Concomitant inhibition of tumor-associated inflammatory responses and rapid enhancement of cyclophosphamide-induced tumor regression by hydrocortisone.

We have demonstrated that hydrocortisone (HC) enhances the antitumor action of cyclophosphamide (CY). When sar coma-bearing C57BL/6J, BALB/cByJ, and C3H/HeJ mice were given a single injection i.p. of CY (300 mg/kg), followed 1 to 3 days later by a s.c. injection of HC (10 mg in 0.1 ml of incomplete Freund's adjuvant), there was a dramatic acceler ation of the reduction in tumor size compared with CY treatment alone. Without prior treatment of mice with CY, HC alone did not influence tumor growth. Histological evaluation and an analysis of the cellular composition of tumors after treatment with CY alone indicated a reduction in the neoplastic content of the tumors, a concomitant increase in the proportion of tumor-associated macrophages, and a marked neutrophil influx 7 to 9 days after CY injection. Similar changes were seen following CY-HC treatment except that a neutrophil infiltrate was not evident. The increase in the proportion of diploid host cells was confirmed by cytofluorimetric analysis of the DMA content of cells obtained by enzymic disaggregation of the tumors. After either CY or CY-HC treatment, the d peak of aneuploid cells disappeared with a concomitant increase in the proportion of cells accumulating in G2-M between days 2 and 4. After this, the G2 peak disappeared, at which time diploid cells comprised most of the cell yield (70 to 80%). When tumors regrew, the original DNA profile seen in control tumors was obtained. Although CY-HC treatment of tumor bearers resulted in a dramatic reduction in tumor size and cellularity, there was no significant prolongation of life when compared to CY treatment alone, indicating that HC was probably not acting on those cells surviving the antitumor effects of CY. The data are discussed in the context of the relative impor tance of the CY-induced acute inflammatory response occur ring at the tumor site, as well as the chronic inflammatory response that is a constitutive part of progressing tumors.