Abstract
Response of tumours to chemotherapy is limited by resistance, inherent or developing during treatment, causes of which include impaired drug delivery and changes in cellular drug transport.
Although high-dose intravenous melphalan, with priming and autologous bone marrow rescue, increased response rates, gastrointestinal toxicity limits further dose escalation. The aims of this study were to increase uptake of melphalan by tumours, by manipulating either their blood flow or cellular melphalan transport, without increasing normal tissue toxicity, and to explore ways of reducing gastrointestinal toxicity.
Blood flow, measured from the fractional distribution of 86Rb-rubidium chloride, 14C-melphalan uptake and melphalan-induced growth delay, were determined in cba mice bearing subcutaneous
fibrosarcomas or human melanoma HX46 xenografts. Four vasodilators, including verapamil, and 3 vasoconstrictors failed to increase blood flow in fibrosarcomas. Only the hypertensive agent, angiotensin II, 1.2ug/kg/min by iv infusion, and the melphalan acid alcohol solvent increased relative blood flow to the fibrosarcomas, but not to HX46 xenografts. Angiotensin II increased 14C-melphalan uptake at 30 minutes, the effect becoming lost by 60 minutes, and had no effect on growth delay of fibrosarcomas. The acid alcohol solvent affected neither 14C-melphalan uptake nor growth delay. It was concluded that enhancement of tumour blood flow was unpredictable and depended on the particular tumour, site and host. Furthermore blood flow did not limit melphalan delivery to the tumours, and the vascular system differed in the fibrosarcomas and HX46 xenografts.
Verapamil increased blood levels of 14C-melphalan administered iv or ip, increased 14C-melphalan uptake by the fibrosarcomas, and potentiated growth delay by melphalan in the fibrosarcomas and HX46 xenografts. Changes in cytotoxicity correlated with pharmacokinetic effects rather than with blood flow. However, verapamil also increased the gastrointestinal (jejunum microcolony assay) and bone marrow (spleen colony assay) toxicity of melphalan in mice, through effects on pharmacokinetics and marrow cellular uptake.
Verapamil increased the cytotoxicity of melphalan to murine bone marrow, in vitro (CFU-GM), and increased 14C-melphalan uptake by the cells in a dose-related, reversible, calcium - independent,
temperature-dependent way, and inhibited melphalan efflux. Similar effects were seen in disaggregated fibrosarcoma cells. Verapamil affected neither uptake nor cytotoxicity of melphalan in human bone marrow and HL60 cells, confirming that melphalan transport by human and murine marrow differs. Mel phal an transport is likely to be altered by verapamil in some human tumours, allowing an increased therapeutic index. Another calcium antagonist, flunarizine, had similar but smaller effects to verapamil. A component of transport of melphalan seems to be shared with other cytotoxic drugs and modified by calcium antagonists.
Vasoactive intestinal peptide reduced blood flow but failed to reduce melphalan uptake or toxicity in the jejunum in mice. Epidermal grov,th factor, trophi"c and cytoprotect i ve to the gastrointestinal tract, failed to limit or enhance recovery from gastrointestinal epithelial damage by melphalan.