ResistancePatterns of Walker Carcinosarcoma256 and Other Rodent Tumors to Cyclophosphamide and L-Phenylalanine Mustard1

Comparison is made of the development of resistance to cyclophosphamide (CPA) and L-phenylalanine mustard (L PAM),of cross-resistance, and chromosomecounts, in Walker carcinosarcoma 256 (W256), rat sarcoma R3 (R3), leukemia Li 210, and Ridgwayosteogenic sarcoma. For developmentof resistance the single maximumtolerated 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 Li 210/CPA reached marked resistance, and Li 210/L-PAM reached moderateresistance. All four Ridgway osteogenic sarcoma sublines were essentially still as sensitive as the parent tumor. Long-establishedresistant sublines from previous studies (>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 sublinesof the other tumors, althoughshowing marked, or in the case of Li 210/CPA, complete resistance to their respectiveinducing agents, retained moderate-to-fullsen sitivity to the other alkylators. W256/CPA and W256/L-PAM were mainly polyploid (>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 Li2iO lines, but was reduced in R3 and Ridgwayosteogenicsarcomalines. The resistance pattern of W256 appears to be compatible with a simple selection mechanism,whereas those of the three other tumors suggest involvementof multiple determinants.This study suggeststhat some, but not all, tumors have universal cross-resistance be tween different types of alkylating agents.