Resistance patterns of Walker carcinosarcoma 256 and other rodent tumors to cyclophosphamide and L-phenylalanine mustard.

ABSTRACT

Comparison is made of the development of resistance to cyclophosphamide (CPA) and L-phenylalanine mustard (L-PAM), of cross-resistance, and chromosome counts, in Walker 256 (W256), rat sarcoma R3 (R3), leukemia L1210, and Ridgway osteogenic sarcoma. For development of resistance the single maximum tolerated doses of CPA or L-PAM were used, each for two sublines in the four tumors. In W256 after only one to five treatment generations, all sublines were resistant, whereas only by generation 10 had R3/CPA, R3/L-PAM, and L1210/CPA reached marked resistance, and L1210/L-PAM reached moderate resistance. All four Ridgway osteogenic sarcoma sublines were essentially still as sensitive as the parent tumor. Long-established resistant sublines from previous studies (greater than 20 treatment generations) were used for cross-resistance, chromosome, and stability studies. All W256-resistant sublines were cross-resistant to CPA, L-PAM, and thiotepa; but the sublines of the other tumors, although showing marked, or in the case of L1210/CPA, complete resistance to their respective inducing agents, retained moderate-to-full sensitivity to the other alkylators. W256/CPA and W256/L-PAM were mainly polyploid (greater than 80% of cells), whereas the other tumors were mainly diploid or near diploid. During 10 to 20 untreated generations the degree of drug resistance remained unchanged in W256 and L1210 lines, but was reduced in R3 and Ridgway osteogenic sarcoma lines. The resistance pattern of W256 appears to be compatible with a simple selection mechanism, whereas those of the three other tumors suggest involvement of multiple determinants. This study suggests that some, but not all, tumors have universal cross-resistance between different types of alkylating agents.