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The major limitation of the usefulness of anthracyclines is the development of drug resistance. Most of the data related to anthracycline resistance has been obtained in experimental animal tumors or in cultured human cell lines. An important characteristic obtained in these models is the common finding of cross-resistance to a series of drugs structurally unrelated to the anthracyclines and with a mechanism of action which apparently differ from that of the anthracyclines. This phenomenon is defined as pleiotropic drug resistance or multidrug resistance (MDR). The cross-resistance demonstrated includes the vinca alkaloids, actinomycin D, colchicin and the epipodophyllotoxins. The best documented mechanism of resistance and mechanism of cross-resistance is decreased cellular drug accumulation. Several findings indicate that the underlying factor of the altered net uptake is an active drug extrusion in the resistant cells. Another important characteristic is the demonstration of a cell surface protein with a molecular weight of about 170,000 (GP 170). Genetic and biochemical evidence indicate that the MDR phenotype in both animal and human cells result from overexpression of the MDR-1 gene which encodes GP 170. Some findings suggest that GP 170 is a transport protein for cytotoxic hydrophobic drugs like the anthracyclines. Other findings suggest that this gene is also associated with intrinsic (natural) anthracycline resistance.

Rubidazone, a semisynthetic daunorubicin derivative, was administered to 33 patients with advanced solid tumors or malignant lymphomas. The doses used were 200, 150, or 100 mg/m2 repeated at 3-week intervals. The antitumor effect was very modest. Partial remission was obtained in only one patient and stable disease was observed for periods of 4--18 weeks in seven additional patients. The major toxic effects were gastrointestinal and myelosuppressive. In two patients, cardiac toxic effects were noted and one patient had an anaphylactic-like reaction. No clinical cross-resistance seemed to exist between rubidazone and adriamycin.

A new oral form of VP-16-213 consisting of a hydrophilic soft gelatin capsule containing a VP-16-213 solution was tested for toxicity in 26 patients. The drug was administered at four different dose levels, 350, 500, 650, and 750 mg/m2, in 5-day courses every 21-28 days. A dose-dependent effect was observed with regard to hematologic toxicity and alopecia. It is concluded that the drinking ampules of VP-16-213 can be replaced with the new oral capsules with a recommended initial dose of 100-130 mg/m2 given in 5-day courses every 21-28 days.

The epipodophyllotoxin derivative VP 16--213 (NSC 141540) was studied by the Cancer and Leukemia Group B in a broad phase II trial at three dose levels: 60 mg/m2, 90 mg/m2, and 135 mg/m2 I.V. twice weekly. No correlation between dose of VP 16--213 and response frequency in a particular disease category could be demonstrated. Of the 382 patients, 8% obtained a complete (CR) or partial remission (PR), 8% showed improvement, and 14% had stable disease. By tumor type the best responses were obtained in lymphomas (8/31 CR + PR), uterus (2/9), prostate (1/5), rhabdomyosarcoma (2/6), neuroblastoma (2/4), colon/rectum (5/81), other gastrointestinal (4/32). In lung tumors, 4/80 patients obtained CR or PR. VP 16--213 has definite antineoplastic activity but the response frequency with the twice weekly schedule may be lower than that reported with other schedules.

Occurrence of cross-resistance between anthracyclines and vinca alkaloids is the rule in experimental tumors with acquired resistance to these drugs. So far, there is no indication that this phenomenon is due to an intracellular mechanism of action common to the two groups of drugs. In nearly all reported studies, acquired experimental resistance and cross-resistance are related to a decreased cellular accumulation of both types of drugs, although other factors also are involved. In Ehrlich ascites tumors, a number of findings at steady-state conditions indicate that the decreased accumulation is dependent on a cellular mechanism for active outward drug transport, which is common to anthracyclines and vinca alkaloids, but changes in inward transport and intracellular binding capacity also contribute. Similar findings have been reported for resistance and cross-resistance in P388 leukemia. Recent results with counteraction of acquired experimental resistance in animal tumors by inhibition of outward drug transport and studies on the effect of different anthracycline derivatives on accumulation of daunomycin in resistant cells are discussed.