Use of 1,2:5,6-dianhydrogalactitol in studies on cell kinetics-directed chemotherapy schedules in human tumors in vivo.

Recently, it has been shown that 1,2:5,6-dianhydrogalactitol (DAG) can cause reversible alterations in cell cycle kinetics. Following treatment of CHO cells in vitro and Ehrlich ascites tumor cells in vivo, significant increases in the fraction of cells in S phase were observed to occur, and this was followed by an increase in the fractions of cells in G2 and mitosis. Treatments with S or G2-M phase-specific drugs at the peak enrichment times after DAG was given resulted in greater cell kills than when given by any other schedule. We have extended these kinetics-directed drug schedule studies to human tumors in vivo. The first phase was to determine whether DAG could be used to perturb cell kinetics in vivo as effectively in patients as it was in vitro. In 14 of 17 tumors studied, increases in the S-phase fractions were observed (ranging from 30 to 240% increases). The hr at which the S-phase peaks were observed (post-DAG treatment) was variable among the patients and among the tumors studied. However, this points out the value of obtaining actual cell kinetics data from serially biopsied tumors growing on the body surface and illustrates the importance that these data may have in helping to select an optimal time at which to give an S phase-specific drug. If such tumor cell kinetics-directed scheduling is ultimately shown to be effective, it will represent a means of individualizing therapy for a large fraction of tumor patients whose tumors are growing on or near the surface of the body. The tumors utilized in these studies were squamous carcinomas of the head and neck, skin, anus, and cervix; adenocarcinomas of the breast and rectum; and malignant melanoma. The second phase of this study will be to determine the tumor responses in patients treated with such kinetics-directed schedules.