Regulation of tumour drug delivery by blood flow chronobiology

Thr chronobiology of various physiological phenomena that impact tumour dru g delivery has not been established. Since the delivery of therapeutic agen ts 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 norm al tissues. Preliminary results by Hori et ttl. Cancer Res 1992, 52, 912-91 6, have demonstrated fluctuations in tumour blood flow in subcutaneous (s.c .) rat rumours with a higher rate at 15-21 h after light onset (HALO) compa red with 3-9 HALO, We used the GW-39 and LS174T human colon carcinoma xenog rafts grown s.c. in nude mice for these studies. VV, VP and BF were determi ned at 3, 7, 10, 13, 17, 20 and 23 HALO. In separate studies, dosing with a small therapeutic agent ([H-3]-5-fluorouracil (5-FU)) or a macromolecule ( [I-131]-131-MN-14-anti carcinoembryonic antigen (CEA) immunoglobulin G (IgG )) was done at LO and 17 HALO and 3, 10 and 17 HALO, respectively, and tiss ue and tumour uptake was determined in each group. well-defined peaks and n adirs 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 rh ythm in tumour. Using cosinor analysis of the BF rate, we have found that t he acrophase (peak) for tumour BF occurs at approximately 17 HALO in both t umour xenografts, while maximal liver, lung and kidney BF occurred at 10-13 HALO. Tumour BF rate ranged from the lon est value of 1.34+/-0.54 mu l/g/m in at 20 HALO to the highest value of 2.79+/-0.57 mu l/g/min at 17 HALO. Li ver BF rate ranged from 4.1+/-1.1 mu l/g/min at 3 HALO to 10.22+/-1.31 mu l /g/min at 10 HALO, and was 5.83+/-1.37 mu l/g/min tit 17 HALO. Thus, the rh ythm of tumour and normal tissue BF are different, creating a window of opp ortunity when tumours can be targeted with a therapeutic agent. At 3 h post injection, 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 %I D/g of [I-131]-MN-14 IgG in tumour at 10 HALO was 11.50+/-1.58 and at 17 HA LO tvas 1.5-fold higher at 16.963+/-2.35 (P < 0.001). In liver at TO HALO, uptake was 6.47+/-0.49 and at 17 HALO was 30% lower at 4.48+/-0.81 (P < 0.0 1). These results suggest that small shifts in the chronobiology of BF in t umour and in normal tissue can have a sizeable impact on the distribution o f chemotherapeutics and antibody-based drugs. (C) 2000 Elsevier Science Ltd . All rights reserved.