Regulation of tumour drug delivery by blood flow chronobiology

The chronobiology of various physiological phenomena that impact tumour drug delivery has not been established. Since the delivery of therapeutic agents is directly influenced in part by tumour vascular volume (VV), vascular permeability (VP) and local blood flow (BF), we have performed a series of studies to assess the natural rhythms of these functions in tumour and normal tissues. Preliminary results by Hori et al. Cancer Res 1992, 52, 912-916, have demonstrated fluctuations in tumour blood flow in subcutaneous (s.c.) rat tumours with a higher rate at 15-21 h after light onset (HALO) compared with 3-9 HALO. We used the GW-39 and LS174T human colon carcinoma xenografts grown s.c. in nude mice for these studies. VV, VP and BF were determined at 3, 7, 10, 13, 17, 20 and 23 HALO. In separate studies, dosing with a small therapeutic agent ([3H]-5-fluorouracil (5-FU)) or a macromolecule ([131I]-131-MN-14-anti carcinoembryonic antigen (CEA) immunoglobulin G (IgG)) was done at 10 and 17 HALO and 3, 10 and 17 HALO, respectively, and tissue and tumour uptake was determined in each group. Well-defined peaks and nadirs were observed for all three vascular functions. The peaks for VV and VP were similar in tumour and normal tissue whereas BF rate had a unique rhythm in tumour. Using cosinor analysis of the BF rate, we have found that the acrophase (peak) for tumour BF occurs at approximately 17 HALO in both tumour xenografts, while maximal liver, lung and kidney BF occurred at 10-13 HALO. Tumour BF rate ranged from the lowest value of 1.34+/-0.54 microliter/g/min at 20 HALO to the highest value of 2.79+/-0.57 microliter/g/min at 17 HALO. Liver BF rate ranged from 4.1+/-1.1 microliter/g/min at 3 HALO to 10.22+/-1.31 microliter/g/min at 10 HALO, and was 5.83+/-1.37 microliter/g/min at 17 HALO. Thus, the rhythm of tumour and normal tissue BF are different, creating a window of opportunity when tumours can be targeted with a therapeutic agent. At 3 h postinjection, the %ID/g of 5-FU in tumour at 10 HALO was 0.14+/-0.09 and at 17 HALO was 0.32+/-0.12 (P<0.02). In liver at 10 HALO, uptake was 0.13+/-0.06 and at 17 HALO was 0. 07+/-0.03 (P<0.05). At 24 h postinjection, the %ID/g of [131I]-MN-14 IgG in tumour at 10 HALO was 11.50+/-1.58 and at 17 HALO was 1. 5-fold higher at 16.96+/-2.35 (P<0.001). In liver at 10 HALO, uptake was 6.47+/-0.49 and at 17 HALO was 30% lower at 4.48+/-0.81 (P<0.01). These results suggest that small shifts in the chronobiology of BF in tumour and in normal tissue can have a sizeable impact on the distribution of chemotherapeutics and antibody-based drugs.