Tumour antitumour activity

Although tumour growth inhibition by 6-mercaptopurine has been attributed to the inhibition of the conversion of inosinic acid to adenylic acid [309, 310, 312], probably at the first step, this conversion by cell-free extracts from the exquisitely sensitive tumour adenocarcinoma 755 was inhibited only at high levels of 6-mercaptopurine ribonucleotide [313]. Furthermore, hadacidin (A -formylhydroxyaminoacetic acid) is an excellent inhibitor of adenylosuccinate synthetase [314, 315], and yet it has little antitumour activity and is not cytotoxic, showing that this inhibition may be relatively unimportant to cells. 

Ikegami Y, Yano S, Nakao K, Fujita F, Fujita M, Sakamoto Y, Murata N, Isowa K (1995) Antitumour activity of the new selective protdn kinase C inhibitor 4 -N-benzoyl staurosporine on murine and human tumour models. Arzneim Forsch 45 1225-1230... 

Peroxy derivatives of steroids have been isolated from both marine and terrestrial sources. They are most commonly 5a, 8a-endoperoxides with variations in the side-chains. The ergosterol peroxide 102 is the most ubiquitous endoperoxide-containing natural product and is isolated from a large number of sources. Ergosterol peroxide 102 was found to have antitumour activity against breast cancer and carcinosarcoma cell lines. A number of other steroidal endoperoxides have been reported which differ in the nature of the side-chain. Compound 103 was found to be an inhibitor of tumour promotion in mouse studies . 

The effectiveness of ICRF 159 had led to several other studies. In the People s Republic of China a high therapeutic index has been claimed for bimolane (22, R = H R, = N-methylmorpholine) and this has led to extensive testing in the USA132-1. X-ray diffraction studies of crystals obtained from solutions which initially contained bimolane have demonstrated the formation of ICRF 154 (22, R = Rj = H). Camerman et al.132) have proposed that bimolane is inherently unstable and that the antitumour activity ascribed to it may be attributable to ICRF-154. It is possible that the N-methylmorpholine substituents increase the lipophilicity sufficiently for the basic ICRF-154 unit to be taken up by tumour cells. 

Table 3.12. ANTITUMOUR ACTIVITY OF MZP (111) AGAINST SELECTED MURINE TUMOURS IN VIVO [91]...

Pruijn, F. B., van Daalen, M., Holford, N. H. G., and Wilson, W. R. (1997) Mechanisms of enhancement of the antitumour activity of melphalan by the tumour blood flow inhibitor 5,6-dimethylxanthenone-4-acetic acid. Cancer Chemother. Pharmacol. 39, 541-546. 

It was quickly established that adriamycin had broad-spectrum antitumour activity and it is still widely used for the treatment of many solid tumours and childhood leukaemia in particular. The other anthracyclines have more limited activities, although daunomycin is the drug of choice (in... 

---