Collateral sensitivity: problems of demonstration in murine leukemia cells.
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Animals↗
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Results for “Collateral sensitivity”
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Carbamoylation of glutathione reductase and changes in cellular and chromosome morphology in a rat cell line resistant to nitrogen mustards but collaterally sensitive to nitrosoureas.
A Walker 256 rat carcinoma cell line (WR) with acquired resistance to nitrogen mustards has been found to lack cross-resistance to nitrosoureas. Although total cellular glutathione pools were similar in the parent (WS) and resistant cell lines (WS, 2.5 X 10(-6); WR, 2.0 X 10(-6) mol/mg protein), glutathione reductase activity was 3.98 in WR compared to 8.67 nmol reduced nicotinamide adenine dinucleotide phosphate oxidized per microgram protein per min in WS cells. Treatment of cells with a carbamoylating nitrosourea, N,N'-bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea, produced a dose-dependent inhibition of glutathione reductase and depletion of thiols in both cell lines. The drug caused no direct DNA strand breakage, but a differential mitotic spindle-chromosome stain showed that spindle formation was inhibited in WR cells at N,N'-bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea concentrations of greater than 50 microM. In WS cells, mitotic figures were still visible at 100 microM. Chromosomal damage was expressed in both cell lines at concentrations of 25 microM. The number and extent of these aberrations were greater in WR than WS. Observed karyotypic abnormalities included polyploidy, chromosome decondensation, and endoreduplication. In interphase cells, transmission electron microscopy showed that the most prevalent drug-induced lesions included (a) disappearance of plasma membrane filopodia, (b) appearance of membrane blebbing, and (c) development of irregular crescent-shaped nuclei. These morphological and cytogenetic changes correlate with cytotoxic responses of these cell lines to N,N'-bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea and would be consistent with drug-induced inhibition of glutathione reductase.
Animals↗
Collateral sensitivity to methotrexate in cells resistant to adriamycin.
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Animals↗
Collateral sensitivity to 4-hydroxyquinolines in Eimeria acervulina strains resistant to meticlorpindol.
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Animals↗
[Transplantability, development and methotrexate sensitivity of mouse leukemia L1210 resistant to olivomycin].
A total of 52-fold passages of leukemia L-1210 were carried out for a year on mice treated intraperitoneally with olivomycin. Prolonged exposure to olivomycin resulted in decreased transplantability of the tumor cells. The tumor cells obtained under the effect of olivomycin were more sensitive (collateral sensitivity) to methotrexate as compared to the cells of the initial strain L-1210. An intramuscular route for transplantation of the tumor cells of leukemia L-1210 is recommended. The dosage intramuscular transplantation of the tumor cells provided simultaneously data on transplantability, tumor size and lifer-time of mice.
Animals↗
Collateral sensitivity-harnessing microbial vulnerabilities as a solution to antimicrobial resistance.
Bacteria exhibit an evolutionary trade-off through their development of collateral sensitivity (CS) which allows them to resist one antibiotic while becoming more vulnerable to another. This vulnerability offers a compelling therapeutic opportunity by selecting against resistant isolates. Laboratory evolution studies, genome sequencing, deep mutagenesis and use of artificial intelligence and machine learning can design the bespoke strategy against multi-drug-resistant bacteria. This review discusses about recent studies that are rationally designed to harness this evolutionary trade-off for the development of alternative antimicrobial strategies. The translational barriers to the clinical implementation of CS are addressed and evidence-based design principles for optimization of CS-guided therapy are discussed.
Bacteria↗
Collateral drug sensitivity induced in CPT-11 (a novel derivative of camptothecin)-resistant cell lines.
Collateral drug sensitivity was induced in CPT-11-resistant cell lines (CPT-K and T). Ten of the 19 kinds of antineoplastic agents (especially, 5 of 6 kinds of DNA topoisomerase II inhibiting agents) were effective in inducing collateral drug sensitivity. Alteration of DNA topoisomerase I seemed to be unrelated to acquisition of multidrug resistance.
Antineoplastic Agents, Phytogenic↗
Establishment and characterization of cisplatin-resistant sublines of human lung cancer cell lines.
Human lung cancer sublines resistant to cisplatin (CDDP) have been developed by continuously exposing cells to gradually increasing doses of CDDP and use of the limiting dilution technique. The cell lines used were PC-7, PC-9 and PC-14 (pulmonary adenocarcinoma) and H69 and N231 (small-cell lung cancer). The resistant phenotype of the resistant sublines was stable for more than 2 months in the absence of drug. PC-7/1.2 (i.e., PC-7 cells growing stably in medium containing 1.2 micrograms/ml of CDDP), PC-9/0.5, PC-14/1.5, H69/0.4, and N231/0.2 have been developed, which are 22.9, 7.1, 3.1, 25.6, and 8.4 times more resistant to CDDP than the respective parent cell line in terms of IC50 in the soft agar colony assay with continuous drug exposure. Cloning efficiency decreased significantly in N231/0.2. The doubling times increased significantly in most of the resistant sublines. Cellular DNA contents increased in all resistant sublines, but statistical significance was observed only in H69/0.4 (p less than 0.05). Cells of the resistant sublines of PC-7, PC-9, PC-14 and H69 were larger than cells of the parent lines, but the differences were not significant. The growth morphologies of all resistant sublines in the drug-free medium were similar to those of parent cell lines. All resistant sublines tested were significantly cross-resistant to carboplatin. The patterns of cross-resistance, cross-sensitivity and collateral sensitivity to adriamycin, mitomycin-C, 5-fluorouracil, vindesine, etoposide, aclacinomycin and vincristine were different in each resistant subline. Verapamil (3.3 micrograms/ml) showed little modifying effect on CDDP resistance in 5 CDDP-resistant sublines tested except N231/0.2 (Modification Index: 0.49). Cyclosporin A (5.0 micrograms/ml) modified CDDP resistance in CDDP-resistant small-cell lung cancer sublines (H69/0.4 and N231/0.2) (Modification Index: 0.45 and 0.07, respectively), while in CDDP-resistant NSCLC sublines (PC-7/1.0 and PC-9/0.5), cyclosporin A reduced the sensitivity to CDDP.
Cell Line↗
Antitumor drug cross-resistance in vivo in a cisplatin-resistant murine P388 leukemia.
Since 1978, over 50 clinically useful antitumor drugs or new candidate antitumor agents have been evaluated in vivo against cisplatin-resistant P388 leukemia (P388/DDPt) in our laboratories. Analysis of this data base has yielded insights into the cross-resistance, collateral sensitivity, and mechanisms of resistance of P388/DDPt. P388/DDPt was cross-resistant or marginally cross-resistant to eight agents [carmethizole.HCl, rhizoxin, dibromodulcitol, spirohydantoin mustard, hepsulfam, arabinosyl-5-azacytosine (ara-AC), tiazofurin, and deoxyspergualin]. Of these eight agents, the latter six have entered various phases of clinical trials. For these trials, it may be important to exclude or to monitor with extra care patients who have previously been treated with cisplatin. P388/DDPt was collaterally sensitive to six agents [fludarabine phosphate (2-F-ara-AMP), amsacrine (AMSA), mitoxantrone, etoposide (VP-16), batracylin, and flavone acetic acid] and, possibly, to two others (merbarone and echinomycin). These observations of collateral sensitivity suggest that a combination of cisplatin plus any one of these drugs might exhibit therapeutic synergism. Therapeutic synergism has been observed in animal models for combinations of cisplatin plus VP-16, AMSA, or mitoxantrone. The observation of collateral sensitivity for P388/DDPt to four agents (AMSA, mitoxantrone, merbarone, and VP-16) that have been reported to interact with DNA topoisomerase II suggests the possible involvement of the latter in cisplatin resistance. Both the increased sensitivity of P388/DDPt to these agents and a portion of its resistance to cisplatin could be the result of an increase in DNA topoisomerase II activity.
Amsacrine↗
A comparative analysis of drug-induced DNA effects in a nitrogen mustard resistant cell line expressing sensitivity to nitrosoureas.
In the Walker 256 rat mammary carcinoma cell line, WR, resistance to nitrogen mustards (NM) is accompanied by collateral sensitivity to chloroethylnitrosoureas (CENUs). DNA-interstrand cross-links, DNA-protein cross-links, and sister chromatid exchange (SCE) induction were assayed in WR and the parent cell line (WS) after treatment with nitrogen mustard (HN2), phosphoramide mustard (PM), chlorozotocin (CLZ) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). Treatment of cells with HN2 caused extensive levels of cross-links, approximately 50% of which were DNA-interstrand, equal in both WR and WS, whereas PM caused no detectable cross-links in either cell line. CLZ induced low levels of DNA-interstrand cross-links, similar in WR and WS, but no DNA-interstrand cross-links could be detected in either cell line after treatment with CCNU. Both CLZ and CCNU induced low levels of DNA-protein cross-links in both cell lines, though higher in WR than WS. There was no difference in the rate of removal of HN2-induced DNA-interstrand or DNA-protein cross-links or total CLZ-induced cross-links by the two cell lines, suggesting that differential repair was not relevant to the expression of resistance. Both HN2 and PM caused more SCEs in WS than in WR, whereas CLZ and CCNU induced more SCEs in WR. Thus, NM-induced SCEs were related to cell killing but not cross-linking, whilst CENU-induced SCEs were related to cell killing and DNA-protein but not DNA-interstrand cross-links. Furthermore, the collateral sensitivity of WR cells to CENUs was not due to the differential induction of DNA-interstrand cross-links or repair of total cross-links, or repair of total cross-links, although higher levels of DNA-protein cross-links occurred in WR, and these may be either a cause or a consequence of increased susceptibility of these cells to CENUs. Presumably NMs and CENUs have several distinct and separate macromolecular targets which result in differential cell killing. It is concluded that a range of lesions occurred after treatment of WR and WS cells with either NMs or CENUs and that, in these cell lines, there is no simple correlation between drug-induced cross-linking, SCE induction and cytotoxicity.
Animals↗
Nucleo-cytoplasmic interaction between oligomycin-resistant mutations in Saccharomyces cerevisiae.
1.A single-gene nuclear mutant of Saccharomyces cerevisiae, isolated as oligomycin-resistant, exhibits in vivo cross-resistance to venturicidin and collateral sensitivity to Synthalin. All three compounds are inhibitors of mitochondrial oxidative phosphorylation. Oligomycin resistance and Synthalin sensitivity are recessive, while venturicidin resistance is dominant. 2. Acytoplasmic mutant, also isolated as oligomycin-resistant, shows collateral sensitivity to both Synthalin and venturicidin. All three traits undergo mitotic segregation in diploids formed by crossing mutant and normal halpoids. 3. A novel nucleocytoplasmic interaction is observed in diploids formed by crossing haploid strains containing the nuclear and the cytoplasmic mutations, respectively. The dominant venturicidin resistance determined by the nuclear gene undergoes mitotic segregation, which results from a suppression of the nuclear phenotype by the cytoplasmic mutation. When a diploid mitotic segregant contains primarily mutant-type mitochondria, venturicidin resistance is completely suppressed. In haploids containing both the nuclear and cytoplasmic mutations, suppression is only partial. 4. Oxidative phosphorylation and ATPase in mitochondrial fractions isolated fromcytoplasmic mutant cells are less sensitive to inhibition by oligomycin than normal, but in vitro sensitivity to venturicidin is not significantly changed. In similar mitochondrial fractions isolated from normal and nuclear mutant cells, no significant differences in sensitivity to either inhibitor are detected. 5. The molecular basis for the nucleocytoplasmic suppression of venturicidin resistance may involve participation of mitochondrial membrane, plasma membrane or both. Either mitochondria can undergo changes in venturicidin sensitivity upon isolation, or the molecular entity which controls access of venturicidin to the mitochondria resides outside of the organelles. 6. Our data establish that aspects of the response in vivo of both venturicidin and Snythalin are controlled by the mitochondrial genome. 7. The nucleocytoplasmic interaction described here is the first example in which a specific restricted mitochondrial mutation modifies the phenotypic expression of a nuclear gene.
Antifungal Agents↗
Collateral susceptibility of adriamycin-, melphalan- and cisplatin-resistant human ovarian tumor cells to bleomycin.
Three cell lines resistant to adriamycin, melphalan and cisplatin were established in vitro from human ovarian cancer cell line A2780. Each subline showed a resistance to its inducing drug of 75-fold in the case of adriamycin, 6-fold in the case of melphalan and 11-fold in the case of cisplatin. However, all of these sublines showed collateral sensitivity to bleomycin. Approximately a 2-fold higher susceptibility to bleomycin was observed generally. The biochemical mechanisms of this collateral sensitivity are not clear at present, but the higher concentration of glutathione in these resistant tumor cell lines might be related to the high susceptibility of these resistant cells to bleomycin.
Bleomycin↗
Effect of homoharringtonine on the viability of murine leukemia P388 cells resistant to either adriamycin, vincristine, or 1-beta-D-arabinofuranosylcytosine.
Cultured murine leukemia P388 cell populations were derived from P388 cells resistant to vincristine (P388/VCR), adriamycin (P388/ADR), and 1-beta-D-arabinofuranosylcytosine (P388/ARA-C) that were developed in vivo and to the parental drug-sensitive cells (P388/O) that were passaged in vivo. The doubling times of the cultured cell populations (mean +/- SD) between cell densities of 5 x 10(4) and 1 x 10(6) cells/ml were 14.2 +/- 2 h (P388/O), 16.5 +/- 1.9 h (P388/VCR), 16.9 +/- 1.2 h (P388/ADR), and 15.0 +/- 1.4 h (P388/ARA-C). Exponentially proliferating cultured cell populations were exposed to selected homoharringtonine (HHT) concentrations for 24 h and the surviving cell fractions were determined by colony formation in semisolid medium. The results, based on differential sensitivity of the cell populations to HHT, indicated that cultured P388/VCR cells were cross-resistant to 0.018-1.8 micrograms/ml HHT, P388/ADR cells were cross-resistant to 0.058-1.8 micrograms/ml HHT, and P388/ARA-C cells were collaterally sensitive to 0.09-0.36 micrograms/ml HHT. The results with the cultured P388/VCR, P388/ADR, P388/ARA-C, and P388/O cell populations were confirmed in animal experiments. CD2F1 mice bearing intraperitoneal (i.p.) implants of 1 x 10(6) P388/VCR, P388/ADR, P388/ARA-C, or P388/O leukemia cells were given HHT i.p. qd on days 1-9 postimplantation. Optimal treatment (less than or equal to LD10) produced in vivo cell kills of 2 to 3 log10 units in P388/O and about 7 log10 units in P388/ARA-C, whereas P388/VCR and P388/ADR cells actually increased by 1-2 log10 units during treatment. The results of this study indicate that cross-resistance (P388/VCR and P388/ADR) or collateral sensitivity to HHT (P388/ARA-C) is a function of the cellular properties of the target tumor cell populations that is independent of host factors.
Alkaloids↗
[Cross-resistance of HO-221 and various antitumor agents in sublines of mouse leukemia].
HO-221, N-[4-(5-bromo-2-pyrimidinyloxy)-3-chlorophenyl]-N'-(2- nitrobenzoyl) urea is a new benzoylphenylurea derivative. The compound exhibits significant antitumor effects against various animal tumors, and was especially effective against the solid tumors implanted subcutaneously. HO-221 inhibits DNA polymerase alpha activity strongly in vitro. In this study, we examined the cross-resistance of HO-221 to various antitumor agents using sublines of mouse leukemia. HO-221 showed antitumor effects in mice bearing L 1210 or P 388 leukemia resistant to 10 antitumor agents, DM (daunomycin), MMC (mitomycin C), CDDP (cisplatin), 5-FU (5-fluorouracil), Ara-C (cytosine arabinoside), MTX (methotrexate), CPA (cyclophosphamide), CQ (carboquone), ADM (adriamycin) and VCR (vincristine), respectively. These antitumor agents were also effective in P 388 leukemia resistant to HO-221 (P 388/HO-221). Furthermore, CDDP- and MMC-resistant sublines showed a collateral sensitivity to HO-221 in vivo. The grow the inhibitory effects were also noted in vitro in ADM-, CDDP- and MMC-resistant cells by HO-221. However, the in vitro experiments didn't show such collateral sensitivity on the resistant sublines. These results suggest that there is no cross-resistance between HO-221 and other known antitumor agents, and that HO-221 seemed to be worth for evaluating clinical usefulness.
Animals↗
Cytotoxic action of cyclosporins on human tumor cell lines is not dependent on immunosuppressive activity.
The cytotoxic activity of cyclosporin A (CsA) and the three non-immuno-suppressive CsA analogues B3-243, WO-039 and B3-665 were studied in tumor cell lines representing both classical and atypical forms of multidrug resistance (MDR): T-ALL GM3639 L100 cells selected for vincristine (vcr) resistance and displaying characteristics of classical MDR, including P-glycoprotein (pgp) expression and increased drug efflux which can be inhibited by pgp blockers (e.g. verapamil), and U-1285/ADR, a small cell lung cancer (SCLC) cell line selected for doxorubicin resistance which lacks pgp, is insensitive to pgp-blockers and shows cross resistance to cis-platinum. At 1 micrograms/ml CsA was the most active agent in reversing Vcr resistance in L100 cells followed by B3-243 and WO-039, with no effect of B3-665. Parental LO cells were only marginally sensitized to Vcr by these agents. No reversing effect of any cyclosporin was observed in the U-1285/ADR or its parental cell line. Compared to LO cells, L100 cells showed a marked hypersensitivity to CsA > B3-243 > WO-039 with B3-665 being inactive. No collateral sensitivity was observed for cyclosporins in U-1285/ADR cells. Although of different magnitude, the pattern of cytotoxic activity for the different cyclosporins alone closely parallelled that of L100 cells for U-1285, U1285/ADR and LO cells. The results indicate that not only the collateral sensitivity in classical MDR but also the cytotoxic actions of cyclosporins per se on tumor cells alone are independent of immunosuppressive activity. The results also suggest a structure-activity relationship for cyclosporin-induced cytotoxicity similar to, but independent of, MDR reversing activity.
Antineoplastic Agents↗
Antifolate studies. Activities of 40 potential antimalarial compounds against sensitive and chlorguanide triazine resistant strains of folate-requiring bacteria and Escherichia coli.
As part of the search for new antimalarial drugs, a screening program was developed using sensitive and chlorguanide triazine (CGT, cycloguanil) resistant strains of the folate-requiring bacteria, Streptococcus faecium durans, Lactobacillus casei, and Pediococcus cerevisiae. The activities of 40 compounds have been studied against these strains and Escherichia coli. Observations have been made on the points of 50% growth inhibition, the fold increase of resistance shown to each compound by the resistant strains as compared with the parent sensitive strains, and the reversal of growth inhibition by folic acid with S. faecium and L. casei by folinic acid with P. cerevisiae and by p-aminobenzoic acid with E. coli. Comparisons have been made of the activities of the test compounds with those of the standard antimalarial antifoltes, CGT and pyrimethamine (PM), and the antibacterial results have been compared with the activities of the compounds against Plasmodium berghei infections in the mouse and against human malaria infections where data are available. Of the 17 compounds reversed by folates, five had patterns of activity similar to CGT and PM in that they were most active against S. faecium and nine compounds exhibited a different pattern, being highly active against all four test bacteria. This suggests that these latter compounds either have different pharmacokinetic properties or have additional modes of action. The three CGT-resistant organisms responded to antifolates in different ways. S. faecium (R) and P. cerevisiae (R) strains were cross resistant to 4,6-diaminotriazines, 2,4-diaminopyrimidines, 2,4-diaminoquinazolines, and active 2,4-diaminopteridines. L. casei (R) was cross resistant to the triazines but was collaterally sensitive to all the other antifolates. Most of the compounds not reversed by folates were much less inhibitory for the test organisms; they were most active against L. casei. In general, their growth inhibitory concentrations varied less for the four test organisms and the responses of the sensitive and CGTR strains were similar. However, there was some cross resistance to five compounds and some collateral sensitivity to five others. Comparison of the bacteriological data with the activities of the compounds against Plasmodium berghei in the mouse showed little correlation between the two test systems; each appears to provide independent and useful information.
Animals↗
Folate requirements of methotrexate-resistant human acute lymphoblastic leukemia cell lines.
We studied the folate requirements of a human acute lymphoblastic leukemia cell line, MOLT-3, and methotrexate (MTX)-resistant sublines established in vitro. The requirement of pteroylglutamate (PGA) for optimal cell growth was different for each cell line. With increasing MTX resistance, there was progressive increase in PGA requirements, moving the PGA concentration-cell growth curve (dose-response curve) 1 log order of magnitude to the right. The increases in the requirement of 5-methyltetrahydrofolate (5-methyl-THF) by the resistant sublines were more pronounced than PGA requirement, moving the dose-response curve nearly 3 log orders in magnitude to the right. The concentrations in vitro of 5-methyl-THF required for optimal growth of the MTX-resistant sublines far exceeded the normal serum 5-methyl-THF concentrations known in humans. These observations show that MTX-resistant cell established in vitro in culture media containing PGA instead of 5-methyl-THF, a physiological folate, cannot be expected to grow in vivo. The collateral sensitivity of transport-impaired MTX-resistant sublines to 2,4-diamino-5-methyl-6-[(3',4',5'- trimethoxyanilino) methyl] quinazoline (trimetrexate, TMQ) was negated in the absence of PGA. With the addition of 5-methyl-THF, the parent cells became more resistant than the transport-impaired sublines to TMQ These data indicate that the collateral sensitivity of MTX resistant cells to the substituted 2,4-diaminoquinazoline is due to functional folate deficiency by virtue of the impaired transport of folate.
Biological Transport↗
Selection of nitrogen mustard resistance in a rat tumor cell line results in loss of guanine-O6-alkyl transferase activity.
Cell killing, DNA-interstrand crosslinks, and DNA-protein crosslinks were assayed in nitrogen mustard-resistant Walker 256 carcinoma (WR) cells and the parent cell line (WS) after treatment with 5-[3-(2-chloroethyl)-1-triazenyl]imidazo-4-carboxamide (MCTIC). The WR cells, which also express collateral sensitivity to chloroethylnitrosoureas, were approximately twice as sensitive to the cytotoxic effects of MCTIC as were WS cells. Following treatment with 100 microM MCTIC, there was a rapid accumulation of both DNA-interstrand and DNA-protein crosslinks in the WR cell line, which reached a maximum at 6 and 12 hr, respectively. There was considerably less crosslinking in the WS cells and both cell lines were proficient in repairing most of the crosslinks by 24 hr. Measurement of guanine-O6-alkyl transferase activity showed the enzyme to be present in WS but not in WR cells. These data indicate that the collateral sensitivity of nitrogen mustard-resistant WR cells to chloroethylating drugs is in part due to the loss of guanine-O6-alkyl transferase activity which is present in the parent line.
Animals↗