CANCER CELL PROGRESSION AND CHEMOIMMUNOTHERAPY - DUAL EFFECTS IN THE INDUCTION OF RESISTANCE TO THERAPY

To determine whether resistance to chemoimmunotherapy is acquired duri ng therapy, we investigated the effects of chemotherapeutic agents and anti-tumour polysaccharide, lentinan, on the progression of Rous sarc oma virus-induced S908.D2 fibrosarcomas. The chemoimmunotherapy was ef fective against the parental S908.D2-bearing mice. Nearly all the mice that were treated with cyclophosphamide (CY) and lentinan achieved co mplete tumour regression. Only a few of the mice that achieved complet e regression of the primary tumours showed a recurrence of the tumour in regional lymph nodes. S908.D2-vp.1 was established from metastatic tumours that developed in the regional lymph nodes of parental S908.D2 -bearing mice during therapy. S908.D2-vp.2-or vp.3 cells were sequenti ally derived in a similar way from S908.D2-vp.1-or-vp.2-bearing mice r espectively, im which complete tumour regression at each primary site was achieved during therapy. These lines acquired resistance to CY and lentinan and also to 5-fluorouracil (5-FU)/5'-deoxy-5-fluorouracil an d lentanin. No significant difference in either the sensitivity to 5-F U or 4-deoxycyclophosphamide in vitro or in the susceptibility to immu ne effector cells was observed between the parental and progressed lin es (S908.D2-vp.1 similar to-vp.3). There was an increase in the level of prostaglandin E(2) (PGE(2)) in the progressed lines during repeated therapy (parental, 1171 pg ml(-1); vp.1, 2199 pg ml(-1); vp.2, 5500 p g m l(-1); vp3, 16187 pg ml(-1)). There was no significant increase in the production of transforming growth factor (TGF-beta). The amount o f interleukin-2 (IL-2) produced by spleen cells isolated from the S908 .D2-vp.2-bearing mice was decreased compared with the amount produced by the parental S908.D2-bearing mice. Furthermore, combination therapy with lentinan and IL-2 achieved complete tumour regression in all the mice transplanted with S908.D2 progressed tumour lines, although IL-2 alone did not show any anti-tumour effects in either the S908.D2 pare ntal or progressed lines. The findings suggest that the reduced produc tion of IL-2 induced an increase in the production of the PGE(2) by pr ogressed tumour lines is involved in the acquisition of resistance.