Reciprocal Cross-Resistance in Human Rhabdomyosarcomas Selected in Vivo for Primary Resistance to Vincristine and L-Phenylalanine Mustard1

Primary resistance to vincristine (VCR) has been selected in rhabdomyosarcoma xenograft 11\Khl 2 by sequential administration of VCR at 1.5 and subsequently 3 mg/kg/passage. The resistant tumor (HxRhl2/ VCR-3) was approximately 4-fold resistant to VCR and resistance was stable in the absence of selecting pressure (>2 yr). HxRhl2/VCR-3 was 2to 3-fold cross-resistant to i.-phenyhlanine mustard (L-PAM) but only slightly cross-resistant to ifosfamide. To determine whether selection for primary resistance to L-PAM conferred cross-resistance to VCR we selected an L-PAM-resistant subline of rhabdomyosarcoma xenograft HxRh28 (HxRh28/L-PAM-13). This tumor was 2to 3-fold resistant to L-PAM and 3-{/>-fluorophenyl)-L-alanyl-3-|m-bis-{2-chloroethyl)aminophenyl|-L-alanyl-L-methionine ethoxyhydrochloride, cross-resist ant to cyclophosphamide and ifosfamide, and completely resistant to VCR under in vivo conditions. Pharmacokinetic studies in HxRhl2/ VCR-3 showed decreased retention of |<V-'H]\ ( R but not alteration in metabolism. Expression of mtlrt. a gene that encodes P-glycoprotein, associated with the multiple drug resistance phenotype, was examined. Expression of marl was detected in both HxRhl2 and HxRh28 tumors, sensitive to VCR, but there was no increase in expression in tumors selected for primary resistance to VCR or L-PAM. Data suggest that mechanisms other than those associated with "classical" multiple drug resistance confer resistance in these tumors. In clinical evaluation against childhood rhabdomyosarcoma, L-PAM has demonstrated only slight activity in patients relapsing on conventional therapy (including VCR) but demonstrated marked activity in patients with advanced previously untreated disease. It appears likely, therefore, that cross-resistance between VCR and L-PAM as demonstrated in this model may have clinical significance.