A physiological pharmacokinetic model was developed to describe the disposition of lycopene, delivered as a tomato beverage formulation in five graded doses (10, 30, 60, 90, or 120 mg), for a phase I study in healthy male subjects (five per dose). Blood was collected before dose administration (0 h) and at scheduled intervals until 672 h. Serum concentrations of carotenoids and vitamins were measured by high performance liquid chromatography analysis. The model was comprised of seven compartments: gastrointestinal tract, enterocytes, chylomicrons, plasma lipoproteins, fast-turnover liver, slow-turnover tissues, and a delay compartment before the enterocytes. As predicted, the percent absorption at the 10 mg dose (33.9 ؎ 8.1%) was significantly greater than at the higher doses; however, the amount of lycopene absorbed (mg) was not statistically different (mean: 4.69 ؎ 0.55 mg) between doses, suggesting a possible saturation of absorptive mechanisms. The slowturnover tissue compartment served as a slow-depleting reservoir for lycopene, and the liver represented the fastturnover pool. Independent of dose, 80% of the subjects absorbed less than 6 mg of lycopene. This may have important implications for planning clinical trials with pharmacological doses of lycopene in cancer control and prevention if absorption saturation occurs at levels that are already being consumed in the population. -Diwadkar-Navsariwala, V., J. A.

Employing the natural product quassinoid brusatol, we currently report cellular and molecular events leading to cell death or terminal differentiation in a panel of leukemic cells. Brusatol and bruceantin exerted significant cytotoxic effects with several leukemic cell lines, but not with K562 or normal lymphocytic cells. Cell lines that were less sensitive to the cytotoxic effects of brusatol responded primarily through induction of terminal differentiation. The differentiated phenotype in cell lines derived from acute or chronic myeloid leukemias (HL-60, K562, Kasumi-1, NB4, U937, BV173) was characterized for producing superoxide and non-specific esterase, and some with up-regulation of CD13 (cluster of differentiation) and downregulation of CD15. Chronic myeloid leukemic cell lines, K562 and BV173, and acute lymphoblastic cell lines, SUPB13 and RS4;11, were induced to differentiate along the erythrocytic pathway. Withdrawal studies showed that brusatol treatment for 48 h was sufficient to induce commitment towards terminal differentiation in HL-60, K562 and SUPB13. Reh cells did not undergo maturation. Analysis of c-MYC protein expression revealed that brusatol or bruceantin down-regulated expression to undetectable levels in cell lines that were most sensitive, based on cell death or terminal differentiation. Generally, c-myc RNA was reduced, but to a lower extent than c-MYC protein levels, indicating c-myc expression was regulated by quassinoids at the post-transcriptional level. Thus, regulation of c-myc expression may represent a critical event that leads to terminal differentiation. Since these responses are facilitated at clinically achievable concentrations, quassinoids may be of value for the management of hematological malignancies.

Paclitaxel as a single agent represents an effective therapeutic alternative for patients with advanced transitional cell carcinoma of the urothelium and renal insufficiency precluding cisplatin or gallium nitrate based chemotherapy. Additionally, paclitaxel appears to be effective in patients in whom prior cisplatin based therapy failed.

Recombinant human interleukin 10 (rhuIL-10) inhibits the production of proinflammatory cytokines and has shown promise in the treatment of inflammatory bowel disease. Clinical trials have been accompanied by a reversible decline in platelet counts. We conducted a randomized, double-blinded, placebo-controlled, parallel group trial in 12 healthy volunteers to investigate the aetiology of rhuIL-10-induced thrombocytopenia. Eight volunteers received 8 microg/kg/d of rhuIL-10 subcutaneously, while four subjects received a placebo alone for 10 d. A reversible decline in the platelet counts from a mean of 275 x 10(9)/l to 164 x 10(9)/l was observed in the IL-10-treated cohort (P = 0.012). A fall in the haemoglobin mean levels was also observed in the IL-10-treated cohort from 13.7 to 11.7 g/dl (P = 0.011). No significant change was observed in the bone marrow cellularity or myeloid/erythroid ratio or in the number of megakaryocytes per high-powered field (HPF). A fall was observed in the number of megakaryocyte colony-forming units (CFU-MKs) after the administration of IL-10 compared with those receiving the placebo (P = 0.068). No difference in the change in granulocyte-macrophage CFUs (CFU-GMs), mixed lineage CFUs (CFU-GEMMs) or erythroid burst-forming units (BFU-Es) was observed when comparing the IL-10- vs. placebo-treated groups (P > 0.465). Serum cytokine levels of thrombopoietin (TPO). IL-6 and granulocyte-macrophage colony stimulating factor (GM-CSF) were not decreased following IL-10 administration. In fact, both TPO and GM-CSF appeared to be slightly increased in the serum. All subjects underwent In111-labelled platelet survival studies with liver/spleen scans to assess splenic sequestration prior to and then on day 7 of treatment. A significant reduction in splenic sequestration of platelets (P =0.012) was observed in the IL-10-treated group, but not in the placebo-treated subjects.

Recombinant human interleukin 10 (rhuIL‐10) inhibits the production of proinflammatory cytokines and has shown promise in the treatment of inflammatory bowel disease. Clinical trials have been accompanied by a reversible decline in platelet counts. We conducted a randomized, double‐blinded, placebo‐controlled, parallel group trial in 12 healthy volunteers to investigate the aetiology of rhuIL‐10‐induced thrombocytopenia. Eight volunteers received 8 μg/kg/d of rhuIL‐10 subcutaneously, while four subjects received a placebo alone for 10 d. A reversible decline in the platelet counts from a mean of 275 × 109/l to 164 × 109/l was observed in the IL‐10‐treated cohort (P = 0·012). A fall in the haemoglobin mean levels was also observed in the IL‐10‐treated cohort from 13·7 to 11·7 g/dl (P = 0·011). No significant change was observed in the bone marrow cellularity or myeloid/erythroid ratio or in the number of megakaryocytes per high‐powered field (HPF). A fall was observed in the number of megakaryocyte colony‐forming units (CFU‐MKs) after the administration of IL‐10 compared with those receiving the placebo (P = 0·068). No difference in the change in granulocyte–macrophage CFUs (CFU‐GMs), mixed lineage CFUs (CFU‐GEMMs) or erythroid burst‐forming units (BFU‐Es) was observed when comparing the IL‐10‐ vs. placebo‐treated groups (P > 0·465). Serum cytokine levels of thrombopoietin (TPO), IL‐6 and granulocyte–macrophage colony stimulating factor (GM‐CSF) were not decreased following IL‐10 administration. In fact, both TPO and GM‐CSF appeared to be slightly increased in the serum. All subjects underwent In111‐labelled platelet survival studies with liver/spleen scans to assess splenic sequestration prior to and then on day 7 of treatment. A significant reduction in splenic sequestration of platelets (P = 0·012) was observed in the IL‐10‐treated group, but not in the placebo‐treated subjects.