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PubMed2006

[Effect of down-regulation of survivin gene on apoptosis and cisplatin resistance in cisplatin resistant human lung adenocarcinoma A549/CDDP cells].

OBJECTIVE: To investigate the effects of survivin antisense oligodeoxynucleoties (ASODN) transfection mediated by cytofectin on apoptosis and cisplatin resistance in cisplatin resistant human lung adenocarcinoma A549/CDDP cells in vitro. METHODS: A549/CDDP cells were cultured routinely in RPMI-1640 medium. Survivin ASODN mediated by cytofectin was transfected into the A549/CDDP cells. Reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry SABC assays were performed to determine the regulation of survivin expression by ASODN. The influence of ASODN transfection on apoptosis was determined by fluoroscence microscopy and Hoechst staining, agarose gel electrophoresis, flow cytometry and caspase-3 colorimetric assay. MTT assay was performed to detect the cell viability, half-maximum inhibitory concentration (IC50) and cisplatin resistance index (RI) were thereby calculated. RESULTS: Transfected by survivin ASODN for 48 h, down-regulation of survivin expression was measured, of which mRNA and protein expression was significantly down-regulated to 41.56% and 0.864 +/- 0.045, respectively (P < 0.05). Transfection with survivin ASODN caused typical apoptotic changes, including characteristic chromatin condensation, nuclear shrinkage, nuclear cleavage and the cells grew more regularly, and some cells were floating. Typical DNA ladder pattern was observed by agarose gel electrophoresis. Furthermore, apoptotic index and caspase-3 activity was enhanced to 34.03% and 1.1298 +/- 0.2502, respectively (P < 0.05). It was significantly different as compared with the control group. While combination with ASODN and 10 micromol/L cisplatin caused far more distinctive apoptotic alterations, of which AI and caspase-3 activity reached to 65.85% and 1.6805 +/- 0.2758, respectively (P < 0.05), and even compared with the single ASODN group, the difference was still significant (P < 0.05). Transfected with survivin ASODN only or with combination of cisplatin for 48 h, the inhibitory rate of cell growth was enhanced to 59.3% and 83.7% (P < 0.05), respectively, while inversely, the cell viability reduced to a lowest value. The half-maximum inhibitory concentration of cisplatin was reduced from 225.03 +/- 10.59 micromol/L to 158.84 +/- 4.26 micromol/L, and the resistant index was conversely reduced from 11.9 to 8.39. Non-sense oligodeoxynucleotides (NSODN) and liposome had no effect on the cells growth (P > 0.05). CONCLUSION: Transfection with survivin ASODN can to a great extent reverse the cisplatin resistance in human cisplatin resistant lung adenocarcinoma cells A549/CDDP in vitro, and can thereby significantly inhibit the growth of the cells. The mechanism of reversal of resistance to cisplatin by this transfection can be associated with specific down-regulation of survivin expression, which decreases the threshold of apoptosis, induces more pronounced apoptosis,and reverses the resistance to apoptosis induced by cisplatin in A549/CDDP cells in vitro.

Adenocarcinoma↗
PubMedDate not supplied

Resistance of in vitro grown IgM immunocytoma cells to cis-diamminedichloroplatinum (II) (cis-DDP) and cross-resistance to other DNA interacting drugs.

Previously, we reported on the resistance to cis-diamminedichloroplatinum(II) (cis-DDP) of tumor cells in IgM immunocytoma tumors. In vitro cell lines were established, from tumors both sensitive and resistant to cis-DDP. The cultured cells obtained from the parent tumor were designated IgM-I, and those from a cis-DDP resistant tumor IgM/cDDP. In vitro dose response studies showed a difference in cis-DDP sensitivity with a resistance factor of approximately 20 at a relative survival of the tumor cells of 50 percent. The resistance factor was determined both in an assay with continuous cis-DDP exposure for 72 h, and in a clonogenic assay after an exposure for 1 h to various dosages of cis-DDP. The IgM/cDDP cells showed cross-resistance, in vitro and in vivo, to the currently used cis-DDP analogs carboplatin (CBDCA or JM8) and iproplatin (CHIP or JM9). Cross-resistance was also observed against the recently developed platinum(IV) compound tetraplatin. In addition, the cell line IgM/cDDP was resistant to other drugs interacting with DNA, such as doxorubicin (DXR), mitomycin C (MMC) and melphalan (L-PAM). For two non DNA-interacting drugs, vincristine (VCR), a mitosis inhibitor, and VP-16, a topoisomerase inhibitor, both cell lines were equally sensitive.

Cisplatin↗
PubMed1989

Establishment of a melphalan-resistant rhabdomyosarcoma xenograft with cross-resistance to vincristine and enhanced sensitivity following buthionine sulfoximine-mediated glutathione depletion.

A melphalan-resistant human rhabdomyosarcoma xenograft, TE-671 MR, was established in athymic mice by serial melphalan treatment of the parent xenograft, TE-671, at the 10% lethal dosage (LD10); significant resistance was evident after ten passages of the tumor. TE-671 MR demonstrated a doubling time of 3.5 days and a latency period to 1000-mm3 tumors of 27.5 days. The glutathione level of TE-671 MR was 2.36 mumol/g tumor, wet weight, 2-fold higher than the parent line. The glutathione S-transferase activity of TE-671 MR was 117.8 mumol/min/mg protein, essentially unchanged from the parent line. Although TE-671 MR demonstrated cross-resistance to vincristine, dot blot analysis did not reveal an elevated expression of mdr1 mRNA in the resistant line. TE-671 MR demonstrated a 9.7-day growth delay following treatment with melphalan at the LD10 (compared to 20.9 days for the parent line). Treatment with L-buthionine-SR-sulfoximine (BSO) resulted in increased sensitivity to melphalan subsequently administered at 50% of the LD10 (melphalan alone, growth delays of 3.7 and 4.6 days in duplicate trials; melphalan plus BSO, growth delays of 7.2 and 9.8 days). Sensitivity to melphalan equal to that of the parent line TE-671 was not achieved, however. Treatment with BSO did not result in significantly enhanced sensitivity to subsequently administered vincristine (50% of the LD10) (vincristine alone, growth delays of 6.8 and 6.9 days in duplicate trials; vincristine plus BSO, growth delays of 10.9 and 7.5 days). These results suggest that generation of melphalan resistance may be associated with development of cross-resistance to vincristine; this resistance may be associated with (although not necessarily mediated by) glutathione elevation; this resistance may be partially overcome by BSO-mediated depletion of glutathione.

Animals↗
PubMed1989

[The mechanism of resistance and its circumvention of cisplatin-resistant human ovarian cancer cells].

In this study, we attempted to elucidate the mechanisms of cisplatin resistance and circumvent the resistance with calmodulin antagonists using a cisplatin-resistant human ovarian cancer cell line (KFr). It was assumed that the cisplatin resistance resulted from impairment of cisplatin transport systems. In particular, we considered that a reduced cisplatin transport function caused by some amino acids had an effect on the resistance mechanism. Reduced uptake of cisplatin as well as cisplatin analogues to KFr cells was observed. Four cisplatin analogues used in this study had cross-resistance to cisplatin. However, the concentration of drugs incorporated into cells was not always correlated with the degree of resistance. Therefore, it is possible that, in addition to the reduced influx function, an other mechanism is involved in the resistance. Combined treatment with cisplatin and calmodulin antagonists significantly increased the uptake of cisplatin by KFr cells and maintained the cellular level. Thus, a combination therapy of cisplatin and calmodulin antagonists seemed to be of clinical use.

Animals↗
PubMed1989

Characterization of a cisplatin-resistant subline of murine RIF-1 cells and reversal of drug resistance by hyperthermia.

The development of tumor cell drug resistance is a major obstacle which often leads to failure of cancer chemotherapy. Therefore, reversing the cell drug resistance would have important implications in cancer treatment. We have developed a cisplatin-resistant mouse tumor cell line from the radiation induced fibrosarcoma (RIF-1) parental line; this line is named RIF/ptr1 versus the parental line RIF/pts1. It is shown that the formation of cisplatin-DNA interstrand cross-links is the same for both cell lines although the intracellular cisplatin concentrations of resistant line is significantly lower. The cytosolic activities of glutathione reductase, glutathione peroxidase, and DT-diaphorase were the same in two cell lines. However, the concentration of glutathione was significantly higher in the resistant line. The resistant line was shown to be more sensitive to the cytotoxicity of heat (43 degrees C) but the combination of heat and drug had the same tumoricidal effect for both cell lines. The addition of verapamil also had a similar effect on both cell lines. We conclude that the major difference between these two lines was the glutathione-related detoxification of platinum. Regardless of drug resistance, the combination of drug and heat can effectively kill both cell lines. Elevated glutathione in RIF/ptr1 cells may be associated both with enhanced heat sensitivity and drug resistance such that combined treatments with drug and heat were equally effective in killing cells of either line.

Animals↗
PubMed1989

Enhanced DNA cross-link removal: the apparent mechanism of resistance in a clinically relevant melphalan-resistant human breast cancer cell line.

Resistance to the cytotoxic effects of alkylating agents is a major limitation to their clinical efficacy. Although a number of animal and human tumor cell models have been developed to study this problem, it has proven difficult to achieve very high levels of resistance to alkylating agents in vitro. This is consistent with the recent clinical evidence that alkylator resistance can be overcome by dose escalations of less than 10-fold. A number of mechanisms of alkylator resistance have been described, more than one of which may occur in the same model. This paper describes a human breast cancer cell subline selected for 3-fold resistance to melphalan and cross-resistant to other alkylators in which only one of the previously described mechanisms of resistance, enhanced removal of DNA interstrand cross-linking, is demonstrable. Northern blot analysis using the human incisional repair gene ERCC-1 cDNA demonstrated that this particular gene product is not the altered function in these cells, so the molecular characterization of the observed enhanced repair is pending. Because these cells are also cross-resistant to radiation and to adriamycin and epipodophyllotoxin, they may represent a clinically relevant model in which to examine the role of DNA repair of lesions resulting from alkylators and other cytotoxic agents.

Blotting, Northern↗
PubMed1985

A close association of adriamycin resistance with expression of cell surface antigens in adriamycin-resistant cell lines of herpes simplex virus type 2-transformed Syrian hamster cells.

We determined the properties of three adriamycin (ADM)-resistant cell lines isolated from a clone of herpes simplex virus (HSV) type 2-transformed Syrian hamster cells. The ADM-resistant lines (ADMR-6, -7 and -9) established by continuous exposure of the cells to ADM were 20 to 30 times more resistant to ADM than was the parent line. These resistant lines exhibited cross-resistance to daunomycin, actinomycin D, chromomycin A3 and vincristine, but not to mitomycin C, bleomycin or methotrexate. Uptake and efflux studies with [3H]ADM indicated that one line (ADMR-9) incorporated and retained lesser amounts of [3H]ADM than did the parent line but the other two lines accumulated and retained as much of the drug as did the parent line. Expression of cell surface antigens, detected by immunofluorescence tests with antiserum to HSV type 1, was at a low level (about 8% positive) in the parent line after replating of the cells, although it was enhanced by treatment of the cells with ADM (0.25 micrograms/ml). However, the antigens were strongly expressed (greater than or equal to 35% positive) on the surface of cells of the three resistant lines in the absence of ADM. Both antigen expression and ADM resistance of the cells were relatively stable in in vitro cultivation but were unstable in in vivo cultivation, suggesting that the constitutive expression of the antigens is closely associated with the phenotype of ADM resistance.

Animals↗
PubMed1986

[Selection of resistant variants by broad spectrum beta-lactam antibiotics: to what extent is there cross resistance between imipenem and other beta-lactam antibiotics?].

Resistant variants can be selected in the presence of most of the recently developed beta-lactam antibiotics thus resulting in cross resistance between penicillin-, cephalosporin- and monocyclic derivatives except for imipenem. Among the Enterobacteriaceae-resistant so-called beta-lactamase-overproducing variants can be selected in some species in the presence of various broad-spectrum beta-lactams except for imipenem. However, imipenem-resistant variants can be selected from clinical Pseudomonas aeruginosa isolates in a frequency comparable to those obtained for other beta-lactams. Imipenem resistance in Pseudomonas aeruginosa is presently understood to be independent of either enzymatic degradation or an alteration of the penicillin-binding proteins; moreover, it has to be attributed to characteristic changes of the outer membrane proteins, thus explaining imipenem resistance due to impaired penetration. Consequently, resistance to imipenem in Pseudomonas aeruginosa has to be considered independent of resistance to other beta-lactams.

Anti-Bacterial Agents↗
PubMed1986

Resistance to anthrapyrazoles and anthracyclines in multidrug-resistant P388 murine leukemia cells: reversal by calcium blockers and calmodulin antagonists.

A series of anthrapyrazoles was examined for their cytotoxic effect on P388 cells resistant (P388R) to anthracyclines, N-[4-(9-acridinylamino)-3-methoxyphenyl] methanesulfonamide, trimetrexate, and vinblastine. The degree of resistance of P388R cells to Adriamycin (ADR) and daunomycin was 50-fold and 38-fold, respectively, when compared to the parent cell line (P388S). The Adriamycin-resistant cells were highly cross-resistant to some anthrapyrazoles, but the degree of cross-resistance was not uniform and was less than 3-fold for one member of the series. The lipophilicity of these compounds appeared to correlate to some extent with the level of resistance. The calcium channel blockers verapamil (VER) and diltiazem and the calmodulin antagonist trifluoperazine potentiated the cytotoxicity of the anthrapyrazoles and ADR in P388R. This potentiating effect was concentration dependent with VER being the most efficacious. VER increased ADR cytotoxicity by greater than 10-fold and CI-937 by almost 40-fold. However, VER, diltiazem, and trifluoperazine had no effect on ADR or anthrapyrazole activity in P388S cells. The antiarrhythmic drug, quinidine, and the detergent, Tween 80, also potentiated ADR activity in P388R cells to the same extent as VER. Both the net accumulation and efflux of [3H]daunomycin were altered in P388R cells by nontoxic concentrations of Tween 80 in a fashion virtually identical to that demonstrated for VER. These data suggest that agents which potentiate drug cytotoxicity in P388R cells may do so by their interaction with the lipid domain of the plasma membrane. In addition, these results demonstrate that some members of the new series of DNA binding drugs, the anthrapyrazoles, may be active against anthracycline-resistant tumors and that, where cross-resistance to them occurs, it can be partially reversed by agents such as VER.

Animals↗
PubMed1986

Cross-resistance patterns and antigen expression in Vinca alkaloid- and other multiple drug-resistant human leukemic cell lines.

The studies presented in this report demonstrate that Vinca alkaloid-resistant human leukemic lymphoblasts display patterns of cross-resistance to other drugs that differ from those of cell lines selected for primary resistance to anthracyclines or epipodophyllotoxins. These various drug-resistant cell lines also showed differential expression of an antigen recognized by an antibody that distinguishes VLB-resistant from VLB-sensitive cells. Furthermore, comparable levels of resistance or cross-resistance to one drug are not predictive of cross-resistance to other drugs. Our data suggest, then, that the MDR phenotype is complex and may be the result of many and different biochemical lesions. Thus, in order to predict MDR, it may be necessary to document more than one of these changes with specific reagents.

Antibodies, Monoclonal↗
PubMed1987

Atypical multiple drug resistance in a human leukemic cell line selected for resistance to teniposide (VM-26).

Resistance to the cytotoxic effects of many natural product drugs after exposure to a single agent is a common observation. The classes of drugs included in the "classic" multiple drug resistance phenotype are Vinca alkaloids, anthracyclines, epipodophyllotoxins, and antibiotics. We report here the characterization of a human leukemic cell line (CEM/VM-1) with "atypical" multiple drug resistance: despite resistance and cross-resistance to etoposide, anthracyclines, mitoxantrone, and 4'-[(9-acridinyl)amino]methanesulphon-m-anisidide (mAMSA), these cells retain sensitivity to the Vinca alkaloids. Further, even though this cell line is approximately equal to 40-fold cross-resistant to the cytotoxic effect of etoposide (VP-16), it is similar to drug-sensitive CEM cells in the cellular pharmacology of [3H]VP-16 as determined by zero time binding, initial influx rate, steady state drug concentration, and unidirectional efflux. Our studies suggest that the resistance of CEM/VM-1 cells to epipodophyllotoxins is due to an altered interaction between drug and its cellular target(s) by a mechanism unrelated to the decreased cellular concentration of drug associated with the "classic" multiple drug resistance phenotype.

Cell Line↗
PubMed1987

Collateral methotrexate resistance in cultured human head and neck carcinoma cells selected for resistance to cis-diamminedichloroplatinum(II).

A human head and neck squamous cell carcinoma line (SCC25) derived from a patient with no prior history of radiotherapy or chemotherapy was made resistant to cis-diamminedichloroplatinum(II) (CDDP) by continuous escalation of weekly 30-min pulses of the CDDP from 0 to 0.2 mM over 20 months and then cloned and pulsed weekly with 0.2 mM CDDP for another 20 months. This afforded a resistant subline, SCC25/CP[1], with an IC50 for CDDP 12-fold higher than that of the parental cells. The SCC25/CP[1] cells unexpectedly proved to be cross-resistant to methotrexate (MTX) (24-fold for 30-min treatment and 8-fold for continuous treatment). Resistance was associated with a modest (about 2-fold) increase in the dihydrofolate reductase (DHFR) content according to radioligand-binding assay, and in the rate of cell division. In addition there was a 4-fold decrease in the fraction of long-chain MTX polyglutamates MTX(G4-6) in the cell after 24 h exposure to either 0.2 or 2.0 microM MTX. When the SCC25/CP[1] cells were kept out of CDDP for 8-9 months and 12 months to give the sublines SCC25/CP[2] and SCC25/CP[3], respectively, MTX sensitivity to continuous exposure returned to normal. The SCC25/CP[3] cells still exhibited a slightly elevated DHFR level, but their generation time became shorter than that of the parental SCC25 line. In addition the SCC25/CP[3] cells had an initial uptake velocity (V0) for MTX that was 9-fold greater than the V0 of the SCC25 or SCC25/CP[1] cells, while its ability to form MTX(G4-6) was comparable to that of the SCC25 cells. When SCC25/CP[2] cells were rechallenged with weekly 0.2 mM CDDP pulses for 4-6 months, a MTX-resistant line, SCC25/CP[4], was produced. The SCC25/CP[4] cells retained a slightly elevated DHFR content and a high proliferation rate, but the V0 for MTX influx was intermediate between SCC25 and SCC25/CP[3] cells. The ability to form the longer-chain polyglutamates MTX(G4-6) was again impaired. Thus, MTX cross-resistance can develop in cultured head and neck carcinoma cells when CDDP is used as the selecting agent for primary resistance. MTX resistance is multifactorial, as it is when MTX itself is used as the selecting agent, and appears to involve various combinations of altered growth rate, DHFR content, MTX uptake, and ability to form noneffluxing long-chain MTX polyglutamate species. These results are potentially of clinical relevance, since CDDP and MTX are often used in combination with other drugs or with radiation to treat patients with squamous cell carcinoma of the head and neck.

Biological Transport↗
PubMed1979

[Genetic study of the resistance of mouse somatic cells to colchicine (high resistance level)].

The studies of the high level of colchicine resistance of mouse L cells have shown that two mutagens (EMS and NMM) do not induce cell variants resistant to 8 microgram/ml of colchicine in the population of mouse heteroploid L-53 cells (subline of L cells, the level of colchicine resistance 140) and that colchicine resistance of L-53 cells gradually diminishes when cells are propagated in non-selective conditions: after 1 month it diminishes 2-fold, after 3 month--9-fold. The extent of the decrease of the drug resistance was the same in 6 independent cultures obtained from the inoculum of 200 cells and in control cultures propagated by large quantities of cells. These data coincide with the results of the previous studies of lower level of colchicine resistance. In both studies the frequency of the occurrence of colchicine resistant variants in selective medium was about 2.10(-4). These data are consistent with the hypothesis that colchicine resistance of mouse L cells is not due to a gene mutation.

Animals↗
PubMed1966

Carbamate-resistance in mosquitos. Selection of Culex pipiens fatigans Wiedemann (=C. quinquefasciatus Say) for resistance to Baygon.

The authors investigated the rate of development and other characteristics of Baygon-resistance in Culex pipiens fatigans (=C. quinquefasciatus) recently colonized from Southern California. Selective pressure against the larvae (strain L) for 35 generations resulted in 25.4-fold resistance in larvae, but only 3-fold and 4.8-fold resistance in adults, as determined by contact and topical application, respectively. Conversely, selective pressure on adults (strain A) for 24 generations resulted in 8.4-fold (contact) and 5.3-fold (topical) resistance in adults, but only 2.7-fold resistance in larvae. About 10% of strain A adults survived 1-hour contact exposure even when the concentration of Baygon was increased 100-fold. This was not due to enhanced phototropism in this stage. Larvae of strain L metabolized (14)C-labelled Baygon at a rate 2.5-fold greater than the non-selected strain. Cross-resistance in strain L to carbamates closely related to Baygon was high, but was extremely low to remotely related carbamates.The authors consider the relatively slow rate of development of resistance to Baygon, the reduced expressivity of the resistance character in adults, and its specificity for the selective agent and for closely related carbamates to be encouraging indications as to the usefulness of this class of compounds for mosquito control.

Carbamates↗
PubMed1980

Antibiotic cross-resistance patterns of ambodryl and promazine resistant mutants.

The antihistaminic drug ambodryl (Am) and the tranquillizer promazine (Pr), which had previously shown significant antimicrobial activities, were used to select bacterial mutants representing different levels of resistance to their action. These Am and Pr mutants were found to have simultaneously developed cross-resistance to penicillin (Pe), streptomycin (Sm), chloramphenicol (Cm), tetracycline (Tc) and kanamycin (Km). Certain first-step Am mutants of sensitive wild-type bacteria which were also sensitive to these antibiotics developed resistance to Pe and Sm as well as to Pr and the antihistamine benadryl (Bn). The next-step mutant of Am resistance not only doubled its resistance to these antibiotics and chemotherapeutics, but broadened its resistance-spectrum to cover Tc and Cm. These observations on cross-resistances seem to be best explained on the basis of a reduction in cell-membrane permeability acting in a nonspecific manner. The role of such cross-resistance in accounting for an overall increase in the minimum inhibitory concentrations (MIC) of many drugs against several groups of bacteria is evaluated.

Anti-Bacterial Agents↗
PubMed1983

Daunorubicin-resistant Chinese hamster ovary cells expressing multidrug resistance and a cell-surface P-glycoprotein.

Independent lines of Chinese hamster ovary cells resistant to the antineoplastic drug, daunorubicin, were obtained by clonal isolation in increasing drug concentrations. A single daunorubicin-resistant phenotype typified by reduced cellular drug accumulation was observed. These mutants displayed a complex phenotype of resistance to a variety of unrelated drugs. Such properties are similar to those of membrane-altered colchicine-resistant lines (V. Ling and L.H. Thompson, J. Cell. Physiol., 83: 103-116, 1974). Analysis of the plasma membrane components of the daunorubicin-resistant clones by gel electrophoresis revealed a prominent cell surface glycoprotein with a molecular weight of about 170,000. This component was immunologically cross-reactive with the cell surface P-glycoprotein of about the same molecular weight, previously identified in colchicine-resistant cells. Thus, it appears that the mechanism of resistance characterized by P-glycoprotein expression could be the basis of many drug-resistant phenotypes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1983

Podophyllotoxin-resistant mutants of Chinese hamster ovary cells: cross-resistance studies with various microtubule inhibitors and podophyllotoxin analogues.

The cross-resistances of several mutants of Chinese hamster ovary cells which have been obtained after one and two selection steps in the presence of the microtubule inhibitor podophyllotoxin (PodRI and PodRII mutants, respectively) towards various other inhibitors of microtubule assembly (e.g., colchicine, Colcemid, vinblastine, griseofulvin, maytansine, steganacin, nocodazole, and taxol) have been examined. Based upon their specific patterns of cross-resistance/sensitivity to various microtubule inhibitors, both the PodRI and PodRII classes of mutants appear to be of more than one kind. Studies on the binding of [3H]podophyllotoxin to cytoplasmic extracts indicate that one of the PodRII mutants which has been shown previously to be affected in a Mr 66,000 to 68,000 microtubule-associated protein shows reduced binding of the drug in comparison to the parental PodS and PodRI cells. The different PodRI and PodRII mutants exhibited proportionally increased cross-resistances to various podophyllotoxin analogues (e.g., deoxypodophyllotoxin, epipodophyllotoxin, beta-peltatin, 4'-demethylpodophyllotoxin, alpha-peltatin, podophyllotoxin-beta-D-glucoside, beta-peltatin-beta-D-glucoside, picropodophyllotoxin, and podophyllic acid) which possess microtubule-inhibitory activity. However, with the exception of one PodRI class of mutant, none of the mutants exhibited any cross-resistance to 4'-demethylepipodophyllotoxin thenylidine-beta-D-glucoside and 4'-demethylepipodophyllotoxin ethylidine-beta-D-glucoside, the 2 podophyllotoxin analogues which lack microtubule-inhibitory activity. The cross-resistance studies with these mutants, which, based upon the biochemical studies and their highly specific patterns of cross-resistance, are presumably affected in microtubules, provide some very novel insights into the mechanisms of action of various microtubule inhibitors. The results presented in this paper also show that the cross-resistance studies with the set of podophyllotoxin-resistant mutants provide a sensitive and highly specific screening procedure for identifying compounds which possess podophyllotoxin-like activity and for investigating the structure-activity relationship among them. The results of structure-activity relationship studies for the various podophyllotoxin analogues examined are discussed.

Animals↗
PubMed1978

R plasmids coding for supra-levels of gentamicin, tobramycin and sisomicin resistance in Proteus morganii and P. mirabilis: high-level resistant strains from two hospitals.

Transfer of high-level gentamycin-tobramycin-sisomycin resistance could be easily demonstrated in strains of P. morganii and P. mirabilis which emerged, in two hospitals, at the end of 1976. First such strains were demonstrated in a patient of a urological ward who died, in September 1976, from generalised sepsis caused by a high-level gentamycin-tobramycin-sisomycin-resistant P. morganii. Since that event, at least nine such strains were isolated in 1976, and the presence of transferable resistant to the antibiotics listed plus other antibacterial substances including carbenicillin and more classical antibiotics could be demonstrated either by a high-frequence direct transfer to suitable recipient strains of Gentamycin or Tobramycin resistance, or by indirect selection, i.e. by analysis of exconjugants selected with kanamycin, streptomycin or carbenicillin. Further numerous strains of P. morganii highly resistant to gentamycin, tobramycin and sisomycin (M.I.C. over 128 mcg/ml) still emerge from wards in the two hospitals monitored and their transferability is under experimental study. It is stressed that, in order to demonstrate a transfer of gentamycin or tobramycin resistance in strains resistant to these substances, it is inevitable to examine properly also exconjugnants showing direct transfer to other, more classical antibiotics. We could not demonstrate, in our strains, any prodromal signs of resistance to netilmycin or amikacin.

Amikacin↗