No description available.

Separate mechanisms underlie the MDR phenotype found in tumour cells selected for resistance to low concentrations of daunorubicin and vincristine sulphate, singly and in combination. The vincristine sulphate selected VCR series were resistant to 4,8,16ng/ml; the daunorubicin selected DNR series were resistant to 10,15,30ng/ml and finally the combination series (DNR:VCR) series were resistant to 1:0.04; 5:0.2 and 10:0.4ng/ml of daunorubicin and vincristine sulphate respectively. The three resistant cell line series thus derived were characterised with respect to the following: a) growth characteristics; b) in vitro cross resistance using the MTT cytotoxic assay; c) amplification of MDR1 and MDR3 genes; d) level of MDR1 and MDR3 transcripts using RNA dot blot analyses; e) overexpression of P-glycoprotein was carried out using a panel of antibodies, C219, MRK-16 and JSB-1; f) drug accumulation studies using the Rhodamine assay, and finally an attempt was made to g) identify any novel amplified sequences. The combination drugs (DNR:VCR) series exhibited characteristics of the classical MDR phenotype at lower levels of resistance; marginally increased levels of P-glycoprotein and its transcript MDR1, and cross resistance to a wide range of structurally and functionally dissimilar drugs. This classic phenotype however gave way to an atypical phenotype in HSB-2 10:0.4DV cell line, with no overexpression of P-glycoprotein and its transcript MDR1 and a cross resistance profile indicative of DNA Topoisomerase II involvement; resistant to anthracyclines, etoposide and only marginally resistant to vincristine, vinblastine and colchicine. In comparison, the single drug exposure cell line series, demonstrated a progressive increase of P-glycoprotein and its transcript MDR1.

Thesis (M.A.)--Boston University / Several culture media were tested. The trichomonads multiplied only in gastric mucin-Loeffler's dried blood serum dissolved in a slight modification of Drbohlav's modified Ringer's solution. Among the species of intestinal trichomonads of the golden hamster that were studied only T. microti and T. wenyoni grew in the artificial culture medium. Several techniques of determining whether or not the hamsters were infected with trichomonads, methods of obtaining population counts, and several staining methods were presented. Protozoa other than T. microti and T. wenyoni were successfully cultured in the modified culture medium. Bacteria-free cultures of trichomonads were assured by adding to the culture medium penicillin and streptomycin in combination, and also terramycin. Cysts induced artificially and those found in the animal's feces were activated by placing them in a warm place or by using aqueous pancreatin solution. These cysts multiplied in the modified culture medium. The resistance of the intestinal trichomonads of the golden hamster to physical and chemical agents was discussed. Many antiseptics, ultraviolet light, high temperatures and low temperatures are lethal for the trichomonads. The trichomonads are resistant to X-rays. Hypotonic or hypertonic solutions of sodium chloride are destructive for these trichomonads. Experiments in vitro, with penicillin, streptomycin, terramycin, aureomycin, ahloromycetin, Carbarsone, Chiniofon, copper sulfate, Phenothiazine were described. Experiments in vivo, with Carbarsone, Chinifon, Phenothiazine, copper sulfate, Vioform, terramycin, and aureomycin were described. Carbarsone showed the best trichomonadicidal action per os. The hamsters are extremely resistant to high doses of Carbarsone. Prolonged administration of Carbarsone is harmful to animals. The pathogenicity of the intestinal trichomonads of the golden hamster was examined. These trichomonads are not pathogenic for man or for the hamsters. The author swallowed a mixed culture of T. microti and T. wenyoni, but no digestive abnormalities were observed subsequently.

Thesis (M.S.)--Boston University

No description available.

The present study involves the preparation of novel mixed-ligand platinum(II) complexes in the hope of expanding the range of platinum(II) complexes that exhibit anticancer activity and which are less toxic and have a broader spectrum of activity than cisplatin and its analogues. To this end, N-(3-R-benzoyl)-N’,N’-diethylthiourea, N-(3-R-benzoyl)-N’-morpholinothiourea, N-(3-Rbenzoyl)-N’,N’-di(2-hydroxyethyl)thiourea (R = NO2, Cl, H, CH3, OCH3), N,N-diethyl-N’-menthyloxycarbonylthiourea and N-menthyloxycarbonyl-N’-morpholinothiourea ligands, and their corresponding mixed-ligand platinum(II) complexes of the type [PtCl(L)(RR’SO)], were synthesised and characterised by elemental analyses, IR, 1H and 195Pt NMR spectroscopy and, in some cases, X-ray crystallography. Dimethylsulfoxide complexes were prepared using all the ligands, while complexes containing unsymmetrically substituted sulfoxides were prepared using the N-benzoyl-N’,N’-diethylthiourea and ,N-diethyl-’-(-)-(3R)-menthyloxycarbonylthiourea ligands only. The molecular structures of cis-(S,S)-[PtCl(DMSO)(L)] (where L = N-benzoyl-N’,N’-diethylthioureato, N-(+)-(3S)-menthyloxycarbonyl-N’-morpholinothioureato), cis-(S,S)-[Pt(N-benzoyl-N’,N’-diethylthioureato)Cl(MPSO)] and cis-[Pt(N-benzoyl-N’,N’-diethylthioureato)2] were determined by X-ray crystallography. The X-ray crystal structure of N,N-diethyl-N’- (-)-(3R)-menthyloxycarbonylthiourea was also determined. The spectroscopic and crystallographic data are consistent with complexes containing a (S,O)-chelated ligand and a sulfur-bonded sulfoxide ligand. However, the 1H and 195Pt NMR studies showed that the alkoxycarbonylthioureato complexes exist as geometric isomers with the sulfoxide coordinated either in a cis-(S,S) or trans-(S,S) arrangement with respect to the sulfur donor atom of the chelated ligand, whereas the acylthioureato complexes yielded only cis-(S,S)-[PtCl(L)(RR’SO)] complexes. The difference in the coordination chemistry of the acylthiourea and alkoxycarbonylthiourea ligands was examined further by treatment of the [PtCl(DMSO)(L)] complexes, where L = Nbenzoyl-N’,N’-diethylthioureato, N-benzoyl-N’-morpholinothioureato, N,N-diethyl-N’-(-)-(3R)- menthyloxycarbonylthioureato and N-(+)-(3S)-menthyloxycarbonyl-N’-morpholinothioureato, with PPh3 to give the corresponding [PtCl(L)(PPh3)] and [Pt(L)(PPh3)2]+ complexes. 31P NMR studies of these complexes reveal that the alkoxycarbonylthioureato ligands bind less strongly than the acylthioureato ligands, which is consistent with the crystallographic studies. The morpholine derivatives of the acylthioureato and alkoxycarbonylthioureato ligand systems also appear to bind less tightly than the diethyl derivatives. The weaker binding properties of the alkoxycarbonylthioureato ligands might be a possible explanation for the observed geometric isomerisation of these complexes, with the mechanism of isomerisation involving a chelate ringiv opening step. Furthermore, crystallographic and 31P NMR studies suggest that the acylthioureato carbonyl oxygen donor atom is relatively softer and therefore has a greater trans-influence than the carbonyl oxygen donor atom of the alkoxycarbonylthioureato ligand. The substitution kinetics of the chloride and sulfoxide leaving groups by azide, iodide, thiocyanate, triphenylphosphine, 2-mercaptobenzimidazole, 4-(dimethylamino)pyridine and thiourea, from selected cis-(S,S)-[PtCl(N,N-dialkyl-N’-(3-R-benzoyl)thioureato)(RR’SO)] complexes, in methanol, were evaluated to determine if variation of the electronic properties of the chelated ligand and variation of the sulfoxide have a significant influence on the reactivity of these complexes. Two consecutive reactions were observed. It was found that neutral nucleophiles initially substitute the dimethylsulfoxide, while anionic nucleophiles substituted the chloride ligand. For all the nucleophiles studied, the first substitution step was evaluated, except for triphenylphosphine and 4-(dimethylamino)pyridine, where the second step was also evaluated. The overall order of reactivity for the first substitution step was; N3 - < DMAP < I- < SCN- < MBI < thiourea < PPh3, with the rate varying three orders of magnitude. The substitution of the dimethylsulfoxide ligand by PPh3 from cis-(S,S)-[Pt(N-benzoyl-N’,N’-diethylthioureato)Cl-(DMSO)] to form cis-(S,P)-[Pt(N-benzoyl-N’,N’-diethylthioureato)Cl(PPh3)] was confirmed by X-ray crystallography. In general, manipulation of the chelating moiety, as well as interchanging the sulfoxide did not alter the reactivity of these complexes to a great extent. The anticancer activity of all the platinum(II) sulfoxide complexes were evaluated against a HeLa cell line, of which three complexes, cis-(S,S)-[PtCl(DMSO)(N,N-diethyl-N’-(3-nitrobenzoyl)- thioureato)], cis-(S,S)-[PtCl(DMSO)(N-morpholino-N’-(3-nitrorobenzoyl)thioureato)] and cis-(S,S)-[PtCl(DMSO)(N-(3-methoxybenzoyl)-N’-morpholinothioureato)] exhibited a concentration dependent anti-proliferative effect, but were less potent than cisplatin. These three complexes displayed a similar dose response in a MCF-7 cell line. Preliminary morphology studies with the three biologically active complexes in a HeLa cell line suggest that they induce cell death by apoptosis. Preliminary pBR322 plasmid DNA binding studies of selected [Pt(acylthioureato)Cl(RR’SO)]complexes clearly indicate that these complexes have a different mode of binding to DNA than cisplatin.

No description available.

Thesis (M.S.)--Boston University

No description available.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences