In Vitro Evaluation of the Novel Chemotherapeutic Agents U-73, 975, U-77, 779, and U-80, 244 in Gynecologic Cancer Cell Lines

Hightower, Randall D.; Sevin, Bernd‐Uwe; Perras, James P.; Nguyen, Hoa N.; Angioli, Roberto; Untch, Michael; Averette, Hervy E.

doi:10.3109/07357909309024852

Cited by 13 publications

(2 citation statements)

References 14 publications

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“…Studies in cell culture showed that bizelesin was more highly cytotoxic than either CC-1065 or its derivative adozelesin (14,17). In whole animal studies, by contrast, bizelesin induced fewer lesions (17) and was less hepatotoxic than the monoalkylator parent CC-1065 (18).…”

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confidence: 99%

Bizelesin, a Bifunctional Cyclopropylpyrroloindole Alkylating Agent, Inhibits Simian Virus 40 Replication in Trans by Induction of an Inhibitor

et al. 1999

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Bizelesin, a bifunctional DNA minor groove alkylating agent, inhibits both cellular and viral (SV40) DNA replication in whole cells. Bizelesin inhibition of SV40 DNA replication was analyzed in SV40-infected cells, using two-dimensional (2D) neutral agarose gel electrophoresis, and in a cell-free SV40 DNA replication assay. Within 1 h of bizelesin addition to infected cells, a similar rapid decrease in both the level of SV40 replication intermediates and replication activity was observed, indicating inhibition of initiation of SV40 DNA replication. However, prolonged bizelesin treatment (>/=2 h) was associated with a reduced extent of elongation of SV40 replicons, as well as the appearance on 2D gels of intense spots, suggestive of replication pause sites. Inhibition of elongation and induction of replication pause sites may result from the formation of bizelesin covalent bonds on replicating SV40 molecules. The level of in vitro replication of SV40 DNA also was reduced when extracts from bizelesin-treated HeLa cells were used. This effect was not dependent upon the formation of bizelesin covalent bonds with the template DNA. Mixing experiments, using extracts from control and bizelesin-treated cells, indicated that reduced DNA replication competence was due to the presence of a trans-acting DNA replication inhibitor, rather than to decreased levels or inactivation of essential replication factor(s).

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confidence: 99%

Bizelesin, a Bifunctional Cyclopropylpyrroloindole Alkylating Agent, Inhibits Simian Virus 40 Replication in Trans by Induction of an Inhibitor

et al. 1999

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“…2 Carzelesin showed activity against a broad panel of human tumor xenografts in preclinical in vivo studies in mice 1 and in vitro in a number of gynecologic cancer cell lines. 3 Carzelesin was designed to be an inactive prodrug, requiring chemical or enzymatic activation to the DNA-reactive form. 1 Activation of carzelesin requires two steps, i.e., (a) hydrolysis of the carbanilate substituent to form U-76,073 followed by (b) ring closure of the chloromethyl group to form the cyclopropyl-containing DNA-reactive U-76,074 (Figure 1).…”

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confidence: 99%

Systematic Study on the Chemical Stability of the Prodrug Antitumor Agent Carzelesin (U-80,244)

Vries

Doppenberg

Henrar

et al. 1996

Journal of Pharmaceutical Sciences

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The chemical stability of the novel anticancer agent carzelesin in aqueous buffer/acetonitrile (1:1, v/v) mixtures has been investigated utilizing a stability-indicating reversed-phase high-performance liquid chromatographic assay. The degradation kinetics of carzelesin has been studied as a function of pH, buffer composition, ionic strength, and temperature. Degradation of carzelesin follows (pseudo-) first-order kinetics. A pH-rate profile, using rate constants extrapolated to zero buffer concentration, was constructed demonstrating that carzelesin is most stable in the pH region 1-4. The degradation rate of carzelesin was not significantly affected by buffer components and by the ionic strength. In addition to the formation of the degradation products U-76,073, U-76,074, and aniline in alkaline medium and in acetate buffer solution, another degradation product was formed in acetate buffer solution. In perchloric acid buffer solution (pH* < 3), U-76,073 and U-76,074 could not be detected as degradation products.

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Enhancement of progesterone receptor levels by interferons in AE-7 endometrial cancer cells

Angioli

Untch

Sevin

et al. 1993

Cancer

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Background. Interferon (IFN) has been reported to increase hormone receptor expression in breast cancer cells and to sensitize them to antiproliferative hormones. Endometrial cancer cells with high progesterone receptor (PR) level respond better to progesterone therapy than cells with either low or absent PR level. The effect of four different interferons (α and β, both natural [n] and recombinant [r]) on cell proliferation and steroid receptor levels was investigated in the PR positive AE‐7 human endometrial cancer cell line over a period of 12 days. Methods. Cells were exposed to 10,100 and 1000 IU/ml of each IFN either for 3 days or continuously for 12 days. Hormone receptors were determined by the monoclonal enzyme immunoassay. Chemosensitivity was evaluated with the adenosine triphosphate–cell viability assay. Results. AE‐7 has a low level of estrogen receptors, which was not significantly affected by IFN exposure. The four IFN showed significantly enhanced PR levels over 12 days in both the 3‐day and continuous‐exposure experiments. No significant difference of PR enhancement was observed between 3 days and continuous exposure to IFN. This increase of receptors did not appear to be dose related. IFN enhanced PR level to a maximum level of about two times control cells. IFN did not produce significant cytotoxicity. Antiproliferative activity was observed with nIFNβ and rIFNβ at 1000 IU/ml dose in continuous‐exposure experiments, which showed survival values of 79% and 69% respectively, compared with control at day 12. Conclusions. These preliminary data on PR expression modulation support other studies, which have shown that IFN modulate hormone receptor expression and, therefore, may play a role in the treatment of endometrial cancer.

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In Vitro Evaluation of the Novel Chemotherapeutic Agents U-73, 975, U-77, 779, and U-80, 244 in Gynecologic Cancer Cell Lines

Cited by 13 publications

References 14 publications

Bizelesin, a Bifunctional Cyclopropylpyrroloindole Alkylating Agent, Inhibits Simian Virus 40 Replication in Trans by Induction of an Inhibitor

Bizelesin, a Bifunctional Cyclopropylpyrroloindole Alkylating Agent, Inhibits Simian Virus 40 Replication in Trans by Induction of an Inhibitor

Systematic Study on the Chemical Stability of the Prodrug Antitumor Agent Carzelesin (U-80,244)

Enhancement of progesterone receptor levels by interferons in AE-7 endometrial cancer cells

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