Camptothecin antitumour activity

Caiolfa VR, Zamal M, Fiorini A, Frigerio E, Pellizzoni C, d Argy R, Ghiglieri A, Castelli MG, Farao M, Pesenti E, Gigli M, Angelucci, Suarato A. Polymer-bound camptothecin Initial biodistribution and antitumour activity studies. J Cont Rel 2000 65 105-119. 

Introduction of a hydrophilic substituent into a potent pharmacophore, such as 10,11-methylenedioxycamptothecin, is the major trend in synthetic studies aimed at obtaining a water-soluble analogue of camptothecin with significant antitumour activity. 

In an early study of hexacyclic analogues of camptothecin, benz[/]-(20/ 5)-camptothecin (58) demonstrated the same order of potency as camptothecin [14], while 10,11-methylenedioxycamptothecin (40) showed significantly greater antitumour activity than camptothecin in mouse leukaemia assays [16]. The relatively low activity of compound (58) may be due to steric effects on the south west region or alteration of the electronic distribution caused by the fused benzene ring. 

Microinjection of compounds (73) and (74) into human SW-480 cells showed that both compounds have the same order of potency for inhibition of DNA synthesis, while the cytotoxic potency against SW-480 of (73) is less than that of (74) [106], This result strongly supports the supposition that intracellular uptake plays a significant role in determining the level of antitumour activity shown by camptothecin analogues. 

Figure 7.11 Examples of topoisomerase inhibitors. Ellipticene acts by both intercalation and inhibition of topoisomerase II enzymes. It is active against nasopharyngeal carcinomas. Amsacrine is used to treat ovarian carcinomas, lymphomas and myelogenous leukaemias. Camptothecin is an antitumour agent...

In the late 1960 s, demonstration of the impressive activity of camptothecin opened the door to clinical investigations. Clinical studies were initiated with the sodium salt of camptothecin (2) because of the lack of water-solubility of the parent compound. However, these studies were discontinued owing to the unpredictable occurrence of myelosuppression and severe haemorrhagic cystitis [6-9], in spite of the fact that promising antitumour responses were observed among patients with gastric and colon cancer. The discontinuation of these early clinical studies slowed down the progress of camptothecin research. 

Topo I purified from this cell line was highly resistant to camptothecin [113]. This mutation of Topo I might arise from the substitution of Asp (GAC) with Gly (GGC) [114], Topo I-deficient yeast strains showed no sensitivity to camptothecin [115,116]. Moreover, the growth inhibitory effects of camptothecin derivatives on tumour cell lines correlate with their inhibitory activities against Topo I-mediated DNA relaxation [19] and to their abilities to accumulate Topo I-DNA cleavable complex [12]. These discoveries confirmed that the antitumour effect of camptothecin and its derivatives result from Topo I inhibition. 

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