabinofuranosyl-2-amino-1,4(2H)-4-iminopyrimidine (ara-AIPy), a new deaminase-resistant analog of cytarabine, exhibited extremely potent antitumor activity against P388 leukemia [400 mg/kg on Days 1-5; increase in life span (ILS), 211%] and significant inhibition against Lewis lung carcinoma (inhibition of tumor weight, 68%) and mammary adenocarcinoma 755 (inhibition of tumor weight, 82%). Schedule-dependency studies indicate that this drug, unlike cytarabine, was effective irrespective of its treatment schedules. The drug exhibited therapeutic efficacy against established P388 tumor transplants (400 mg/kg on Days 3-7; ILS, 131%) and inhibited the tumor growth effectively even when administered as a single dose on Day 1 by both ip (2000 mg/kg; ILS, 150%) and iv (500 mg/kg; ILS, 68%) routes. Ara-AIPy was most effective when administered on Days 1, 3, 5, 7, and 9 after tumor transplantation (400 mg/kg; ILS, 210%, with 50% of animals 60-day survivors). Ara-AIPy inhibited the growth of L1210 leukemia when both the tumor transplantation and the drug treatment were administered by iv route (500 mg/kg on Days 1, 5, and 9; ILS, 181%). The routes of administration of ara-AIPy experiments showed that the drug was effective by both ip and iv routes of administration; however, better therapeutic values were obtained by ip schedules. These studies demonstrate that ara-AIPy exhibits highly significant and broad-spectrum antitumor activity against a variety of experimental animal tumor models and suggest a possible future role for this drug in the treatment of human neoplasia.
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PMID:Evaluation of antitumor activity of 1-beta-D-arabinofuranosyl-2-amino-1,4(2H)-4-iminopyrimidine in murine tumors. 356 67

Liposomes have been used in recent years as carriers for drugs and molecules of biological importance. In cancer chemotherapy, however, the advantages of liposome encapsulation of antitumor drugs remain uncertain, with the possible exception of the usefulness of encapsulated 1-beta-D-arabinofuranosyl-cytosine (ara-C), an antitumor drug of a very short half-life. Liposome-encapsulated ara-C has been shown by others to enhance significantly the survival time of mice bearing leukemia, and the enhancement may be attributable to the role of liposomes as a slow release system for ara-C. We now further explore the advantages of two sustained release systems for ara-C, namely the liposome-encapsulated ara-C and 1-beta-D-arabinofuranosylcytosine-5'-diphosphate-L-1,2-dipalmitin (ara-CDP-L-dipalmitin, a prodrug of ara-C). Intravenously implanted Lewis lung carcinoma is used as a solid tumor model. The therapeutic effectiveness of the two slow release forms of ara-C given by either i.v. or i.p. injections is examined. Viable tumor cells (1.0 X 10(5) cells/mouse) were inoculated i.v. and treatment was initiated 24 hr later using three schedules of multiple treatments for liposomal ara-C and single or multiple injections of ara-CDP-L-dipalmitin. Liposomal ara-C given by the i.p. route consistently increased the number of cures (greater than 120 days survival). For example, when nine small doses (10 mg/kg) were given on consecutive days by i.p. injections, 50% of mice given liposomal ara-C were cured, compared with 10% cures in the group given ara-C liposomes by i.v. and no cures in mice receiving free ara-C given according to the same schedules. On the other hand, ara-CDP-L-dipalmitin given at a single dose is more effective than an equal dose divided in five injections. However, no cures have been obtained by treatments with ara-CDP-L-dipalmitin. These results have further demonstrated the advantage of liposomes as carriers for antitumor drugs of short half-life.
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PMID:The treatment of intravenously implanted Lewis lung carcinoma with two sustained release forms of 1-beta-D-arabinofuranosylcytosine. 654 Jun 91

The antitumor activity and the pharmacological fate of N4-palmitoyl-1-beta-D-arabinofuranosylcytosine (N4-palmitoyl-ara-C) administered p.o. were examined in mice and were compared with those of the parent compound 1-beta-D-arabinofuranosylcytosine (ara-C). N4-Palmitoyl-ara-C administered p.o. showed chemotherapeutic effects superior to those of ara-C when used against P388 leukemia, L1210 leukemia, mammary adenocarcinoma 755, and colon 38 adenocarcinoma. The derivative also inhibited the spontaneous pulmonary metastasis of s.c.-inoculated Lewis lung carcinoma more efficiently than did ara-C. After a single p.o. injection of a suspension of N4-palmitoyl-[2-14C]ara-C at a therapeutic dose of 350 mu/kg, a high concentration of the drug was found in the liver, lung, and plasma of portal venous blood. The level of the drug in other tissues and peripheral plasma was rather low. The two main metabolites, identified as ara-C and 1-beta-D-arabinofuranosyluracil, were found in plasma and various tissues. Plasma ara-C concentration was maintained for at least 6 hr in the range of 2.3 to 5.1 nmol/ml after p.o. administration of N4-palmitoyl-ara-C (350 mu/kg). On the other hand, when an equimolar amount of ara-C was given, the plasma levels of the drug decreased rapidly; from 2 to 6 hr after administration, the level (1.0 to 4.1 nmol/ml) was less than that obtained with N4-palmitoyl-ara-C. These results suggested that N4-palmitoyl-ara-C administered p.o. is absorbed as an intact form from the gastrointestinal tract and that the absorbed compound is the depot form of ara-C, releasing ara-C over a prolonged period of time.
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PMID:Antitumor effects and pharmacology of orally administered N4-palmitoyl-1-beta-D-arabinofuranosylcytosine in mice. 669 34

2'-Deoxy-2'-isocyano-1-beta-D-arabinofuranosylcytosine (8, NCDAC) has been synthesized as a potential antitumor antimetabolite from a corresponding 2'-azido-2'-deoxy-1-beta-D-arabinofuranosyluracil derivative 2a. Uracil and thymine analogues 6a and 6b of 8 were also prepared. Attempts to synthesize 2'-deoxy-2'-isocyanocytidine (14b) failed due to the insertion of the 2'-alpha isocyano group into the 3'-OH group, affording the 2',3'-oxazoline derivative 15b. Stability of the isocyano derivative 6a and 2',3'-oxazoline derivative 15a under basic and acidic conditions were examined. The isocyano group in 6a was stable in basic conditions but unstable even in weakly acidic conditions to furnish the corresponding 2'-beta formamide derivative 17. Compound 15a was easily hydrolyzed the corresponding 2'-alpha formamide derivative 16 on treatment with H2O at room temperature. The cytotoxicity of 8, 6a, and 6b was examined in mouse and human tumor cells in vitro and compared with that of ara-C. Of these nucleosides, 8 was moderately cytotoxic to these cell lines. In vivo antitumor activity of 8 against Lewis lung carcinoma cells was also investigated and 8 showed only moderate tumor volume inhibition.
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PMID:Nucleosides and nucleotides. 123. Synthesis of 1-(2-deoxy-2-isocyano-beta-D-arabinofuranosyl)cytosine and related nucleosides as potential antitumor agents. 827

Gemcitabine is a new deoxycytidine analog that exhibits significant cytotoxicity against a variety of cultured murine and human tumor cells. The cytotoxic action of gemcitabine appears to be due to the inhibition of DNA synthesis by inhibition of ribonucleotide reductase and by competition with dCTP for incorporation into DNA. We have previously shown that gemcitabine, but not cytosine arabinoside (ara-C), has a broad spectrum of antitumor activity against 7 different types of murine solid tumors. The activity of gemcitabine was schedule dependent. To further characterize its activity, gemcitabine was tested against 12 human carcinoma xenografts. When given on an every 3 day x 4 schedule, the following percent inhibitions (at maximally tolerated doses [MTD]; MTD/2) in tumor growth were seen: MX-1 mammary (93%; 80%), CX-1 colon (92%; 82%), HC-1 colon (96%; 92%), GC3 colon (98%; 94%), VRC5 colon (99%; 100%), LX-1 lung (76%; 61%), CALU-6 lung (75%; 38%), NCI-H460 lung (45%; 46%), HS766T pancreatic (73%; not tested), PaCa-2 pancreatic (69%; 40%), PANC-1 pancreatic (70%; 60%), and BxPC-3 pancreatic (9%; 19%). In contrast, only the LX-1 lung carcinoma xenograft was responsive to ara-C treatment, which inhibited tumor growth by a marginal 62 percent. Thus, like its activity against murine solid tumors, gemcitabine has excellent antitumor activity against a broad spectrum of human solid tumors.
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PMID:Comparison of the antitumor activity of gemcitabine and ara-C in a panel of human breast, colon, lung and pancreatic xenograft models. 895 78

(E)-2'-deoxy-2'-(fluoromethylene) cytidine (MDL101,731) is a new deoxycytidine analog which shows potent antitumor activity against several human tumor models. We previously showed that MDL101,731 inhibited human ribonucleotide reductase (RNR) in HeLa S3 human cervical carcinoma cells. Recently, it has been reported that another deoxycytidine analog, 2'-deoxy-2'-methylidenecytidine (DMDC) which also inhibits RNR from Escherichia coli, does not inhibit RNR in intact L1210 murine leukemia cells. MDL101,731 was designed as an inhibitor of RNR, so it is important to know the contribution of the RNR inhibitory activity of the drug on its antitumor efficacy in vivo. Therefore, we examined the relationship between the antitumor activity and RNR inhibitory activity of MDL101,731 using LX-1 human lung carcinoma which was highly sensitive to this drug. MDL101,731 showed strong inhibition of RNR activity in LX-1 lung carcinoma by both i.v. and p.o. administration. Administration of 15 mg/kg i.v. and 30 mg/kg p.o. of MDL101,731, doses which showed almost the same degree of antitumor activity against LX-1 lung carcinoma on a daily 5 day schedule, caused a similar degree and similar kinetics of inhibition of RNR in LX-1 lung carcinoma at least for 12 h after administration. On the other hand, DMDC as well as 1-beta-D-arabinofuranosyl-cytosine (ara-C), which is a well-known deoxycytidine analog and inhibits DNA polymerase alpha, did not inhibit RNR in LX-1 lung carcinoma at doses demonstrating antitumor activity. These results indicate that MDL101,731 exhibited antitumor activity through inhibition of RNR activity in tumor cells in vivo and the mechanism of antitumor action of MDL 101,731 might be different from those of DMDC and ara-C, at least in part.
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PMID:The relationship between the antitumor activity and the ribonucleotide reductase inhibitory activity of (E)-2'-deoxy-2'-(fluoromethylene) cytidine, MDL 101,731. 977 10


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