In the past several years many laboratories have studied the significance of α and β tubulin proteins in antimicrotubule drug resistance. These studies have extended to several antimicrotubule agents in various carcinoma cell lines. Early studies showed mutations and alterations in the steady state soluble and polymerized α and β tubulin fractions in drug resistant cell lines Cabral et al, 1986;Minotti et al, 1991). Although the existence of different α and β tubulin isotypes and their tissue specific expression was reported in the past, only recently demonstrated were the effects of individual β tubulin isotypes on overall microtubule functions including assembly, dynamics, drug sensitivity and drug binding. Banerjee et al (1990) have shown that β III isotype depleted tubulin assembles into microtubules at a faster rate than unfractioned tubulin. These microtubules are also more sensitive to paclitaxel-induced assembly compared to unfractioned tubulin (Lu and Luduena, 1993). Subsequent studies revealed alterations in the expression of specific β tubulin isotypes as result of antimicrotubule drug resistance (Haber et al, 1995;Ranganathan et al, 1996;1998a;1998b;Kavallaris et al, 1997;Kavallaris et al, 1999). In addition, combination studies have shown that cyclosporin A enhances paclitaxel efficacy in lung carcinoma cell lines by modulating β tubulin isotype composition (Ross and Antoniono, 1999). Recently, Kavallaris et al, (1999) have shown that antisense oligonucleotides to β III isotype sensitized the drug resistant cells to paclitaxel. In addition, mutations in β I isotype were reported in paclitaxel resistant human ovarian carcinoma cells (Giannakakou et al, 1997), breast carcinoma cells (Wiesen and Horwitz, 2000) and non-small-cell lung cancer patients (Monzo et al, 1999) with tumours that were unresponsive to paclitaxel therapy.Antimicrotubule drug resistance associated changes in tubulin isotypes prompted several investigators to determine the contribution of individual isotypes by transfecting cells and examining their antimicrotubule drug response. Wu et al (1998) have shown that transfection of β IVa isotype into human leukemic cell line failed to confer resistance to paclitaxel. Blade et al (1999) have over-expressed rodent β I , β II or β IVb isotypes in CHO cells and shown that these isotypes do not confer resistance to paclitaxel. Our previous work demonstrated increases in β III and β IVa isotypes in human prostate carcinoma cells that were made resistant to estramustine or paclitaxel (Ranganathan et al, 1996(Ranganathan et al, , 1998a. In addition, acute exposures to these agents resulted in elevations of β III levels. To further understand the function of β III isotype in antimicrotubule drug response, parental DU145 human carcinoma cells were transfected with the human β III cDNA. The results presented herein indicate that regulation of tubulin in cells is complex and that attempts to increase levels of a single isotype may lead to compensatory changes in the expression of other isotypes. Sum...