Activity of Topotecan, a New Topoisomerase I Inhibitor, Against Human Tumor Colony-Forming Units In Vitro

Metastatic pheochromocytoma continues to be an incurable disease, and treatment with conventional cytotoxic chemotherapy offers limited efficacy. In the present study, we evaluated a novel topoisomerase I inhibitor, LMP-400, as a potential treatment for this devastating disease. We found a high expression of topoisomerase I in human metastatic pheochromocytoma, providing a basis for the evaluation of a topoisomerase 1 inhibitor as a therapeutic strategy. LMP-400 inhibited the cell growth of established mouse pheochromocytoma cell lines and primary human tumor tissue cultures. In a study performed in athymic female mice, LMP-400 demonstrated a significant inhibitory effect on tumor growth with two drug administration regimens. Furthermore, low doses of LMP-400 decreased the protein levels of hypoxia-inducible factor 1 (HIF-1α), one of a family of factors studied as potential metastatic drivers in these tumors. The HIF-1α decrease resulted in changes in the mRNA levels of HIF-1 transcriptional targets. In vitro, LMP-400 showed an increase in the growth-inhibitory effects in combination with other chemotherapeutic drugs that are currently used for the treatment of pheochromocytoma. We conclude that LMP-400 has promising antitumor activity in preclinical models of metastatic pheochromocytoma and its use should be considered in future clinical trials.

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Activity of Intoplicine (RP60475), a New DNA Topoisomerase I and II Inhibitor, Against Human Tumor Colony-Forming Units In Vitro

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/86.1.30 ◽

1994 ◽

Vol 86 (1) ◽

pp. 30-33 ◽

Cited By ~ 10

Author(s):

J. R. Eckardt ◽

H. A. Burris ◽

J. G. Kuhn ◽

M. C. Bissery ◽

M. Klink-Alakl ◽

...

Keyword(s):

Topoisomerase I ◽

Human Tumor ◽

Dna Topoisomerase I ◽

Dna Topoisomerase ◽

Colony Forming Units

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Activity of CPT-11 (irinotecan hydrochloride), a topoisomerase I inhibitor, against human tumor colony-forming units

Anti-Cancer Drugs ◽

10.1097/00001813-199404000-00011 ◽

1994 ◽

Vol 5 (2) ◽

pp. 202-206 ◽

Cited By ~ 33

Author(s):

Yasuhiro Shimada ◽

Mace Rothenberg ◽

Susan G Hilsenbeck ◽

Howard A Burris ◽

Donna Degen ◽

...

Keyword(s):

Topoisomerase I ◽

Human Tumor ◽

Irinotecan Hydrochloride ◽

Topoisomerase I Inhibitor ◽

Colony Forming Units

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Antitumor activity of esorubicin in human tumor clonogenic assay with comparisons to doxorubicin.

Journal of Clinical Oncology ◽

10.1200/jco.1984.2.4.282 ◽

1984 ◽

Vol 2 (4) ◽

pp. 282-286 ◽

Cited By ~ 12

Author(s):

S E Salmon ◽

L Young ◽

B Soehnlen ◽

R Liu

Keyword(s):

Antitumor Activity ◽

Clonogenic Assay ◽

Human Tumor ◽

Therapeutic Index ◽

In Vivo Studies ◽

Early Results ◽

Colony Forming Units ◽

Human Solid Tumors

The new anthracycline analog, esorubicin (4'deoxy-doxorubicin, ESO), was tested against fresh biopsies of human solid tumors in vitro in clonogenic assay and the results were contrasted to those obtained with doxorubicin (DOX). ESO appeared to be significantly more potent on a weight basis than DOX in these studies, and exhibited a spectrum of antitumor activity in vitro that was in general qualitatively similar to that observed with DOX. In vitro antitumor activity was observed in a wide variety of human cancers including anthracycline-sensitive tumor types. ESO has previously been reported to have decreased cardiac toxicity in preclinical models as compared to DOX. Comparative testing of these anthracyclines on granulocyte-macrophage colony-forming units (GM-CFUs) and tumor colony forming units (TCFUs) indicated that the in vitro GM-CFU assay is more sensitive to these myelosuppressive drugs than are TCFUs, and underscores the need for in vivo studies to determine normal tissue toxicity and the therapeutic index of a drug. Early results of phase I studies suggest that with respect to myelosuppression, the maximally tolerated dose of ESO will be about half that of DOX. The increased in vitro antitumor potency observed for ESO and a spectrum of activity (even at one half the dose of DOX) supports the broad testing of ESO in the clinic to determine whether it will prove to be a more effective and less toxic anthracycline.

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Position-Selective Synthesis and Biological Evaluation of Four Isomeric A-Ring Amino Derivatives of the Alkaloid Luotonin A

Molecules ◽

10.3390/molecules24040716 ◽

2019 ◽

Vol 24 (4) ◽

pp. 716 ◽

Cited By ~ 7

Author(s):

Amra Ibric ◽

Stefan Eckerstorfer ◽

Martin Eder ◽

Ivan Louko ◽

Leopold Tunjic ◽

...

Keyword(s):

Topoisomerase I ◽

Human Tumor ◽

Biological Evaluation ◽

Transfer Hydrogenation ◽

Amino Compound ◽

M Cell ◽

Luotonin A ◽

Amino Derivatives ◽

Derivatives Of

Following two orthogonal synthetic routes, a series of all four possible A-ring amino derivatives of the natural product Luotonin A (a known Topoisomerase I inhibitor) was synthesized. In both strategies, intramolecular cycloaddition reactions are the key step. The target compounds were obtained in good yields by mild catalytic transfer hydrogenation of the corresponding nitro precursors. In-vitro evaluation of the antiproliferative activity towards human tumor cell lines revealed the 4-amino compound (5b) to be the most effective agent, showing an interesting profile of cytotoxic activity. Among other effects, a significant G2/M cell cycle arrest was observed for this compound, suggesting that either Topoisomerase I is not the only biological target, or that some atypical mechanism is responsible for inhibition of this enzyme.

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The Aza-Analogous Benzo[c]phenanthridine P8-D6 Acts as a Dual Topoisomerase I and II Poison, thus Exhibiting Potent Genotoxic Properties

Molecules ◽

10.3390/molecules25071524 ◽

2020 ◽

Vol 25 (7) ◽

pp. 1524 ◽

Cited By ~ 3

Author(s):

Georg Aichinger ◽

Falk-Bach Lichtenberger ◽

Tamara N. Steinhauer ◽

Inken Flörkemeier ◽

Giorgia Del Favero ◽

...

Keyword(s):

Comet Assay ◽

Topoisomerase I ◽

Human Tumor ◽

Proliferating Cells ◽

Covalently Linked ◽

Underlying Mechanisms ◽

Dna Strand ◽

Ht 29

The benzo[c]phenanthridine P8-D6 was recently found to suppress the catalytic activity of both human topoisomerase (Topo) I and II. Concomitantly, potent cytotoxic activity was observed in different human tumor cell lines, raising questions about the underlying mechanisms in vitro. In the present study, we addressed the question of whether P8-D6 acts as a so-called Topo poison, stabilizing the covalent Topo–DNA intermediate, thus inducing fatal DNA strand breaks in proliferating cells. In HT-29 colon carcinoma cells, fluorescence imaging revealed P8-D6 to be taken up by the cells and to accumulate in the perinuclear region. Confocal microscopy demonstrated that the compound is partially located inside the nuclei, thus reaching the potential target. In the “in vivo complex of enzyme” (ICE) bioassay, treatment of HT-29 cells with P8-D6 for 1 h significantly enhanced the proportion of Topo I and II covalently linked to the DNA in concentrations ≥1 µM, indicating effective dual Topo poisoning. Potentially resulting DNA damage was analyzed by single-cell gel electrophoresis (“comet assay”). Already at 1 h of incubation, significant genotoxic effects were observed in the comet assay in concentrations as low as 1 nM. Taken together, the present study demonstrates the high Topo-poisoning and genotoxic potential of P8-D6 in human tumor cells.

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