ANTHRACYCLINE ANTIBIOTICS IN CANCER-THERAPY - FOCUS ON DRUG-RESISTANCE

30 years ago an anthracycline antibiotic was shown to have antineoplas tic activity. This led to the development of well over 1000 analogues with a vast spectrum of biochemical characteristics. Many biological a ctions have been described. The original anthracyclines are active aga inst many types of cancer and are an integral part of several curative combinations. They are ineffective against other tumours. Although so me analogues show an altered spectrum of activity or an improved thera peutic index relative to the older agents, it is not clear that cardio toxicity can be totally avoided with these agents. Primary and seconda ry resistance to anthracyclines remain major clinical problems. Pharma cokinetic studies have been of limited help in explaining this. Overex pression of a surface-membrane permeability glycoprotein (Pgp) was ide ntified in ovarian cancer of patients who had clinical multidrug resis tance in 1985. This led the way for the discovery of a number of resis tance mechanisms in vitro. Some of these have been found in more than 1 type of cell line, and more than 1 mechanism may exist in a single c ell, Additional resistance proteins have been identified, qualitative and quantitative alterations of topoisomerase II have been described, and some mechanisms in other systems have not yet been identified. Som e of these may prove to be important in clinical drug resistance. Drug s such as calcium antagonists and cyclosporin, studied initially for t heir ability to block the Pgp pump, appear to be heterogeneous in this capacity and may have additional sites of action. It will be critical for clinical studies to define the precise resistance mechanism(s) th at must be reversed. To date this has been difficult, even in trials o stensibly dealing with the original Pgp. Liposomes can potentially alt er toxicity and target drug delivery to specific sites. In addition, t hey may permit the use of lipophilic drugs that would otherwise be dif ficult to administer systemically. Resistant tumours may be sensitive to anthracyclines delivered by liposomes. To reduce cardiac toxicity, administering doxorubicin (adriamycin) by slow infusion through a cent ral-venous line should be considered whenever feasible. Monitoring of cardiac ejection fraction and the use of endomyocardial biopsy will pe rmit patients to be treated safely after they reach the dose threshold at which heart failure begins to be a potential risk. A number of str ucturally modified anthracyclines with the potential advantages of dec reased cardiotoxicity and avoidance of multidrug resistance mechanisms are entering clinical trials. Meanwhile, the vast weight of clinical experience leaves doxorubicin as a well tolerated and effective choice for most potentially anthracycline-sensitive tumours.