Ability of Cyclophosphamide in the Absence of Cross-Linking Activity to Exert the Immunomodulatory Effect Required for the Cure of Mice Bearing a Large MOPC-315 Tumor

Abstract

We have previously shown that mice bearing a late-stage, large primary MOPC-315 plasmacytoma and extensive metastases can be cured by a low dose of the bifunctional alkylating drug, cyclophosphamide (BiCY) (J. C. D. Hengst et al., Cancer Res., 40: 2135–2141, 1980). Here we show that therapy with the monofunctional form of cyclophosphamide (MoCY) can also cure such mice. However, a dose of at least 150 mg of MoCY per kg is required to approximate the curative effectiveness of the lowest curative dose of BiCY, i.e., 15 mg/kg. This need for a 10-fold higher dose of MoCY is due, at least in part, to the 10-fold lower direct tumoricidal and/or tumoristatic activity of MoCY compared to BiCY. Consequently, a 10-fold higher dose of MoCY is required to directly reduce the tumor burden to the level reduced by 15 mg of BiCY per kg. Other than dose, the therapy of the mice with 150 mg of MoCY per kg was similar in its essential features to that shown previously for therapy with 15 mg of BiCY per kg (J. C. D. Hengst et al., Cancer Res., 40: 2135–2141, 1980; J. C. D. Hengst et al., Cancer Res., 41: 2163–2167, 1981; Q-W. Ye et al., Cancer Immunol. Immunother., 16: 162–169, 1984; Q-W. Ye and M. B. Mokyr, Cancer Res., 44: 3873–3879, 1984; M. B. Mokyr and S. Dray, Cancer Res., 43: 3112–3119, 1983), namely: (a) the drug does not directly eradicate all tumor cells; (b) host T-cell-dependent antitumor immunity is also required for the curative effect; (c) the therapy of tumor bearers leads to the rapid appearance of an augmented antitumor immune potential in their hitherto immunosuppressed spleen; and (d) the cured mice are resistant to a subsequent challenge with at least 300-fold the minimal lethal tumor dose. Thus, cross-linking is not an essential property for the immunomodulatory activity of BiCY nor for its direct antitumor effect. However, in the presence of cross-linking activity, a much lower dose of drug is effective.