Inhibition of HT-29 Human Colon Cancer Growth under the Renal Capsule of Severe Combined Immunodeficient Mice by an Analogue of 1,25-Dihydroxyvitamin D₃, DD-003

Abstract

An analogue of 1,25-dihydroxyvitamin D₃, 22(S)-24-homo-26,26,26,27,27,27-hexafluoro-1α,22,25-trihydroxyvitamin D₃ (DD-003), showed 10-fold greater inhibiting effect than 1,25-dihydroxyvitamin D₃ on the growth of HT-29 human colonic adenocarcinoma cells in culture. To examine the anticancer activity of DD-003 in vivo, a fibrin clot of HT-29 cells was prepared with fibrinogen and thrombin and implanted under the renal capsule of the severe combined immunodeficient mouse. Starting 7 days after implantation of HT-29 tumor, mice were given 3 µg/kg body weight of DD-003 or the vehicle i.p. every other day for 5 times. The HT-29 tumor grew rapidly in control mice; malignant growth was clearly observed with mitosis, massive tumor angiogenesis, and invasion into normal kidney tissue. Tumors in DD-003 treated mice were smaller with less invasion compared to the control. Administration of DD-003 inhibited growth of HT-29 tumor by 63%. Serum calcium concentrations and body weights of the treated mice were similar to those of the control. DD-003 inhibited growth of HT-29 tumor in a dose-dependent manner over the range of 0.1–10 µg/kg body weight, with no increase of serum calcium concentration observed at any dose level. When DD-003 was withdrawn after 2 weeks of treatment, tumor growth resumed. Since chemosensitivity tested by the subrenal capsule assay correlates well with clinical response, DD-003 may be clinically applicable in procedures such as postsurgical chemotherapy of colon cancer.