Comparative activity of the cyclopropylpyrroloindole compounds adozelesin, bizelesin and carzelesin in a human tumor colony-forming assay

Manuel Hidalgo, Elzbieta Izbicka, Cesario Cerna, Lionel Gomez, Eric K. Rowinsky, Steven D. Weitman, Daniel D. Von Hoff

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Adozelesin, bizelesin and carzelesin are synthetic cyclopropylpyrrotoindole (CPI) analogs, a class of potent antineoplastic agents modeled an the antitumor antibiotic CC-1065, that specifically hind to the minor groove of DNA and preferentially alkylate AT-rich regions. These compounds were evaluated against fresh human tumors in a human tumor colony-forming assay (HTCFA) to assess and to compare their relative antitumor spectra, concentration-response relationships and schedule-dependence. Human tumor colony-forming units were treated with adozelesin acid bizelesin at concentrations of 0.02, 0.1 and 0.5 ng/ml as a continuous exposure for 14 days, and to 0.2, 1.0 and 5.0 ng/ml as a 1 h exposure. Carzelesin concentrations were 0.04, 0.2 and 1 ng/ml as a continuous exposure, and 0.6, 3.0 and 15.0 ng/ml as a 1 h exposure. A response was scored if there was 50% or less colony survival. The three analogs had similar antitumor activity against colon carcinoma, kidney carcinoma and melanoma colony-forming units. Adozelesin also displayed activity against both breast and non-small cell lung carcinoma colony-forming units, and carzelesin was active against ovarian carcinoma colony-forming units. Significantly positive concentration-response relationships were apparent with all three agents. Responses increased from below 15% at the lowest concentration to above 45% at the highest concentration for the three drugs on all schedules (p < 0.01). At the highest concentration, the overall response rate was significantly higher (p < 0.01) with carzelesin on the continuous schedule (71%) compared to the 1 h schedule (46%). However, overall response rates for adozelesin and bizelesin were similar on both schedules (1 h/continuous: adozelesin, 67/58%; bizelesin, 49/44%), indicating that adozelesin and bizelesin are less schedule dependent than carzelesin in the HTCFA. These results demonstrate that the CPIs have broad-spectrum activity against human tumor colony-forming units in the HTCFA at very low concentrations, as well as differences with regard to schedule dependence which may help guide the optimal clinical development of these agents.

Original languageEnglish (US)
Pages (from-to)295-302
Number of pages8
JournalAnti-cancer drugs
Issue number3
StatePublished - Aug 26 1999


  • Adozelesin
  • Bizelesin
  • Carzelesin
  • Human tumor colony-forming units

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research


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