Preclinical antitumor activity of water-soluble paclitaxel derivatives

PURPOSE: Five water-soluble paclitaxel derivatives were extensively evaluated for their antitumor activities relative to the parent drug. METHODS: Both subcutaneous (s.c.) murine (M109 lung) and human (A2780 ovarian, L2987 lung) tumor models were used for this purpose. RESULTS: Consecutive daily intravenous (i.v.) paclitaxel therapy of mice bearing s.c. M109, beginning on day 4 or 5 posttumor implant and continuing for 5 days, resulted in a range of maximum gross log cell kill (LCK) values (reflective of delays in tumor growth) and maximum relative median survival time (% T/C) values (reflective of increases in lifespan) of 1.0-2.1 and 132-162% (and one outlying result of 235%), respectively. Against the same tumor model, using the same treatment schedule, each of the water-soluble derivatives was active, with maximum LCK of 1.3-2.5 and T/C of 124-254%. These LCK and %T/C values were always within 0.5 LCK and 15%, respectively, of the concomitantly obtained maximum effects of paclitaxel. When tested in several experiments against staged (50-100 mg) s.c. A2780 tumors, using various i.v. treatment schedules, the water-soluble derivatives achieved a maximum LCK of 1.4-3.8. Evaluated in parallel, paclitaxel achieved a maximum LCK of 2.1-4.5 following every other day x 5 i.v. therapy. When paclitaxel was assayed in several experiments using the staged (50-100 mg) s.c. L2987 tumor model, maximum LCK of 0.9->4.1 were produced following every other day x 5 i.v. therapy. Concomitant testing of the water-soluble derivatives, using the same i.v. treatment schedule, resulted in maximum LCK of 0.2->4.1. In each of the tumor models used, the consistently active, and usually the most active, water-soluble derivative was BMS-185660. The levels of activity observed were comparable (within 1 LCK) to those achieved concomitantly using paclitaxel, and its potency was only slightly inferior to the parent drug. CONCLUSIONS: Based on the evaluations performed in three distal site tumor models, we conclude that BMS-185660 is a water-soluble paclitaxel derivative with preclinical antitumor activity comparable to that of the parent drug.     

Distribution of a stable isotope of chromium (53Cr) in serum, urine, and breast milk in lactating women

To determine the fate and distribution of chromium during lactation, six lactating women (25-38 y old) were given three doses of the tracer 53Cr (7.55 micromol/d, or 400 microg/d) on days 1, 2, and 3 of the study. Diet records, blood samples taken while subjects were fasting, and 24-h composite milk and urine samples were collected from day 0 to day 6. Fasting blood samples, morning milk samples, and 24-h urine samples were also collected on days 8, 10, 15, 30, 60, and 90. 53Cr and natural and total chromium concentrations in biological fluids were measured with gas chromatography-mass spectrometry and total urinary chromium was measured with atomic-absorption spectrometry. 53Cr was detectable in serum 2 h after dosing and continued to be detected from day 30 to day 60. Changes in total serum chromium concentration in response to the oral dose suggested that chromium concentrations in blood were not tightly regulated. 53Cr was not detected in breast milk and no significant changes in natural chromium concentration in milk were observed in response to the oral doses, suggesting that breast-milk chromium concentrations are independent of intake. The estimated chromium intake of exclusively breast-fed infants was 2.5 nmol/d (0.13 microg/d), below the lower end of the range of estimated safe and adequate daily dietary intakes (10-40 microg/d) for infants 0-6 mo of age. The baseline chromium concentration in urine and the minimum 53Cr absorption in lactating women were comparable with values for nonpregnant, nonlactating subjects. Chromium losses in breast milk do not appear to be compensated for via increased absorption or decreased excretion.     

Reconstruction of the shoulder joint using an acetabular allograft. A report of two cases

Wide resection of tumors involving the glenoid region of the scapula compromises a center of motion in the shoulder joint and can cause significant loss of function. Two patients with aggressive tumor of the scapula were treated with wide resection and reconstruction using an osteoarticular acetabular allograft. The ball and socket geometry of the newly reconstructed joint and secure reattachment of soft tissues in the allograft provided a stable shoulder joint. The functional results of the two patients were 87% and 93%, respectively according to the Musculoskeletal Tumor Society system. In a select group of patients with locally aggressive lesions of the scapula, a surgical reconstruction with an osteoarticular allograft would yield satisfactory functional and cosmetic results.