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To investigate the mechanisms responsible for the postpartum suppression of reproductive function, LH and PRL levels were determined at 10-min intervals for 8 h in 10 lactating women, in 10 nonlactating women treated with bromocriptine, and in 5 nonpuerperal women. The lactating women were studied on postpartum day 7 (n = 5) or between days 28 and 35 (n = 5). All nonlactating women were studied on day 7. Five of them were treated with the opioid antagonist naltrexone to evaluate the role of endogenous opioids. By using a specific LH assay which does not cross-react with hCG, we were able to measure pulsatile LH secretion in the early puerperium for the first time. On day 7, LH levels were below the detection limit in both lactating and nonlactating women, hence no pulses could be detected. Chronic opioid blockade in bromocriptine-treated non-lactating women did not result in increased LH levels. Pulsatile LH secretion was present between days 28 and 35 of lactation, although pulse amplitude (P less than 0.05) and mean LH level (P less than 0.05) were lower than in nonpuerperal women. Mean LH in lactating women was negatively correlated with mean PRL (-0.87, P less than 0.05). Deconvolution analysis of the PRL responses to suckling revealed that PRL was secreted in distinct bursts, separated by intervals of secretory quiescence. Mean duration of PRL bursts was 40 +/- 4 min and the maximum secretory rate was reached around the end of suckling. We conclude that pulsatile LH secretion is completely suppressed during early lactation and partially suppressed during late lactation. Because the duration of suckling was similar, the relatively strong suppression during the early puerperium must be due to additional inhibitory factors. It has been suggested that endogenous opioids are involved in this process, but our results in puerperal women do not support this hypothesis.

We have investigated the antiproliferative effects of recombinant human alpha- and gamma-Interferon (IFN) and recombinant human Tumor Necrosis Factor alpha (TNF) against the hormone-independently growing PC3 and DU145 prostatic tumor lines. Subcutaneous, peritumoral administration of the drugs was started 24 hours after subcutaneous implantation of 1-2 mm3 tumor pieces. IFN was given three times per week and TNF five times per week. IFN-alpha (dose-range 0.5-5 ng/gram bodyweight) had significant growth-inhibiting effects against the PC3 tumor, but showed no significant antitumor effects against the DU145 tumor. IFN-gamma monotherapy (dose-range 8-80 ng/gram bodyweight) was less effective than IFN-alpha. 500 ng/gram TNF produced growth inhibition of both tumors, whereas the lower dose (50 ng/g) was only effective against the PC3 tumor. IFN-alpha and -gamma combination treatment had significant antiproliferative effects against the PC3 tumor, but not against the DU145 tumor. Combinations of IFN-alpha and TNF were very effective against both xenografts; some combinations resulted in complete growth inhibition. IFN-gamma and TNF combinations also showed significant antitumor effects against both tumor lines. We therefore conclude that cytokine combination treatment may provide a new approach in the treatment of hormone-escaped prostatic tumors.

Growth curves of two human tumour cell lines grown as multicellular tumour spheroid (MTS) were used to obtain survival estimates by back-extrapolation after split and single dose irradiation. Neuroblastoma (NB-100) and squamous cell carcinoma (HN-1) single cells from monolayer culture were assessed for repair of sublethal and potentially lethal damage. The extent of repair was calculated on an iso-effect basis. When grown as spheroids squamous cell carcinoma cells showed a higher capacity to repair sublethal damage than neuroblastoma cells. Repair of potentially lethal damage did not contribute to this higher capacity of HN-1 cells, since this cell line was found to be deficient for this type of repair. Using the recovery ratio to estimate the beta-component of the survival curves, it was found that differences in repair capacity were determined by the alpha-component of the equation. Our results show the feasibility of back-extrapolating multicellular tumour spheroid growth curves to obtain survival estimates that can be applied to establish sublethal damage repair capacity.