dx-52-1 and Neoplasms

dx-52-1 has been researched along with Neoplasms* in 3 studies

Reviews

1 review(s) available for dx-52-1 and Neoplasms

ArticleYear
[Hypoxia-inducible factor 1: regulation, involvement in carcinogenesis and target for anticancer therapy].
    Bulletin du cancer, 2005, Volume: 92, Issue:2

    Hypoxia-inducible factor-1 is a heterodimer made up of an oxygen-regulated HIF1alpha subunit and a constitutively expressed HIF1beta subunit. Among the 70 target genes of HIF-1 known so far, several are involved in angiogenesis, erythropoiesis, cell proliferation, cell viability, and glucose and iron metabolisms. Intratumoral hypoxia or genetic alterations can lead to HIF-1 alpha over-expression. HIF-1 over-expression has been associated with an increased patient mortality rate in many cancer types. Also, in vitro suppression of hif1alpha gene expression has been shown to be efficient in tumour growth repression. During the past five years, drugs able to indirectly inhibit HIF1 activity have been rationally or empirically developed. Some are currently evaluated in clinical trials, but further work has still to be undertaken to rationally identify new specific inhibitors of HIF1 and to test their efficacy as anticancer therapeutics. This review focuses on HIF1 regulation, HIF1 involvement in tumour promotion, the different HIF-1 inhibitors currently tested and their mechanisms of action.

    Topics: Animals; Cell Hypoxia; DNA-Binding Proteins; Drug Screening Assays, Antitumor; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Indazoles; Isoquinolines; Mice; Neoplasm Proteins; Neoplasms; Nuclear Proteins; RNA, Messenger; Transcription Factors; Transcriptional Activation; Transplantation, Heterologous

2005

Trials

1 trial(s) available for dx-52-1 and Neoplasms

ArticleYear
Phase I clinical trial of 7-cyanoquinocarcinol (DX-52-1) in adult patients with refractory solid malignancies.
    Cancer chemotherapy and pharmacology, 2001, Volume: 48, Issue:5

    A phase I study of the antitumor antibiotic 7-cyanoquinocarcinol, DX-52-1, was conducted in patients with refractory solid malignancies. This study sought to determine the maximum tolerated dose and principal toxicities of this agent and to characterize its pharmacokinetic behavior.. Patients were required to have adequate bone marrow, renal and hepatic function. DX-52-1 was administered by i.v. continuous infusion over a 6-h period each week for four consecutive weeks followed by a 2-week rest period, which constituted one cycle of treatment.. Initial dose levels were 3, 6, and 10 mg/m2. An intermediate dose level of 8 mg/m2 was added after acceptable toxicity was observed at the 6 mg/m2 dose level, but dose-limiting toxicities, including life-threatening ones, were seen at the 10 mg/m2 dose level in all three patients. The maximum tolerated dose (MTD) was subsequently determined to be 6 mg/m2. Because a clear pattern of toxicities was not initially evident, a larger than usual number of additional patients (16) were enrolled at the MTD to better distinguish toxicities due to the study drug from those secondary to the patients' underlying malignancies. Even at the MTD, the drug was poorly tolerated, with gastrointestinal toxicities (abdominal pain, nausea, vomiting and increased liver function tests) predominating and dose-limiting. Pharmacokinetic studies revealed that the mean maximum plasma concentration of DX-52-1 in patients evaluated at the MTD (138.8 +/- 59.3 ng/ml, n = 19) was considerably lower than the concentrations required for cytostatic or cytotoxic activity against sensitive human tumor cell lines in vitro. Further, the weekly dose intensity of the most efficacious treatment schedule identified during in vivo antitumor efficacy studies was 60 times greater than the 6 mg/m2 weekly dose tolerated by cancer patients. None of the 33 patients participating in this study, including the 22 patients evaluated at the MTD, had any response to treatment.. Given the poor tolerability, the inability to achieve drug levels necessary to inhibit in vitro or in vivo tumor growth, and the lack of any responses in our study, DX-52-1, as given by this schedule, does not appear to warrant further investigation in phase II studies.

    Topics: Adult; Aged; Antibiotics, Antineoplastic; Female; Humans; Isoquinolines; Male; Middle Aged; Neoplasms

2001

Other Studies

1 other study(ies) available for dx-52-1 and Neoplasms

ArticleYear
Reversing hypoxic cell chemoresistance in vitro using genetic and small molecule approaches targeting hypoxia inducible factor-1.
    Molecular pharmacology, 2006, Volume: 69, Issue:2

    The resistance of hypoxic cells to conventional chemotherapy is well documented. Using both adenovirus-mediated gene delivery and small molecules targeting hypoxia-inducible factor-1 (HIF-1), we evaluated the impact of HIF-1 inhibition on the sensitivity of hypoxic tumor cells to etoposide. The genetic therapy exploited a truncated HIF-1alpha protein that acts as a dominant-negative HIF-1alpha (HIF-1alpha-no-TAD). Its functionality was validated in six human tumor cell lines using HIF-1 reporter assays. An EGFP-fused protein demonstrated that the dominant-negative HIF-1alpha was nucleus-localized and constitutively expressed irrespective of oxygen tension. The small molecules studied were quinocarmycin monocitrate (KW2152), its analog 7-cyanoquinocarcinol (DX-52-1), and topotecan. DX-52-1 and topotecan have been previously established as HIF-1 inhibitors. HT1080 and HCT116 cells were treated with either AdHIF-1alpha-no-TAD or nontoxic concentrations (0.1 microM;

    Topics: Adenoviridae; Antineoplastic Agents, Phytogenic; Cell Hypoxia; Cell Line, Tumor; Cell Nucleus; Drug Resistance, Neoplasm; Etoposide; Genetic Vectors; Green Fluorescent Proteins; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Isoquinolines; Neoplasms; Oxygen; Sequence Deletion; Topotecan; Transcriptional Activation

2006