Primary and acquired resistance to antineoplastic chemotherapy. A preclinical and clinical study

Due to ethical restrictions, dose-response relationships may not be appreciated in clinical trials as clearly as in preclinical tumor models. Furthermore, tumor heterogeneity sets the pharmacology of antineoplastic agents somewhat apart from general pharmacology, since for each individual tumor there may be a distinct dose-response curve describing tumor-inhibitory effects of a given drug. This has been documented by a panel of human tumor xenografts derived from patients with disseminated malignant melanoma who participated in an open Phase II clinical trial. Patients who were refractory to dacarbazine received the combination of ifosfamide and cisplatin and vice versa. In the xenograft model four additional DNA-damaging agents were tested. Heterogeneity of response to antineoplastic drug treatment was evident in three ways: (1) tumor volume responses of individual mice bearing a certain xenograft line varied considerably after exposure to a certain drug at a specified dose level; (2) at equitoxic dose levels response of a given xenograft line to different DNA-damaging agents was quite heterogeneous, covering a range of almost two decades; and (3) if the panel of xenograft lines derived from different donors was exposed to a battery of DNA-damaging drugs at the LD 10/30 level, some lines revealed unique chemosensitivity patterns in contrast to more uniform resistance displayed by a minority of lines. Preclinical and clinical responses correlated well, and thus the relevance of dose-response relationships observed in the xenograft model to clinical treatment strategies is discussed.