Variability of tumor response to chemotherapy. II. Contribution of tumor heterogeneity

The role of tumor-to-tumor variability in response to chemotherapy was investigated in mice bearing mammary adenocarcinoma 16/C treated with melphalan. Lissamine green, a triphenylmethane dye, was given systemically to delineate areas of perfusion in the tumors. The regions of low perfusion ranged from less than 10% to greater than 90% of the mass of individual tumors. The variation in perfusion was as large between bilateral tumors in a mouse as between tumors in different hosts. The presence of viable cells capable of continued growth in the regions of low perfusion was demonstrated by bioassay. Concentrations of melphalan following i.p. administration varied by as much as tenfold or more between regions of low and high perfusion. Concentrations of melphalan in the well-perfused regions were similar to plasma concentrations at 30 min after administration, but elimination from the plasma was more rapid. The levels of melphalan in the tumor were higher following the initial dose than following succeeding doses in a multiple dose schedule. The results indicate that tumor-to-tumor variations in perfusion and drug distribution are major factors in variable tumor response.