PubMed · 6598408
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S Oka, G Mathé, P S Mitrou. 1984. Aclacinomycin A.. https://doi.org/10.1016/0305-7372(84)90027-6
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Daunorubicin (DNR) is a major front-line drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Previously, we showed that in vitro resistance to DNR at diagnosis is related to a poor long-term clinical outcome in childhood ALL and that relapsed ALL samples are more resistant to DNR than untreated ALL samples. In cell line studies, idarubicin (IDR), aclarubicin (ACR) and mitoxantrone (MIT) showed a (partial) lack of cross-resistance to the conventional anthracyclines DNR and doxorubicin (DOX), but clinical studies in childhood ALL have been inconclusive about the suggested lack of cross-resistance. In the present study we determined the in vitro cross-resistance pattern between DNR, DOX, IDR, ACR and MIT in 48 untreated and 39 relapsed samples from children with ALL using the MTT assay. The relapsed ALL group was about twice as resistant to DNR, DOX, IDR, ACR and MTT as the untreated ALL group. Thus, resistance developed to all five drugs. We found a significant cross-resistance between DNR, DOX, IDR, ACR and MIT, although in some individual cases in vitro anthracycline cross-resistance was less pronounced. We conclude that IDR, ACR and MIT cannot circumvent in vitro resistance to DNR in childhood ALL. Clinical studies may still prove whether IDR, ACR or MIT has a more favourable toxicity profile than DNR.
The aklavinone 11-hydroxylase gene and two doxorubicin resistance genes cloned from Streptomyces peucetius subsp. caesius ATCC 27952 were introduced into doxorubicin-sensitive Streptomyces galilaeus ATCC 31133, an aclacinomycin producer. The doxorubicin resistance genes drrA and drrB endowed S. galilaeus with high-level resistance to doxorubicin, indicating that the resistance mechanism for doxorubicin might be different from that for aclacinomycin A. Transformation of S. galilaeus ATCC 31133 with plasmid pMC213 containing the aklavinone 11-hydroxylase gene (dnrF) resulted in the production of many red pigments. A new metabolite was purified, and the position of the newly introduced hydroxyl group was determined. This result indicated that the aklavinone 11-hydroxylase gene was stably expressed in S. galilaeus ATCC 31133 and that it gave rise to a hybrid aclacinomycin A which showed highly specific in vitro cytotoxicity against leukemia and melanoma cell lines.
The mechanism of adsorption of aclacinomycin A onto polyisobutylcyanoacrylate nanoparticle and the factors effecting the adsorption were studied. The adsorption process reached equilibrium in 15 minutes. The results showed that the surface charge densities of the nanoparticles, pH, ionic strength and temperature effected the adsorption. Adsorption isotherms of aclacinomycin A onto polyisobutylcyanoacrylate nanoparticles could be described with Freundlich equation Y = 1.0188 C0.6494 (r = 0.9945) and with Langmuir equation C/Y = 0.7363C + 0.4027 (r = 0.9331) respectively. The main actions between aclacinomycine A and polyisobutylcyanoacrylate nanoparticles were electrostatic and ionic action.