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The Antitumor Effects of the Quinoline-3-Carboxamide Linomide on Dunning R-3327 Rat Prostatic Cancers¹

The Johns Hopkins Oncology Center [T. I., J. C. L., J. T. I.] and the Department of Urology [J. T. I.], The Johns Hopkins School of Medicine, Baltimore, Maryland 21205; and Kabi Pharmacia Therapeutics, S-22363 Lund, Sweden [P. I. C., B. H-A.]

Linomide (N-phenylmethyl-1,2-dihydro-4-hydroxyl-1-methyl-2-oxoquinoline-3-carboxamide) is a quinoline 3-carboxamide which previously has been demonstrated to produce immunomodulator and antitumor effects when given in vivo. To test the possible antitumor effects of linomide against prostatic cancers, rats bearing five distinct Dunning R-3327 rat prostatic cancer sublines were treated daily with i.p. injections of linomide. These studies demonstrated that linomide has a reproducible antitumor effect against all of the prostatic cancers tested regardless of their growth rate, degree of morphologic differentiation, metastatic ability, or androgen responsiveness. This antitumor effect is observed only in vivo, not in vitro, and involves a cytotoxic response of the prostatic cancer cells. This cytotoxic response results in the retardation of the growth rate (i.e., increased tumor volume doubling time) of primary prostatic cancers and in metastatic lesions. Linomide's growth retardation is reversible, and thus continuous daily treatment with linomide is required for maximal antitumor response. Pretreatment of rats with linomide before tumor inoculation has no effect in addition to that produced by initiating linomide treatment at the time of tumor inoculation. No enhancement of either natural killer cell number or natural killer cell cytotoxic activity is induced by linomide treatment in the tumor-bearing rats. In addition, depletion of natural killer cell activity via injections of asialo-G_MI antiserum does not prevent the antitumor effects of linomide in vivo. Likewise, the antitumor effects of linomide are also produced in prostatic cancer-bearing athymic nude rats. These results suggest that the requirement for host involvement in the antitumor effects of linomide against rat prostatic cancers may involve both immune and nonimmune host mechanism(s) (e.g., antiangiogenesis).

¹ Supported in part by NIH Grant CA50601.

² To whom requests for reprints should be addressed, at the Johns Hopkins Oncology Center, 422 N. Bond Street, Baltimore, MD 21231.

Received 10/24/91. Accepted 3/25/92.

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