OVARIAN RETICULAR CELL-SARCOMA OF THE MOUSE (M5076) MADE RESISTANT TO CYCLOPHOSPHAMIDE

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  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (12) , 5674-5680
Abstract
Resistance of mouse M5076 (M5) ovarian reticular cell sarcoma to cyclophosphamide (CTX) was obtained in vivo by repeated drug treatment followed by transplantation of the regrowing tumor. After 16 passages, an M5 subline resistant to CTX (M5-CTX-16R) was obtained. Median survival times were .apprx. 29 and .apprx. 39 days for M5 and M5-CTX-16R, respectively. Survival of M5-bearing mice given a single i.p. dose of 200 or 300 mg/kg was 160 and 168% of controls, respectively; in M5-CTX-16R it was 103 and 123%, respectively. The resistance was not reversible after 14 additional passages with no further CTX treatment. M5 and M5-CTX-16R appear similar in histological features, pattern of metastasis formation and DNA content, as assessed by flow cytometry (hypotetraploid). Metastases of M5-CTX-16R were also resistant to CTX. Flow cytometry studies 12 and 24 h after CTX treatment revealed a block in S and G2-M phases in both tumors. After 48 h and at subsequent times, no cytokinetic perturbation was evident in M5-CTX-16R; in M5, marked accumulation of cells in G2-M was observed at 48, 72, 96 and 120 h. Cross-resistance was found between CTX, L-phenylalanine mustard, chlorambucil and hexamethylmelamine. M5-CTX-16R was sensitive, but less so than M5, to cis-platinum, 1,3-bis(2-chloroethyl)-1-nitrosourea and imidazole-4-carboxamide,5-(3,3-dimethyl-1-triazene). Adriamycin was equally active on M5 and M5-CTX-16R, while 4''-demethylepipodophyllotoxin-9-(4,6-O-ethylidine-.beta.-D-glucopyranoside) was inactive. This model appears to be suitable for studies on the mechanism of resistance to CTX and alkylating agents and for screening new, non-cross-resistant drugs.