Evaluation of C-2-substituted 19-nor-1alpha,25-dihydroxyvitamin D3 analogs as therapeutic agents for prostate cancer.

1alpha,25-Dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) is known to inhibit the proliferation and invasiveness of prostate cancer cells. However, 1alpha,25(OH)(2)D(3) can cause hypercalcemia and is not suitable as a therapeutic agent. 19-Nor-vitamin D derivatives are known to be less calcemic when administered systemically. In order to develop more potent anti-cancer agents with less calcemic side effect, we therefore utilized (3)H-thymidine incorporation as an index for cell proliferation and examined the antiproliferative activities of nine C-2-substituted 19-nor-1alpha,25(OH)(2)D(3) analogs in the immortalized PZ-HPV-7 normal prostate cell line. Among the nine analogs we observed that the substitution with 2alpha- or 2beta-hydroxypropyl group produced two analogs having antiproliferative potency that is approximately 500- to 1000-fold higher than 1alpha,25(OH)(2)D(3). The (3)H-thymidine incorporation data were supported by the cell counting data after cells were treated with 1alpha,25(OH)(2)D(3), 19-nor-2alpha-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) or 19-nor-2beta-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) for 7 days. 19-Nor-2alpha-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) and 19-nor-2beta-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) were also shown to be about 10-fold more active than 1alpha,25(OH)(2)D(3) in cell invasion studies using prostate cancer cells. In conclusion, a substitution at the C-2 position of 19-nor-1alpha,25(OH)(2)D(3) molecule with a hydroxypropyl group greatly increased the antiproliferative and anti-invasion potencies. Thus, these two analogs could be developed to be effective therapeutic agents for treating early and late stages of prostate cancer.

Influence of the varus-valgus instability on the contact of the femoro-tibial joint.

The varus-valgus instability of the knee joint is mainly due to ruptured or lax collateral ligaments. The purpose of this investigation was to study the influence of the varus-valgus instability on the contact pressures of the femoro-tibial joint. Six fresh knee specimens of human cadavers were tested to measure the contact pressure on the tibia plateau of the knee joint at varus or valgus alignment under various loads and at full extension. Pressure transducers and Bourdon tube pressure gauges were used simultaneously for recording pressure. At neutral alignment of the knee with the menisci intact, the peak pressure increased linearly with forces up to 4 MPa. With increasing varus alignment, the peak contact pressure on the medial plateau not covered by the menisci increased up to a maximum of 7.3 MPa at 5 degrees varus, and at 5 degrees valgus, the peak pressure on the lateral plateau was 7.8 MPa. After total meniscectomy, the contact pressure increased up to a maximum of 7.4 MPa at a force of 2700 N. With increasing varus alignment, the contact pressure on the medial plateau increased to 8.1 MPa at 5 degrees varus and on the lateral plateau 9.2 MPa at 5 degrees valgus.