The in vitro effects and cross-resistance patterns of some novel anthracyclines

Abstract

Summary A range of new anthracyclines, structurally related to adriamycin (ADM), has been synthesised and studied in vitro. Three compounds described in this paper (Ro 31-1215; Ro 31-1741; Ro 31-2035) are all 4-demethoxyanthracyclines. In the mouse mammary tumour cell line, EMT6/Ca/VJAC, using a 1 h drug exposure followed by colony formation as the response endpoint, we found Ro 31-1215 and Ro 31-1741 to be 2-3 x and 4-7 x more potent then ADM, whilst Ro 31-2035 was 3-4 x less potent. For continuous drug exposure and suppression of population growth as the endpoint, the potency of Ro 31-1741 was similar to that of ADM, whereas that of Ro 31-1215 was 1.5-2 x higher and that of Ro al., 1978;Kaye & Merry, 1985). The mechanism of such resistance is currently the subject of much ongoing laboratory work and a variety of strategies for overcoming resistance are being investigated (Tsuruo et al., 1983;Skovsgaard et al., 1984).Over the last 10 years a large number of analogues of ADM have been produced with the major objective of finding a drug which is less cardiotoxic for a given amount of anti-tumour effect (Naff et al., 1982

Effects of Interferons and Tumour Necrosis Factor-α on Human Lung Cancer Cell Lines and the Development of an Interferon-Resistant Lung Cancer Cell Line

“…Our results on IFN-a, IFN-y and TNF-a confirm previous data published by two independent groups on the respective effect of IFN and TNF on human lung cancer cells (6,7). However, we cannot on the basis of this representative panel of human lung cancer cell lines confirm the synergistic, cytotoxic effect of IFN-y and TNF-a described by Dubois et al in 1989 (21).…”

Retention of activity by selected anthracyclines in a multidrug resistant human large cell lung carcinoma line without P-glycoprotein hyperexpression

“…On the other hand, the strategy which we have described (Twentyman et al, 1986a;Scott et al, 1986;Coley et al, 1989aColey et al, , 1990) of using anthracycline analogues which do not show reduced accumulation in MDR cells is effective both in the presence and absence of P-glycoprotein. It therefore may have more general applicability.…”

“…One has been the use of 'resistance modifiers' such as verapamil which at least partially restore sensitivity in MDR cells to the agents to which they have become resistant (Tsuruo et al, 1983(Tsuruo et al, , 1984Ramu et al, 1984;Kessel & Wilberding, 1985;Kessel, 1985). The other approach involves the identification of analogues of MDR-associated drugs which retain activity in resistant cells, most probably because they are not effluxed as efficiently by P-glycoprotein (Twentyman et al, 1986a;Scott et al, 1986;Coley et al, 1989a). In previous studies we have shown with our P-glycoproteinpositive cell lines that these include anthracyclines having either a 9-alkyl substitution in the A-ring or sugar modifications such as replacement of the amino group of the daunosamine moiety with a morpholinyl ring (Scott et al, 1986;Coley et al, 1989a).…”

Characterisation of a mouse tumour cell line with in vitro derived resistance to verapamil

“…Furthermore, Cano-Gauci and Riordan (1987) (Twentyman et al, 1986b;Coley et al, 1989a,b) (Mosmann, 1983). The assay has been modified by us and its use with EMT6 cells has been previously described (Twentyman & Luscombe, 1987 (Taylor, 1980) was added to I ml of cell suspension.…”