This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Borden, E. C. Articles by Bryan, G. T. Search for Related Content PubMed PubMed Citation Articles by Borden, E. C. Articles by Bryan, G. T.

Schedule-dependent Variations in the Response of Murine P388 Leukemia to Cyclophosphamide in Combination with Interferons-/ß¹

Departments of Human Oncology [E. C. B., Y. A. S., J. F. H., G. T. B.] and Medicine [E. C. B.], University of Wisconsin Clinical Cancer Center, Madison, Wisconsin 53792

Positive therapeutic effects of interferons (IFNs) in combination with other therapies will depend on defining modalities, doses, and timing of treatment in the setting of varied tumor burdens. When 10⁴ P388 leukemia cells were inoculated i.p. on day 0 in BALB/c x DBA/2 F₁ mice, all mice died within 18 days if left untreated. Murine IFN-/ß (5 x 10⁵ units) injected daily i.p. on days 5–9 resulted in 20% increase in life span (ILS) (P < 0.0001). Cyclophosphamide (CY) (100, 33, or 15 mg/kg) was injected i.p. once 2 days before start (day 3), simultaneously with start (day 5), or 2 days after cessation of IFN treatment (day 11). When 100 mg/kg CY alone were injected on day 3 or 5, all mice survived more than 90 days and were considered cured. When IFN was given after this curative dose of CY, more tumor deaths occurred; up to 100% of the mice died when 100 mg/kg CY on day 3 were combined with IFN on days 5–9. Increased mortality with the combination was not due to added toxicity of CY and IFN since the mice developed abdominal tumors and ascites. Mice not inoculated with tumor cells and treated similarly suffered only a transient weight loss, had only moderate white count depression, and did not die. When IFN was injected before CY on days 1–5 (instead of days 5–9), IFN did not alter the effectiveness of CY (100 mg/kg on day 5).

In contrast to these results, when CY (100 mg/kg) was administered on day 11, after IFN (days 5–9), an augmented survival occurred with 119% ILS and 40% cures (CY alone on day 11 resulted in 69% ILS but no cures). In addition, when CY at a lower dose of 15 mg/kg was injected in combination with IFN, survival was consistently augmented by IFN; e.g., CY alone on day 3 caused 40% ILS and with IFN (days 5–9) 60% ILS (P < 0.0001). Qualitatively similar findings were obtained when P388 leukemia cells were inoculated s.c. and the drugs delivered i.p. Inhibition by IFN of antitumor effects of a second alkylating agent, 1,3-bis(2-chloroethyl)-1-nitrosourea, was also identified. Thus, IFN-/ß potentiated suboptimal CY effects for P388 leukemia, had neutral effects when injected before CY treatment, and inhibited antitumor activity of curative CY or nitrosourea schedules.

¹ Supported in part by research grants from the American Cancer Society and Triton Biosciences, Inc.

² American Cancer Society Professor of Clinical Oncology. To whom requests for reprints should be addressed, at the Department of Human Oncology, University of Wisconsin Clinical Cancer Center, K4/414 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792.

Received 9/ 8/87. Revised 1/27/88. Accepted 1/29/88.