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

Abstract

Adozelesin, bizelesin and carzelesin are synthetic cyclopropylpyrroloindole (CPI) analogs, a class of potent antineoplastic agents modeled on the antitumor antibiotic CC-1065, that specifically bind 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 and 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.

• Authors: M Hidalgo, E Izbicka, C Cerna, L Gomez, E K Rowinsky, S D Weitman, D D Von Hoff
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 10 Issue 3 Pg. 295-302 (Mar 1999) ISSN: 0959-4973 [Print] England
• PMID: 10327036 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzofurans
• Cyclohexanecarboxylic Acids
• Cyclohexenes
• Duocarmycins
• Indoles
• carzelesin
• adozelesin
• Urea
• bizelesin

Topics

• Antineoplastic Agents (pharmacology)
• Benzofurans (pharmacology)
• Cyclohexanecarboxylic Acids (pharmacology)
• Cyclohexenes
• Drug Screening Assays, Antitumor
• Duocarmycins
• Humans
• Indoles (pharmacology)
• Tumor Cells, Cultured
• Urea (analogs & derivatives, pharmacology)