INSITU SELECTION OF A HUMAN RHABDOMYOSARCOMA RESISTANT TO VINCRISTINE WITH ALTERED BETA-TUBULINS

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  • 1 January 1985
    • journal article
    • research article
    • Vol. 45  (6) , 2706-2712
Abstract
In order to simulate more closely conditions in which resistance to vincristine (VCR) is selected in human solid tumors, a human rhabdomyosarcoma grown as a xenograft in immune-deprived mice was selected for resistance in situ. Karyotype analysis showed the resistant line, H .times. Rh18/VCR-3, to have a diploid modal number, with no apparent translocations, whereas the predominant population in the parental, sensitive H .times. Rh18 xenograft demonstrated a modal number near-tetraploid with many maker chromosomes. From the rapid rate at which resistance was selected and from karyotypic evidence, data strongly suggests that H .times. Rh18/VCr-3 was a subpopulation within the parent tumor. When grown in the same host, H .times. RH18/VCr-3 tumors accumulated less drug and the rate of [3H]VCR loss was 5-fold greater than in H .times. RH18 tumors. Thus, accumulation and retention of [3H]VCR in H .times. Rh18/VCR-3 resistant tumors was identical to that of [3H]vinblastine (VLB) in H.times. Rh18 xenografts. H .times. Rh18 xenografts were intrinsically resistant to VLB. Analysis by high-performance liquid chromatography of [3H]VCR:protein complexes in H .times. RH18 cytosols indicated 1 binding species (MW 95,000-116,000), probably the tubulin heterodimer. Of interest was the observation that .beta.-tubulin species, identified on Western blots by monoclonal antibody, differed in these tumors. In H .times. Rh18/VCR-3, less acidic 8-tubulins of H .times. Rh18 were decreased or absent, with 3 additional more acidic isoforms present in the resistant line. As vincristine may bind to the .beta.-subunit of tubulin, this may have importance to vincristine resistance in vivo.