A spline-based procedure for monotone curve smoothing is proposed and is illustrated by application to dose-response curves. It is then shown how such smoothing can be applied to assess possible synergism or antagonism of two drugs.

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The microtubule stabilizing agent peloruside A binds to a unique site on the tubulin alpha,beta-heterodimer compared to taxoid site drugs such as paclitaxel (Taxol), docetaxel (Taxotere), epothilone A, and discodermolide. Because the binding sites differ, peloruside A may be able to synergize with these taxoid site drugs when added in combination to cultured cells. Ovarian carcinoma cells (1A9) and myeloid leukemic cells (HL-60) were treated with different concentrations of peloruside A and taxoid site drugs, both compounds given singly and in combination in the nanomolar range, and the antiproliferative activity, G2/M blocking potency, and microtubule stabilizing activity of the treatments assessed. Cell proliferation was monitored using the MTT cell proliferation assay, cell cycle block was determined by flow cytometry, and stabilization of the tubulin polymer was assessed by Western blotting for beta-tubulin distributions in supernatant and pellet fractions of cell lysates. A combination index (CI) was calculated from the equation CI = D1/Dx1 + D2/Dx2 in which D1 and D2 are the concentrations of drug 1 and drug 2 that in combination give the same response as drug 1 alone (Dx1) or drug 2 alone (Dx2). A CI of less than 1 indicates synergy, equal to 1, additivity, and greater than 1, antagonism. Confidence intervals for each CI value were obtained using a bootstrapping procedure. In cell proliferation assays, statistically significant synergy was found between peloruside A and paclitaxel and epothilone A. Combinations of these two taxoid site drugs, however, also showed synergy in their effects on cell proliferation. These results confirm that peloruside A, when added in combination with other microtubule stabilizing agents, acts synergistically to enhance the antimitotic action of the drugs, but also highlight the complexity of drug interactions in intact cells.

If two successive trait measurements have a less-than-perfect correlation, individuals or populations will, on average, tend to be closer to the mean on the second measurement (the so-called regression effect). Thus, there is a negative correlation between an individual's state at time 1 and the change in state from time 1 to time 2. In addition, whenever groups differ in their initial mean values, the expected change in the mean value from time 1 to time 2 will differ among the groups. For example, birds feeding nestlings lose weight, but initially heavier birds lose more weight than lighter birds, a result expected from the regression effect. In sexual selection, males who remain unmated in the first year are, on average, less attractive than mated males. The regression effect predicts that these males will increase their attractiveness in the second year more than mated males. In well-designed experiments, changes in the experimental and control groups would be compared. In observational studies, however, no such comparison is available, and expected differential effects must be accounted for before they can be attributed to external causes. We describe methods to correct for the regression effect and assess alternative causal explanations.

Concurrent administration of sodium thiosulfate (STS) can protect against the nephrotoxic effects of even very-high-dose cisplatin (CDDP) (i.e., 270 mg/m2 given intraperitoneally). The effect of STS on the pharmacology and toxicity of CDDP was investigated in patients receiving at each treatment 90 mg of CDDP/m2 intraperitoneally, with STS given concurrently on alternate cycles by the intravenous route. The patients received a total of 38 courses of therapy, 21 without STS and 17 with STS. STS reduced the total exposure to diethyldithiocarbamate-reactive CDDP for the peritoneal cavity and plasma by 36% and 25%, respectively. When given alone, CDDP caused a statistically significant acute reduction in creatinine clearance levels; this reduction was less evident when STS was given. We conclude that, whereas STS does reduce systemic exposure, the magnitude of this effect was not sufficient to account for the ability of STS to protect against high-dose CDDP.