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Concomitant Inhibition of Tumor-associated Inflammatory Responses and Rapid Enhancement of Cyclophosphamide-induced Tumor Regression by Hydrocortisone¹

The Jackson Laboratory, ³ Bar Harbor, Maine 04609

We have demonstrated that hydrocortisone (HC) enhances the antitumor action of cyclophosphamide (CY). When sarcoma-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 acceleration 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 DNA content of cells obtained by enzymic disaggregation of the tumors. After either CY or CY-HC treatment, the G₁ 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 importance of the CY-induced acute inflammatory response occurring at the tumor site, as well as the chronic inflammatory response that is a constitutive part of progressing tumors.

¹ Supported by USPHS Grant CA 27523 awarded by the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed.

³ The Jackson Laboratory is fully accredited by the American Association for Accreditation of Laboratory Animal Care.

Received 5/17/82. Accepted 8/10/82.