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At least 19 recordsLinked to original sources
PubMed1992

Expression of collateral sensitivity to cisplatin, methotrexate, and fluorouracil in a human ovarian carcinoma cell line following exposure to fractionated x-irradiation in vitro.

Examples of collateral sensitivity, even in experimental tumor systems, remain few. Preliminary data from this laboratory indicated that certain tumor cells expressed increased sensitivity to cisplatin after exposure in vitro to x-irradiation. To further clarify whether the type of fractionated radiation procedure used clinically can induce hypersensitivities to certain antitumor drugs we have pre-exposed the human ovarian carcinoma cell line JA-T/P derived from a tumor from an untreated patient to fractionated x-irradiation (total dose 50 Gy) in vitro. The resultant subline JA-T/DXR-10 expressed collateral sensitivity to cisplatin (CDDP), methotrexate (MTX) and fluorouracil (5-FU), but not to acute x-irradiation. Hypersensitivity to CDDP was associated with decreased activity of DNA polymerase beta (3.5-fold, P less than .01), but unaltered glutathione metabolism. Pre-incubation with cyclosporin A or with 3-aminobenzamide significantly enhanced (twofold, P less than .01) CDDP-induced cytotoxicity in JA-T/P cells, but not in the DXR-10 subline. Consistent with MTX hypersensitivity dihydrofolate reductase activity was significantly decreased (2.9-fold, P less than .01). Despite collateral sensitivity to 5-FU, however, thymidylate synthase activity was increased (twofold, P less than .05) suggesting alternative mechanisms for 5-FU-induced cytotoxicity in these JA-T/DXR-10 cells. These data demonstrate that DNA repair and associated reduced folate metabolism can be modified not only by drugs but also by fractionated x-irradiation.

Cisplatin↗
PubMed1992

Mechanisms of collateral sensitivity to fluorouracil of a cis-diamminedichloroplatinum(II)-resistant human non-small lung cancer cell line.

A cisplatin(CDDP)-resistant subline of a human lung cancer cell line, PC-7/CDDP, was 4.7-fold more resistant to CDDP than the parent line in a colony-forming assay. The sensitivity of this cell line to anthracyclines, vinca-alkaloid, etoposide, mitomycin C, and bleomycin was similar to that of the parental line, PC-7. However, PC-7/CDDP exhibited 4-fold higher sensitivity to fluorouracil (FUra). Possible mechanisms associated with the collateral sensitivity to FUra were studied in PC-7/CDDP cells. The sensitivity of both cell lines to FUra did not correlate with the effect of FUra on RNA. On the other hand, FUra induced a greater reduction in dTTP pools and more single strand breaks in PC-7/CDDP than in PC-7 cells. These results suggest that the pathway for de novo deoxyribonucleotide synthesis may be a target for FUra in PC-7/CDDP cells. However, inhibition of thymidylate synthase after FUra treatment did not correlate with the DNA-directed activity of FUra. Based on the above findings, the decreased salvage synthesis of dTTP was considered a possible mechanism of the greater reduction of dTTP pools in PC-7/CDDP cells. However, the activity of dThd kinase was the same in both cell lines. In the presence of physiological concentrations of exogenous dThd in the serum, uptake of dThd was less in PC-7/CDDP cells than that in PC-7 cells. Our data suggest that FUra-induced cytotoxicity in PC-7/CDDP cells is associated with the inhibition of dTTP synthesis and that the decreased uptake of dThd is a possible mechanism of the collateral sensitivity to FUra in PC-7/CDDP cells.

Adenocarcinoma↗
PubMed1975

Modification and inheritance of pleiotropic cross resistance and collateral sensitivity in Saccharomyces cerevisiae.

A meiotic segregant (oliPR1) was isolated with a phenotype of multiple cross resistance and collateral sensitivity. Strain oliPR1 has increased sensitivity to ethidium bromide, dequalinium chloride, acriflavin, paromomycin and neomycin, and increased resistance to oligomycin, rutamycin, venturicidin, triethyltin bromide, antimycin, carbonylcynamide-m-chlorophenylhydrazone, tetra-N-butylammonium bromide, dibenzyldimethylammonium chloride, triphenylmethlphosphonium bromide, chloramphenicol, carbomycin, tetracycline, triton X-165 and cycloheximide. Single gene inheritance of the cross resistance and collateral sensitivity was shown by 2:2 parental ditype segregation and reversion of the complete phenotype by a spontaneous revertant. The locus conferring the oliPR1 phenotype was mapped 11.7 units from an unspecified centromere. Antibiotic resistance showed incomplete dominance, with the level of hybrid resistance dependent upon the inhibitor tested. Resistant diploids that produced four resistant ascospores were the result of mitotic recombination prior to meiosis. A partial revertant phenotype (sensitive to all inhibitors except oligomycin, antimycin and carbonylcyanide-m-chlorophenylhydrazone) was shown to be due to a single nuclear gene causing partial suppression of oliPR1. Anaerobic pretreatment, 37degrees and 0.5 MKC1 were observed to reduce the growth of oliPR1 when challenged with seven diverse inhibitors (antimycin, carbonylcyanide-m-chlorophenylhydrazone,-chloramphenicol, cycloheximide, oligomycin, triethyltin bromide, and triphenylmethylphosphonium bromide). Resistance to cycloheximide was not altered by the [rho--] state. A revertant of oliPR1 (sensitive to the above inhibitors but resistant to ethidium bromide, paromycin and neomycin) showed anaerobic and temperature sensitization to ethidium bromide, paromomycin and neomycin. Continuous monitoring of oxygen uptake by the revertant afteranaerobic pretreatment revealed that anaerbiosis sensitized respiratory adaptation of the revertant to neomycin. It is proposed that oliPR1 is a mutation resulting in the alteration of plasma membrane permeability to many diverse inhibitors.

Antimycin A↗
PubMed1977

Collateral sensitivity between methylene dimethane sulfonate and halogenated methotrexate derivatives in the Yoshida sarcoma in vivo and in vitro.

A Yoshida lymphosarcoma line (YMDR8) resistant to methylene dimethane sulfonate (MDMS) showed collateral sensitivity against three halogenated methotrexates: 3'-bromomethotrexate (NSC-98580), 3'-bromo-5'-chloromethotrexate (NSC-98579), and 3',5'-dichloromethotrexate (NSC-29630); however, it was cross-resistant to methotrexate itself. Two other independently derived MDMS-resistant cell lines, YMDR7 and YMDR9, also demonstrated collateral sensitivity against 3'-bromomethotrexate, but with the latter, the origin of the "induced" sensitivity probably was not due to interference with antigenic or oncogenic properties of the cell line. When these agents were used in vivo (in Wistar rats) and in vitro, subpopulation changes within the tumor lines could be observed. The possible importance of this parameter in the development of such sensitivity is discussed.

Animals↗
PubMed1976

Some physiological alteration associated with pleiotropic cross resistance and collateral sensitivity in Saccharomyces cerevisiae.

A mutant strain (2-20) isolated by growth on medium containing oligomycin and cycloheximide was also found to be cross resistant to antimyicn, cerulenin, chloramphenicol, tetracycline, triethyltin and triphenylmethylphosphonium bromide, but collaterally sensitive to dequalinium chloride, gentamycin, neomycin, paromomycin and thiolutin. Growth of 2-20, compared to the parental strain and 2 complete revertants, under a variety of environmental conditions revealed that strain 2-20 had an enhanced sensitivity to increased osmolality, elevated pH, and high temperature; in addition, strain 2-20 was unable to polymerize aminoimidazole ribotide at 37 degrees C as shown by the failure to develop a red colony in the presence of ade 2. Four complex solid media (glucose--KCI, galactose, ethanol, ethanol--KCI, Table 1) unable to sustain the growth of strain 2-20 were arbitrarily chosen to monitor cellular growth under different physiological conditions. Tetrad analysis indicated that the complex phenotype (cross resistance, collateral sensitivity, inablity to polymerize aminoimidazole ribotide, absence of growth under adverse physiological conditions) was inherited by an allele of a locus previously shown to result in a permeability barrier of the plasma membrane to chloramphenicol. 582 of 640 subclones used to isolate revertants of 2-20, under four different physiological conditions, were observed to produce a complete revertant of the complex phenotype. It is proposed that the pleiotropic phenotype could result from an alteration of the plasma membrane and mitochondrial inner membrane by a single nuclear gene mutation.

Alleles↗
PubMed1976

Pleiotropic phenotype of colchicine-resistant CHO cells: cross-resistance and collateral sensitivity.

Colchicine resistant (CHR) mutants of CHO cells with reduced permeability to colchicine display extensive cross-resistance to a number of apparently unrelated compounds including puromycin, daunomycin, emetine, ethidium bromide and gramicidin D. A positive correlation was observed between the level of cross-resistance and the relative hydrophobicity of these compounds. The mutants also showed increased (collateral) sensitivity to local anaesthetics (procaine, tetracaine, xylocaine and propanolol), steroid hormones (1-dehydrotestosterone, corticosterone and 5beta-pregnan-3,20-dione) and some Triton X compounds. In general, the degree of the pleiotropic response (cross-resistance or collateral sensitivity) correlated with the degree of colchicine resistance in mutant lines. These results are consistent with the pleiotropic phenotype being the result of the same mutation(s) which confer colchicine resistance and support a model for resistance in which the reduced permeability is assumed to be the result of an alteration in the modulation of the fluidity of the surface membrane.

Anesthetics, Local↗
PubMed1992

Collateral sensitivity to nitrosoureas in multidrug-resistant cells selected with verapamil.

We have examined the effects of the nitrosoureas, streptozotocin (STZ) and 1,3-bis(chloroethyl)-1-nitrosourea (BCNU), on a human multiple myeloma cell line, RPMI 8226, and its drug-resistant variants. Cell lines selected for doxorubicin (DOX) resistance alone displayed a STZ and BCNU cytotoxicity profile similar to that of the parent cell line. In contrast, two of the drug-resistant variants selected with DOX plus verapamil, an agent which inhibits P-glycoprotein-mediated multidrug resistance, displayed a collateral sensitivity to STZ and BCNU. Verapamil was included in the selection protocol because it has been shown to inhibit the P-glycoprotein-mediated multidrug resistance phenotype and is now in clinical trials as a chemosensitizing agent. The collateral sensitivity to these nitrosoureas seen in the DOX plus verapamil-selected cell lines is due to the functional loss of a DNA repair molecule, O6-Methylguanine DNA methyltransferase (MGMT). The functional loss of MGMT is secondary to the loss of MGMT gene expression. The loss of MGMT gene expression is not due to loss or gross rearrangement of the MGMT-coding region. If this selection pressure applied in vitro reflects the in vivo situation, then new chemotherapeutic strategies may be devised to exploit this phenomenon. These cell lines will serve as useful models for delineating mechanisms which govern MGMT expression.

Base Sequence↗
PubMed1992

Alteration of type II regulatory subunit of cAMP-dependent protein kinase in human cisplatin-resistant cells as a basis of collateral sensitivity to 8-chloro-cAMP.

A cyclic adenosine 3',5'-monophosphate (cAMP) analogue, 8-chloro-cAMP (8-Cl-cAMP), had a collateral growth-inhibitory effect on a cis-diamminedichloroplatinum(II) (CDDP)-resistant human cancer cell lines (PC-14/CDDP). The non-selective analogues dibutyryl-cAMP, 8-bromo-cAMP and forskolin, which are cAMP agonists, showed far less cytotoxicity than 8-Cl-cAMP in both cell lines. There was no significant difference in cAMP content between PC-14 and PC-14/CDDP. Because 8-Cl-cAMP has been shown to bind selectively to the site I receptor of the type II regulatory subunit (RII) of cAMP-dependent protein kinase, we determined the level of expression of regulatory subunits in PC-14 and PC-14/CDDP cells by photoaffinity labeling. PC-14/CDDP cells had a higher RII level, low site I receptor of type I regulatory subunit (RI) level, and a lower RI/RII ratio than the parental PC-14 cells. Exposure to 8-Cl-cAMP increased the RI and RII level in PC-14/CDDP cells in dose- and time-dependent manners. On the other hand, in parental PC-14 cells, RII was not detected and the levels of RI and RII were not increased by exposure to 8-Cl-cAMP. These results suggested that the change in RI and/or RII levels caused by 8-Cl-cAMP was correlated with 8-Cl-cAMP-induced growth inhibition and that the collateral sensitivity to 8-Cl-cAMP in CDDP-resistant cells was due to the increased RII level. Our results suggest that 8-Cl-cAMP can be used in combination with CDDP and that measurement of RI and RII levels and/or the RI/RII ratio is a useful tool to predict CDDP sensitivity.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMedDate not supplied

Collateral sensitivity to azidothymidine in methotrexate resistant human leukemia cells.

Resistance to methotrexate (MTX) is a well established clinical problem and strategies to circumvent this would obviously be beneficial. The human leukemia cell line, CCRF-CEM, was grown in folinic acid to study MTX resistance-reflecting more in vivo conditions. A 15.8-fold resistant subline, CEM/MTX, was evolved by stepwise increases in MTX exposure. The MTX resistant cell line exhibited both increased dihydrofolate reductase (DHFR) activity due to gene amplification as well as impaired MTX uptake. An additional mechanism of resistance to MTX was a 2-fold increase in thymidine kinase (TK). As a result of this increased TK activity, the CEM/MTX cells were collaterally sensitive to the nucleoside analogue, azidothymidine (AZT). CEM cells resistant to MTX possess properties that can be exploited by AZT and these studies may have clinical implications.

Drug Resistance↗
PubMed1992

Characterization of a cisplatin-resistant human ovarian carcinoma cell line expressing cross-resistance to 5-fluorouracil but collateral sensitivity to methotrexate.

In vitro exposure of the TR170 ovarian carcinoma cell line to six intermittent 24-h treatments with a 90% inhibitory concentration of cisplatin (CDDP) (0.15 micrograms/ml; 0.5 microM) resulted in a 2-fold stably resistant subline designated TR170/CP+ (B.T. Hill et al., Int. J. Cancer, 39: 219-225, 1987). Resistance to CDDP in these CP+ cells has now been associated with reduced uptake of 195mCDDP (2-fold; P less than 0.01) and decreased removal of specific Pt-DNA adducts, quantitated immunochemically, indicative of an apparent increased tolerance of CDDP-induced DNA damage. Specifically these resistant cells appeared deficient in removal of the major cis-Pt-(NH3)2d(pGpG) adduct and the difunctional cis-Pt(NH3)2d(GMP)2 lesion, showed less efficiency in removing cis-Pt(NH3)2d(pApG) adducts, but proved as proficient as the parental cell line in removing DNA-DNA interstrand cross-links. Activities of DNA polymerase-alpha and -beta were comparable in both lines, and no significant alterations in glutathione metabolism were identified. Response to acute X-irradiation was not modified in these TR170/CP+ cells, but they showed marked (10-fold) cross-resistance to 5-fluorouracil and, unusually, proved collaterally sensitive (12-fold) to methotrexate. Resistance to 5-fluorouracil was associated with significantly increased thymidylate synthase activity (P less than 0.01), but this was not reflected in altered gene expression, while increased sensitivity to methotrexate was accompanied by increased drug uptake but by unaltered activity and expression of dihydrofolate reductase. These results indicate that exposure to CDDP can result in numerous alterations, both intracellularly and at the cellular membrane, reflected in significant changes in the tumor cells' responses to the cytotoxic effects of a range of antitumor drugs. The clinical relevance of these observations remains to be established.

Antineoplastic Agents↗
PubMed1989

Differential effect of collaterally sensitive antimetabolites on P388 murine leukemia sensitive and resistant to adriamycin in vitro.

Experiments were carried out in vitro using DNA polymerase and ribonucleotide reductase inhibitors to investigate their cytotoxicity to P388 murine leukemia sensitive (P388/S) and resistant (P388/R) to adriamycin (ADR). DNA polymerase inhibitors such as cytosine arabinoside (ara-C) and aphidicolin elicited comparative inhibition of DNA biosynthesis in both parental and ADR-resistant tumor cells. However, ribonucleotide reductase inhibitors such as hydroxyurea (HU) and caracemide were collaterally more sensitive to P388/R cells. Inosine diglycolaldehyde (Inox) was ineffective in showing such a response. Pretreatment with HU significantly increased intracellular ADR levels and inhibition of RNA biosynthesis by ADR in P388/R cells while, in P388/S cells, sequential or concurrent treatment with HU did not enhance intracellular ADR levels. Mechanisms underlying such an effect, implications due to reduced intracellular ATP levels in drug-resistant cells, and the possible utility of using ribonucleotide reductase as a target in drug-resistant tumors for the therapeutic benefit are discussed.

Animals↗
PubMed1978

[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↗
PubMed2026

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↗
PubMed1990

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↗
PubMed1991

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↗