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Results for “Collateral sensitivity”

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At least 19 recordsLinked to original sources

PubMed1993

Severe depletion of cellular thiols and glutathione-related enzymes of a carmustine-resistant L1210 strain associates with collateral sensitivity to cyclophosphamide.

Cyclophosphamide (CPA) increased the life span of both carmustine (BCNU)-resistant (L1210/BCNU) and BCNU-sensitive L1210 (L1210/0) leukaemic mice; their sensitivity to CPA, however, was extremely different. The BCNU-resistant strain was much more sensitive (collaterally) to CPA than was its sensitive counterpart. The collateral sensitivity was accompanied by a severe reduction in the activity of glutathione-related enzymes and in protein thiol (SH) and non-protein SH levels in BCNU-resistant cells. The activity of glutathione reductase (GSSG-R) was 2 times higher in the L1210/0 cells than in the L1210/BCNU cells. Glutathione-S-transferase (GST) was also almost 2 times more active in the sensitive cells than in the resistant strain. To develop resistance against CPA with a single treatment (60 mg/kg) per passage, the L1210/BCNU strain needed 26 passages, whereas the L1210/0 strain required significantly fewer. The resistance developed against CPA was associated with a moderate elevation of thiols in the L1210/CPA cells, whereas this elevation was approximately 3 times more pronounced in the L1210/BCNU/CPA cells. The severely reduced activity of GST in the L1210/BCNU strain was markedly increased when these cells were made resistant to CPA; the GSSG-R activity, however, remained low, suggesting an irreversible injury of this enzyme by BCNU.

Animals↗

PubMed1997

In vitro cross-resistance and collateral sensitivity in seven resistant small-cell lung cancer cell lines: preclinical identification of suitable drug partners to taxotere, taxol, topotecan and gemcitabin.

The acquisition of drug-resistant tumour cells is the main problem in the medical treatment of a range of malignant diseases. In recent years, three new classes of anti-cancer agents, each with a novel mechanism of action, have been brought forward to clinical trials. These are the topoisomerase I (topo I) poisons topotecan and irinotecan, which are both camptothecin derivatives, the taxane tubulin stabilizers taxol and taxotere and, finally, the antimetabolite gemcitabin, which is active in solid tumours. The process of optimizing their use in a combination with established agents is very complex, with numerous possible drug and schedule regimens. We describe here how a broad panel of drug-resistant small-cell lung cancer (SCLC) cell lines can be used as a model of tumour heterogeneity to aid in the selection of non-cross-resistant regimens. We have selected low-fold (3-10x) drug-resistant sublines from a classic (NCI-H69) and a variant (OC-NYH) SCLC cell line. The resistant cell lines include two sublines with different phenotypes towards alkylating agents (H69/BCNU and NYH/CIS), two sublines with different phenotypes against topo I poisons (NYH/CAM and NYH/TPT) and three multidrug resistant (MDR) sublines (H69/DAU, NYH/VM, and H69/VP) with combinations of mdr1 and MRP overexpression as well as topoisomerase II (topo II) down-regulation or mutation. Sensitivity to 20 established and new agents was measured in a standardized clonogenic assay. Resistance was highly drug specific. Thus, none of the cell lines was resistant to all drugs. In fact, all resistant cell lines exhibited patterns of collateral sensitivity to various different classes of drugs. The most intriguing pattern was collateral sensitivity to gemcitabin in two cell lines and to ara-C in five drug-resistant cell lines, i.e. in all lines except the lines resistant to topo I poisons. Next, all sensitivity patterns in the nine cell lines were compared by correlation analysis. A high correlation coefficient (CC) for a given pair of compounds indicates a similar pattern in response in the set of cell lines. Such data corroborate the view that there is cross-resistance among the drugs. A numerically low coefficient indicates that the two drugs are acting in different ways, suggesting a lack of cross-resistance between the drugs, and a negative correlation coefficient implies that two drugs exhibit collateral sensitivity. The most negative CCs (%) to the new drug leads were: taxotere-carmustine (BCNU) (-75), taxol-cisplatin (-58), ara-C-taxol (-25), gemcitabin-doxorubicin (-32), camptotecin-VM26 (-41) and topotecan-VP16 (-17). The most negative correlations to the clinically important agent VP-16 were: cisplatin (-70); BCNU (-68); camptothecin (-38); bleomycin (-33), gemcitabin (-32); ara-C (-21); topotecan (-17); melphalan (-3); and to the other main drug in SCLC treatment cisplatin were: doxorubicin (-70); VP-16 (-70); VM-26 (-69); mAMSA (-64); taxotere (-58); taxol (-58). Taxol and taxotere were highly correlated (cross-resistant) to VP-16 (0.76 and 0.81 respectively) and inversely correlated to cisplatin (both -0.58). Similarly, camptothecin and topotecan were correlated to cisplatin but inversely correlated to VP-16 and other topo II poisons. From the sensitivity data, we conclude that collateral sensitivity and lack of cross-resistance favours a cisplatin-taxane or topo I-topo II poison combination, whereas patterns of cross-resistance suggest that epipodophyllotoxin-taxane or topo I poison-cisplatin combinations may be disadvantageous.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1993

Antitumor alkylating agents: in vitro cross-resistance and collateral sensitivity studies.

Cell lines resistant to five antitumor alkylating agents (CDDP, PAM, 4-HC, HN2, and BCNU) were developed from five parental human tumor lines representative of solid tumors with a range of sensitivities to antitumor alkylating agents. The parental cell lines were SCC-25 squamous carcinoma of the head and neck, MCF-7 breast carcinoma, SW2 small-cell lung cancer, SL6 non-small-cell lung carcinoma, and G3361 melanoma. Survival curves using colony formation as the endpoint were generated for each of the 25 cell lines to each of the five alkylating agents. Comparison of the drug concentrations that reduced the survival of the alkylating agent-resistant cell lines by 90% (IC90 values) with the IC90 values obtained for the corresponding parental cell lines was used as a measure of the resistance/sensitivity of the alkylating agent-resistant lines to each drug tested. Although cross-resistance among the alkylating agents was generally uncommon, several patterns of response emerged. Cross-resistance occurred in 27 of the 105 determinations and occurred most frequently in the cell lines in which resistance was developed to PAM (57%) or BCNU (38%). Cross-resistance to HN2 occurred most frequently. Collateral sensitivity was equally as common, occurring in 25 of the 105 determinations. Collateral sensitivity occurred most frequently in the cell lines made resistant to 4-HC. The 4-HC-resistant cell lines were most frequently collaterally sensitive to PAM and to BCNU. Cross-resistance developed most frequently in the MCF-7 breast carcinoma and SCC-25 squamous-cell carcinoma cell lines, whereas collateral sensitivity developed most frequently in the SW2 small-cell lung cancer line and the G3361 melanoma cell line and least frequently in the MCF-7 breast carcinoma cell line and the SL6 non-small-cell lung cancer cell line. The implication of these findings for the development of strategies for clinical treatment are discussed.

Alkylating Agents↗

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↗

PubMed1984

Collateral sensitivity of a methotrexate-resistant L1210 cell line to the vinca alkaloids.

L1210 mouse leukaemia cell lines showing a 20,000-fold differential sensitivity to methotrexate have been shown to exhibit some collateral sensitivity to at least two of the vinca alkaloids, vinblastine and vindesine. Vinblastine is the more cytotoxic for both cell lines. The extent of the collateral sensitivity decreases in the order vindesine greater than vinblastine greater than vincristine. Total cellular uptake studies with radiolabelled methotrexate showed only a two- to three-fold greater incorporation in the sensitive line. On the other hand, a two-fold greater incorporation of labelled vincristine occurred in the resistant line. No significant difference in the uptake occurred following labelled vinblastine treatment by the two cell lines. It is unlikely that differences in uptake account for the altered drug responses observed in the two cell lines.

Animals↗

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↗

PubMed1995

Collateral sensitivity to radiation and cis-platinum in a multidrug-resistant human leukemia cell line.

Although collateral sensitivity to gamma radiation has previously been described in multidrug-resistant tumor cell lines, we describe here a multidrug-resistant human T-cell acute lymphatic leukemia cell line, L100, which displayed increased sensitivity to both gamma radiation and cis-platinum. Cis-platinum cytotoxicity of parental L0 cells and L100 cells was enhanced, whereas radiation sensitivity of L0 and L100 cells was unaltered by glutathione depletion. These results indicate that disparate mechanisms are operative in the collateral sensitivity of L100 cells to gamma radiation and cis-platinum.

Antineoplastic Agents↗

PubMed1994

Cross-resistance to antitumor diarylsulfonylureas and collateral sensitivity to mitochondrial toxins in a human cell line selected for resistance to the antitumor agent N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)urea.

Diarylsulfonylurea (DSU) antitumor agents represent a new class of oncolytic compounds with an unknown, potentially novel, mechanism of action. At high concentrations of several of these agents, cytotoxicity appears to be a consequence of uncoupling of mitochondria. However, the mechanism of action at pharmacologically achievable concentrations is unknown. To further study these agents a subline of human colon carcinoma, GC3/c1, was selected for resistance to N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)urea (ISCU) (Sulofenur). This clone (designated LYC5) was stably resistant for 2 years in the absence of selection pressure and was characterized for cross-resistance to other antitumor DSU and therapeutically used oncolytic agents. LYC5 was cross-resistant to six of seven DSU analogues examined when cells were exposed to drugs for 7 days. However, the degree of resistance was inversely related to the potency of the individual DSU against the parental GC3/c1 clone. Consequently, against LYC5 cells there was a relatively narrow range for concentrations inhibiting colony formation by 50% (4-fold), compared with that in GC3/c1 cells (12-fold range). With a single exception, each DSU examined caused uncoupling of oxidative phosphorylation in isolated mitochondria at 50 microM, and data suggest that cytotoxicity in LYC5 cells may be a consequence of mitochondrial impairment. In contrast, LYC5 cells were collaterally sensitive to the mitochondrial toxins rotenone, antimycin, and oligomycin, by 11.4-, 7.2-, and 36.9-fold respectively. LYC5 cells were also collaterally sensitive to vincristine (7.7-fold), Actinomycin D (5.9-fold), and rhodamine-123 (10.5-fold), agents associated with P-glycoprotein (Pgp)-mediated multidrug resistance (MDR). LYC5 cells were slightly more sensitive to Melphalan and doxorubicin (2.8- and 2.3-fold, respectively) but not to cisplatin or dideazatetrahydrofolic acid. Collateral sensitivity to vincristine and Actinomycin D was consistent with decreased Pgp levels in LYC5 cells. Immunohistochemical staining and Western blotting with anti-Pgp antibodies indicated an 8-fold reduction in Pgp levels in LYC5 cells, relative to expression in parental GC3/c1 cells. Consequently, association of mitochondrial toxins with resistance in MDR KB8-5 cells was examined in the presence or absence of the MDR-reversing agent verapamil. KB8-5 cells had equal or greater sensitivity, compared with parental KB3-1 cells, to rotenone, antimycin, and oligomycin and also to each DSU analogue examined. In addition, verapamil tended to have a protective effect against these mitochondrial toxins.(ABSTRACT TRUNCATED AT 400 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗

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↗

PubMed1986

Potential of continuous tumour cell lines for establishing patterns of cross-resistance and collateral sensitivity in vitro.

The potential value of continuous tumour cell lines for establishing in vitro patterns of cross-resistance and collateral sensitivity has been examined. Results are presented for a series of sublines of the murine L5178Y lymphoma in which resistance has been induced in vitro by repeated exposure to the following antitumour drugs: methotrexate, 5-fluorouracil, adriamycin, vincristine and vindesine. A comparison has also been made between data derived from a murine (L5178Y) and a human tumour (LoVo) cell line, derived from a colon carcinoma, in which 5-fluorouracil resistance has been induced. Preliminary results suggest that the human tumour model may be more relevant clinically. It has also been demonstrated that prior exposure to fractionated X-irradiation in vitro can result in the expression of resistance or collateral sensitivity, depending on the drug evaluated. Furthermore, the expression of cross-resistance to certain drugs appears to differ, depending on the method used to induce or select for resistance in vitro. If confirmed, these latter observations may have major clinical implications for the combined modality approach to cancer treatment.

Animals↗

PubMed1994

Increased expression of DNA topoisomerase I gene and collateral sensitivity to camptothecin in human cisplatin-resistant bladder cancer cells.

We established three cis-diamminedichloroplatinum(II) (cisplatin)-resistant cell lines, T24/DDP5, T24/DDP7, and T24/DDP10, by the stepwise exposure of T24 human bladder cancer cells to increasing concentrations of cisplatin. The resistance to cisplatin of T24/DDP5, T24/DDP7, and T24/DDP10 cells was 2.2-, 5.2-, and 8.4-fold that of the parental T24 cells, respectively. The cisplatin-resistant cell lines also showed an increased resistance to vincristine, although their sensitivities to Adriamycin and etoposide resembled that of T24. In contrast, the cisplatin-resistant cells developed a collateral sensitivity to (4s)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)carbonyl oxy]dione hydrochloride trithydrate, a camptothecin derivative, and its active metabolite, 7-ethyl-10-hydroxy-camptothecin, that targets DNA topoisomerase I. Both a Northern blot analysis and an immunoblot analysis demonstrated increased cellular levels of DNA topoisomerase I mRNA in the resistant cell lines. However, the expression of DNA topoisomerase II in the three resistant cell lines did not differ significantly from that in the T24 cells. No significant differences in the glutathione S-transferase pi levels were observed, although the intracellular content of glutathione in the T24/DDP7 cells was slightly but significantly increased. In addition, the intracellular platinum concentration correlated negatively with the degree of cisplatin resistance and was found to be significantly decreased in T24/DDP10 at an external cisplatin concentration of 20 micrograms/ml. These results suggest that the increased levels of DNA topoisomerase I mRNA thus play an important role in cisplatin resistance and produce a collateral sensitivity to (4s)-4,11-diethyl-4-hydroxy-9[(4-piperidinopiperidino)carbonylo xy]dione hydrochloride trithydrate and 7-ethyl-10-hydroxycamptothecin in these cisplatin-resistant bladder cancer cell lines. In addition, the presence of decreased intracellular cisplatin accumulation may also contribute to the acquisition of resistance to cisplatin in these cell lines.

Blotting, Northern↗

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↗

PubMed1996

Cross resistance and collateral sensitivity between cytotoxic drugs and radiation in two human bladder cell lines.

The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) test was employed as a means of studying the cross resistance and collateral sensitivities of two bladder cell lines able to grow in the presence of several antineoplastic drugs and/or despite the effects of radiotherapy. This cross resistance and collateral sensitivities were investigated in the context of two antineoplastic drugs (i.e. doxorubicin (an anthracycline) and vinorelbine (a Vinca alkaloid) and radiotherapy. The results show that cell lines able to grow in the presence of anticancer drugs develop a significant degree of resistance to antineoplastic compounds and may also develop resistance to radiotherapy. On the other hand, most cell lines treated first with radiotherapy develop a significant degree of resistance towards ionizing radiation and may also display increased sensitivity towards anticancer drugs. If these results obtained in vitro are clinically relevant, they may have important applications in the treatment of patients. Nevertheless, it will be necessary to validate the results on extensive series of chemo- and/or radioresistant cell lines exhibiting different mechanisms of resistance.

Antibiotics, Antineoplastic↗

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↗

PubMed2005

Concentration-dependent collateral sensitivity of cisplatin-resistant gastric cancer cell sublines.

The cisplatin-resistant gastric cancer cell sublines, SNU-601/Cis2 and /Cis10, were 49 and >530 times more resistant to cisplatin, respectively, compared with the drug-sensitive cells, SNU-601/WT. The SNU-601/Cis2 showed cross-resistance to carboplatin, heptaplatin, doxorubicin, mitomycin C, and 5-fluorouracil compared with the SNU-601/WT whereas the SNU-601/Cis10 displayed collateral sensitivity to these drugs with the exception of cisplatin compared with the SNU-601/Cis2, suggesting that the cross-resistance and collateral sensitivity of cisplatin-resistant gastric cancer cells are dependent upon cisplatin concentrations. Altered expression of the antioxidant and transporter genes (metallothionein, catalase, superoxide dismutases, P-glycoprotein, and the breast cancer resistance protein) was involved in these phenotypes of the cisplatin-resistant gastric cancer cell lines.

Antineoplastic Agents↗

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↗

PubMed1982

Collateral sensitivity of 6-mercaptopurine-resistant sublines of P388 and L1210 leukemia to the new purine antagonists, 5-carbamoyl-1H-imidazol-4-yl piperonylate and 4-carbamoylimidazolium 5-olate.

Two new purine antagonists, 5-carbamoyl-1H-imidazol-4-yl piperonylate (SL-1250) and 4-carbamoylimidazolium 5-olate (SM-108), were investigated for their antitumor activities against 6-mercaptopurine (6-MP)-resistant sublines of P388 and L1210 leukemia. It was found that both resistant sublines exhibited collateral sensitivity instead of cross-resistance to these new antipurine drugs. Since more potent cytotoxic activities of these drugs against 6-MP-resistant cells were observed even in vivo cell culture systems, this collateral sensitivity was proved on a cellular basis. Biochemical studies revealed that 6-MP-resistant sublines of both P388 and L1210 leukemia are deficient in hypoxanthine-guanine phosphoribosyltransferase activity. In these cells, not only the activation of 6-MP to its nucleotide but also the synthesis of guanosine 5'-monophosphate via the salvage pathway seems to be severely restricted. However, SL-1250 and SM-108 can be activated to their nucleotide even in these 6-MP-resistant cells because the activation of these compounds is proceeded by adenine phosphoribosyltransferase. In conclusion, suppression of de novo purine synthesis with SL-1250 and SM-108 seems to be a very efficient means of killing these 6-MP-resistant cells, which lack a salvage pathway for guanosine 5'-monophosphate.

Animals↗

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↗