Enhancement of the activity of phenoxodiol by cisplatin in prostate cancer cells.

Phenoxodiol is a novel isoflav-3-ene, currently undergoing clinical trials, that has a broad in vitro activity against a number of human cancer cell lines. Phenoxodiol alone inhibited DU145 and PC3 in a dose- and time-dependent manner with IC(50) values of 8+/-1 and 38+/-9 microM, respectively. The combination of phenoxodiol and cisplatin was synergistic in DU145, and additive in PC3, as assessed by the Chou-Talalay method. Carboplatin was also synergistic in combination with phenoxodiol in DU145 cells. The activity of the phenoxodiol and cisplatin combination was confirmed in vivo using a DU145 xenograft model in nude mice. Pharmacokinetic data from these mice suggest that the mechanism of synergy may occur through a pharmacodynamic mechanism. An intracellular cisplatin accumulation assay showed a 35% (P<0.05) increase in the uptake of cisplatin when it was combined in a ratio of 1 microM:5 microM phenoxodiol, resulting in a 300% (P<0.05) increase in DNA adducts. Taken together, our results suggest that phenoxodiol has interesting properties that make combination therapy with cisplatin or carboplatin appealing.

Intravenous administration of 9-aminocamptothecin to dogs with lymphoma.

A colloidal dispersion formulation of 9-aminocamptothecin (9-AC) was administered intravenously to 10 dogs with previously untreated, spontaneously occurring, multicentric lymphoma. The dogs received a 72-h infusion of 9-AC at a rate of 46.5-51.25 microg m(-2) h(-1) (total dose range 3.35-3.69 mg m(-2)). This dose range was associated with myelosuppression, consisting principally of neutropenia with a nadir at 7 days following the start of infusion. Neutropenia and thrombocytopenia were the most common toxicoses and are most likely to be dose-limiting toxicities; low-grade gastrointestinal signs were rarely seen. Concentrations of 9-AC lactone, as well as clinical toxicities, compare favourably with those found in humans. Tumour responses were seen in all treated dogs. Response to other chemotherapy, following cessation of 9-AC treatment, was not obviously compromised even in dogs clinically resistant to 9-AC. 9-AC is a novel treatment drug for canine lymphoma, which appears to show great promise.

9-Aminocamptothecin: a topoisomerase I inhibitor with preclinical activity in prostate cancer.

9-Aminocamptothecin (9-AC) is a topoisomerase I inhibitor currently being developed as an antineoplastic agent. The aim of these preclinical studies was to assess the activity of 9-AC against prostate cancer, a malignancy notoriously insensitive to most cytotoxic agents in the clinic. The activity of 9-AC was first tested in vitro against one hormone-sensitive (LNCaP) and three hormone-resistant (PC-3, PC-3M, and DU145) human prostate cancer cell lines. After 96 h of drug exposure, concentrations required to inhibit cell viability to 50% of control values (IC50s) were 34.1, 10, 6.5, and 8.9 nm for PC-3, PC-3M, DU145, and LNCaP, respectively. Because 9-AC is known to undergo rapid hydrolysis, we assayed lactone levels in tissue culture medium over 24 h and found that the half-life was 20 min, with only 15%of the drug remaining as lactone at steady state. Consequently, the IC50s calculated from a single dose of the drug may represent overestimates. Subsequently, we tested the activity of a colloidal dispersion formulation of 9-AC against PC-3 implanted into flanks of nude mice. 9-AC was given for a total of 3 weeks by daily oral gavage (excluding weekends) or by twice weekly s.c. injections. 9-AC inhibited tumor growth at the lowest oral dose (0.35 mg/kg/day), whereas higher oral doses (0.75 and 1 mg/kg/day) and s.c. administration (4 mg/kg/week) caused tumor regression. 9-AC was well tolerated at all doses, with no toxic death or weight loss of more than 10% observed in any group. Finally, we considered that the activity of 9-AC seen in the mouse xenograft model might be explained, in part, by the relatively acidic tumor microenvironment, which would favor the formation of the more potent lactone. Simultaneous determination of plasma and tumor 9-AC lactone concentrations confirmed this hypothesis. Taken together, these studies suggest that 9-AC should be submitted for clinical trials in patients with prostate cancer.

Enhancement of paclitaxel activity against hormone-refractory prostate cancer cells in vitro and in vivo by quinacrine.

Cytoplasmic phospholipase A2 (PLA2) is known to be phosphorylated and activated by MAP kinase (Lin et al 1993, Cell 72: 269-278), an important downstream component of signal transduction, whereas paclitaxel has been shown to inhibit isoprenylation of ras proteins (Danesi et al 1995, Mol Pharmacol 47: 1106-1111). Given that quinacrine (Q), a PLA2 inhibitor, and paclitaxel (P) might act at different sites in the cell signalling pathway, our aim was to test whether they were synergistic in combination against prostate cancer cells. Cell viability of PC-3, PC-3M and DU145 cells in 96 - well plates was assessed 96 h after drugs were added concurrently. Using Chou analysis, we demonstrated synergy for the combination against all three cell lines. Further, synergy was present under both conservative (mutually non-exclusive) and non-conservative (mutually exclusive) models. Studies in the nude mouse xenograft model support the finding of synergy in vitro. In DU145-bearing mice, Q (50 mg kg(-1)) and P (0.5 mg kg(-1)) given daily for 12 consecutive days, either concurrently or sequentially, was more effective than either drug alone, at twice the dose intensity. In an enzyme-linked immunosorbent (ELISA) apoptosis assay, arachidonic acid was able to partially reverse Q- and P-induced apoptosis, suggesting PLA2 pathway involvement. Finally, the combination of lovastatin, another inhibitor of ras isoprenylation, and quinacrine had synergistic inhibitory effects on the growth of PC-3 cells in vitro, suggesting that the combination of these two classes of compounds might serve as an attractive therapeutic approach for prostate cancer.

Prognostic factors in ovarian cancer.

Epithelial ovarian cancers vary considerably in their biologic behavior and this is reflected in the variety of clinicopathologic factors that are used for predicting outcome. This article assesses the potential value of some of the newer prognostic factors and critically evaluates the more commonly used clinicopathologic variables.