Reciprocal Cross-Resistance In Human Rhabdomyosarcomas Selected In Vivo For Primary Resistance To Vincristine And L-Phenylalanine Mustard

Peter J Houghton, Julie K. Horton, Janet A. Houghton

Research output: Contribution to journalArticle

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Abstract

Primary resistance to vincristine (VCR) has been selected in rhabdomyosarcoma xenograft HxRh12 by sequential administration of VCR at 1.5 and subsequently 3 mg/kg/passage. The resistant tumor (HxRh12/ VCR-3) was approximately 4-fold resistant to VCR and resistance was stable in the absence of selecting pressure (>2 yr). HxRh12/VCR-3 was 2 to 3-fold cross-resistant to L-phenyalanine 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 2 to 3-fold resistant to L-PAM and 3-(p-fluorophenyl)-L-alanyl-3-[m-bis-(2-chloroethyl)-aminophenyl]-L-alanyl-L-methionine ethoxyhydrochloride, cross-resistant to cyclophosphamide and ifosfamide, and completely resistant to VCR under in vivo conditions. Pharmacokinetic studies in HxRh12/ VCR-3 showed decreased retention of [G-3H]VCR but not alteration in metabolism. Expression of mdrl, a gene that encodes P-glycoprotein, associated with the multiple drug resistance phenotype, was examined. Expression of mdr1 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.

Original languageEnglish (US)
Pages (from-to)6288-6293
Number of pages6
JournalCancer Research
Volume47
Issue number23
StatePublished - Jan 1 1987
Externally publishedYes

Fingerprint

Melphalan
Rhabdomyosarcoma
Vincristine
Phenylalanine
Mustard Plant
Ifosfamide
Multiple Drug Resistance
Neoplasms
Heterografts
P-Glycoprotein
Methionine
Cyclophosphamide

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Reciprocal Cross-Resistance In Human Rhabdomyosarcomas Selected In Vivo For Primary Resistance To Vincristine And L-Phenylalanine Mustard. / Houghton, Peter J; Horton, Julie K.; Houghton, Janet A.

In: Cancer Research, Vol. 47, No. 23, 01.01.1987, p. 6288-6293.

Research output: Contribution to journalArticle

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abstract = "Primary resistance to vincristine (VCR) has been selected in rhabdomyosarcoma xenograft HxRh12 by sequential administration of VCR at 1.5 and subsequently 3 mg/kg/passage. The resistant tumor (HxRh12/ VCR-3) was approximately 4-fold resistant to VCR and resistance was stable in the absence of selecting pressure (>2 yr). HxRh12/VCR-3 was 2 to 3-fold cross-resistant to L-phenyalanine 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 2 to 3-fold resistant to L-PAM and 3-(p-fluorophenyl)-L-alanyl-3-[m-bis-(2-chloroethyl)-aminophenyl]-L-alanyl-L-methionine ethoxyhydrochloride, cross-resistant to cyclophosphamide and ifosfamide, and completely resistant to VCR under in vivo conditions. Pharmacokinetic studies in HxRh12/ VCR-3 showed decreased retention of [G-3H]VCR but not alteration in metabolism. Expression of mdrl, a gene that encodes P-glycoprotein, associated with the multiple drug resistance phenotype, was examined. Expression of mdr1 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.",
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