kh-1060 and Prostatic-Neoplasms

1,25 dihydroxyvitamin D3 (1,25D) and retinoids may play an important role in preventing progression of prostate cancer.. We examined the ability of four novel 20-epi-vitamin D3 analogs (CB1093, KH1060, KH1266, and CB1267), either alone or in combination with 9-cis retinoic acid (RA) to inhibit colony growth of a human prostate cancer cell line, LNCaP, using soft agar as well as bone marrow stroma. Also, the effect of these analogs on the cell cycle and expression of Ki-67, p21(waf-1), and p27(kip1) in LNCaP cells was examined.. The analog CB1267 was the most potent, with 8 x 10(-10) M of the analog inhibiting 50% colony growth (ED50) of LNCaP. 9-cis-RA also inhibited colony growth of LNCaP (ED50, 5 x 10(-7) M). Combined, CB1267 and 9-cis-RA synergistically inhibited colony growth and significantly increased the number of LNCaP cells in G0/G1 phase. Cell cycle arrest was associated with increased levels of p21(waf-1) and p27(kip1) and decreased expression of Ki-67 protein. Pulse-exposure to this combination (5 x 10(-8) M) irreversibly inhibited colony growth, both in soft agar and on normal human bone marrow stroma.. Combination of a new vitamin D3 analog (CB1267) and a retinoid (9-cis-RA) potently inhibited colony formation of LNCaP prostate cancer cells in vitro, suggesting further studies in animal models. This combination may afford an interesting therapeutic approach to low-burden prostate cancer.

Topics: Alitretinoin; Antineoplastic Agents; Bone Marrow Cells; Calcitriol; Cell Cycle; Cell Cycle Proteins; Cell Division; Cell Survival; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclins; Drug Synergism; Humans; Male; Microtubule-Associated Proteins; Prostatic Neoplasms; Stromal Cells; Tretinoin; Tumor Cells, Cultured; Tumor Suppressor Proteins

Management of prostate cancer that has spread outside of the prostate capsule is a difficult problem. Innovative, non-toxic approaches to the disease are required. New, relatively non-toxic vitamin D3 analogs have recently been synthesized. We report that several of these compounds have marked antiproliferative effects on prostate cells.. The clonal antiproliferative activity of five novel analogs of 1,25 dihydroxyvitamin D3 [1,25(OH)2D3, (cmpd C)] as well as 1,25(OH)2D3 itself was tested on three human prostate cancer cell lines (PC-3, LNCaP, and DU-145). The analogs were 20-epi-22oxa-24a,26a,27a-tri-homo-1 alpha,25(OH)2D3 (code name: KH 1060); 24a26a27a-tri-homo-22,24-diene-1 alpha,25(OH)2D3 (code name: EB 1089); 1,25(OH)2-16ene-D3 (code name: HM); 1,25(OH)2-16ene-23yne-D3 (code name: V); 1,25(OH)2-20-epi-D3 (code name: MC 1288)].. With the parent compound [1,25(OH)2D3], the effective dose that inhibited 50% clonogenic growth of PC-3 and LNCaP was 10(-8)M and 7 x 10(-9)M, respectively. For these prostate cancer cell lines, KH 1060 was the most potent analog by an order of 25- to 35-fold as compared to cmpd C. The second and third most potent analogs were HM and MC 1288. DU-145 was resistant to all the vitamin D3 analogs. The major side-effect of 1,25(OH)2D3 is the production of hypercalcemia. The relative inhibitory index (RII) was determined by comparing the antiproliferative activity of the analog to its ability to produce hypercalcemia in mice injected intraperitoneally every other day. The KH 1060 had the best RTI: 50- to 70-fold greater than 1,25(OH)2D3 for PC-3 and LNCaP, respectively.. A trial of one or more of these innovative compounds should be considered for treatment of minimal residual disease of prostate cancer.

Topics: Animals; Antineoplastic Agents; Calcitriol; Calcium; Cell Division; Cholecalciferol; Humans; Male; Mice; Mice, Inbred BALB C; Prostatic Neoplasms; Tumor Cells, Cultured