Abstract
Amsacrine, an anticancer drug first synthesised in 1970 by Professor Cain and colleagues, showed excellent preclinical activity and underwent clinical trial in 1978 under the auspices of the US National Cancer Institute, showing activity against acute lymphoblastic leukaemia. In 1984, the enzyme DNA topoisomerase II was identified as a molecular target for amsacrine, acting to poison this enzyme and to induce DNA double-strand breaks. One of the main challenges in the 1980s was to determine whether amsacrine analogues could be developed with activity against solid tumours. A multidisciplinary team was assembled in Auckland, and Professor Denny played a leading role in this approach. Among a large number of drugs developed in the programme, N-[2-(dimethylamino)-ethyl]-acridine-4-carboxamide (DACA), first synthesised by Professor Denny, showed excellent activity against a mouse lung adenocarcinoma. It underwent clinical trial, but dose escalation was prevented by ion channel toxicity. Subsequent work led to the DACA derivative SN 28049, which had increased potency and reduced ion channel toxicity. Mode of action studies suggested that both amsacrine and DACA target the enzyme DNA topoisomerase II but with a different balance of cellular consequences. As primarily a topoisomerase II poison, amsacrine acts to turn the enzyme into a DNA-damaging agent. As primarily topoisomerase II catalytic inhibitors, DACA and SN 28049 act to inhibit the segregation of daughter chromatids during anaphase. The balance between these two actions, one cell cycle phase specific and the other nonspecific, together with pharmacokinetic, cytokinetic and immunogenic considerations, provides links between the actions of acridine derivatives and anthracyclines such as doxorubicin. They also provide insights into the action of cytotoxic DNA-binding drugs.
Highlights
Cancer chemotherapy has gone through three phases over the last 70 years
This brief review commences with an outline of the molecular targets of amsacrine and how a study of amsacrine analogues led to the synthesis of N-[2-(dimethylamino)ethyl]-acridine-4-carboxamide (DACA), which had novel features
Molecules 2021, 26, 552 the Lewis lung (3LL) tumour was used to screen for active drugs, and a large number of new analogues of amsacrine were synthesised and tested
Summary
Cancer chemotherapy has gone through three phases over the last 70 years. The first was dominated by the development of cytotoxic drugs that damaged the genetic makeup of the cancer cell, the second was dominated by drug-specific signalling pathways and the third was associated with enhancing host immune responses to eliminate cancer cells. Subsequent research at the ACSRC has demonstrated the importance of embracing a number of scientific disciplines, including physics, chemistry, molecular biology, toxicology, pharmacology and immunology, in attempts to answer this question This brief review commences with an outline of the molecular targets of amsacrine and how a study of amsacrine analogues led to the synthesis of N-[2-(dimethylamino)ethyl]-acridine-4-carboxamide (DACA), which had novel features. Molecules 2021, 26, 552 the Lewis lung (3LL) tumour was used to screen for active drugs, and a large number of new analogues of amsacrine were synthesised and tested One feature of these results was that some analogues containing a substituted carboxamide substituent on the acridine chromophore showed moderate activity against this lung carcinoma [14]. Important clues to the importance of this placement were provided by the results of studies by Wakelin, Denny and others, who showed that the dynamics of dissociation of DACA from the DNA-binding complex were strongly affected by the placement of the side chain [19,20]
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