Effects of 3'-(3-cyano-4-morpholinyl)-3'-deaminoadriamycin and structural analogues on DNA in HT-29 human colon carcinoma cells.

Abstract

The potent Adriamycin (ADR) analogue, 3'-(3-cyano-4-morpholinyl)-3'-deaminoadriamycin (CMA), produces DNA-DNA cross-links in human and murine tumor cells. The cellular pharmacology of CMA, its derivative, 5-imino-3'-(3-cyano-4-morpholinyl)-3'-deaminoadriamycin (ICMA), 3'-(4-morpholinyl)-3'-deaminoadriamycin (MA), and ADR was evaluated in HT-29 human colon carcinoma cells to determine the structural requirements for the cross-linking activity of CMA, and the role of this activity in the antitumor effect of this agent. CMA was 50-fold more cytocidal than ICMA to HT-29 cells, 300-fold more toxic than MA, and 150-fold more potent than ADR. Both CMA and ICMA produced DNA-DNA cross-links in HT-29 cells but, consistent with its reduced cytotoxicity, the imino derivative was 30-fold less active than CMA. No DNA-DNA cross-links were observed with MA or ADR. CMA also showed cross-linking activity in isolated HT-29 nuclei, indicating that cytoplasmic activation was not required for this effect. Both CMA and ICMA produced cross-links in isolated lambda-phage DNA with CMA being 40-fold more active than the imino derivative, and this activity was unchanged in the presence or absence of a reducing agent. While MA and ADR produced DNA strand breaks in HT-29 cells, this damage was not observed with CMA and ICMA. This study indicates that the potent antitumor activity of CMA may be related to its ability to induce DNA cross-links, which can occur without the need for metabolic activation. The cyanide group appears to be essential for cross-linking and the quinone group may also be involved, but by a mechanism unrelated to its reduction.

• Authors: M I Jesson, J B Johnston, C D Anhalt, A Begleiter
• Journal: Cancer research (Cancer Res) Vol. 47 Issue 22 Pg. 5935-8 (Nov 15 1987) ISSN: 0008-5472 [Print] United States
• PMID: 3664494 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• DNA, Neoplasm
• Morpholines
• Doxorubicin
• 3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin

Topics

• Antineoplastic Agents (pharmacology)
• Cell Line
• Colonic Neoplasms
• DNA, Neoplasm (drug effects)
• Doxorubicin (analogs & derivatives, pharmacology)
• Humans
• Kinetics
• Morpholines (pharmacology)
• Structure-Activity Relationship