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PubMed1990

Increased sensitivity to Vinca alkaloids in cells overexpressing calmodulin by gene transfection.

Mouse C127 cells, transfected with the chicken calmodulin (CaM) gene and overexpressing CaM protein, were used to evaluate the effect of elevated levels of CaM on the sensitivity of these cells to various anticancer drugs. Clones C2 and C3 overexpress CaM mRNA by 40- and 80-fold, respectively, and CaM protein 3- and 8-fold, respectively. These cell lines were tested for their sensitivity to vincristine, vinblastine, bleomycin, and Adriamycin by comparing the 50% inhibitory concentration in a 72-h growth inhibition assay. The 50% inhibitory concentration values for vincristine with C2 and C3 cells were 6.27 +/- 0.56 nM and 6.60 +/- 0.96 nM, respectively. These values were significantly lower than 13.9 +/- 0.79 nM for the parental C127 cells and 14.0 +/- 1.55 nM for clone 6.8 (the control cell line for transfection without the chicken CaM gene) at P less than or equal to 0.005. The proliferation of C2 and C3 cells was inhibited at lower concentrations of vinblastine as well. The 50% inhibitory concentration values for the C2 and C3 cell lines were approximately one-half those required for C127 or clone 6.8 cells. However, no significant difference in the sensitivity to the DNA-binding drugs, bleomycin and Adriamycin, was observed between the different cell lines. The uptake of [3H]vinblastine was evaluated and found to be increased 1.6- and 2.8-fold in C2 and C3 cells, respectively, as compared with that value obtained for C127 cells. Moreover, the efflux of [3H]vinblastine from vinblastine-loaded cells was also observed to be decreased in the C2 and C3 cell lines. These data suggest that the increase in CaM expression in the C2 and C3 cell lines might be related to the higher sensitivity of these cells to Vinca alkaloids. This increased sensitivity appears to be due to the increase in intracellular concentration of the Vinca alkaloids as a result of an increase in drug uptake and a decrease in efflux. Moreover, the increased sensitivity of clones C2 and C3 to Vinca alkaloids appears to be specific to this class of drugs in that no collateral effects were observed for the DNA-damaging drugs, Adriamycin and bleomycin.

Animals↗
PubMed1996

Induction of apoptosis in malignant and camptothecin-resistant human cells.

Flow cytometry studies demonstrate that androgen-independent human prostate carcinoma DU-145 cells are arrested at the G1-phase of the cell cycle in the presence of suramin, but they die by apoptosis in the presence of 9-nitrocamptothecin (9NC). The addition of cytostatic concentrations of suramin increases the apoptotic action of 9NC on DU-145 cells, and induces apoptosis in 9NC-resistant DU-145/RC cells that were derived from the parental DU-145 cells by continuous exposure to progressively increased concentrations of 9NC. In addition, the topoisomerase II-directed drug etoposide exerts more extensive apoptotic action on DU-145/RC than DU-145 cells. Increased resistance of DU-145 cells to 9 NC and collaterally increased sensitivity to etoposide and suramin appear to correlate with alterations in the structure rather than synthesis of topoisomerases and possibly with specific cellular proteins that regulate apoptosis. The results suggest that etoposide and suramin may be successful alternative treatments for 9NC-resistant androgen-independent prostate cancer.

Androgens↗
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↗
PubMed1982

Selective cytotoxicity of haloethylnitrosoureas in a carcinoma cell line resistant to bifunctional nitrogen mustards.

A Walker 256 rat carcinoma cell line (WR) has been shown to be resistant to a broad spectrum of bifunctional nitrogen mustards (NM) in cell culture. The parent cell line (WS) from which the WR cells were selected retains marked sensitivity to this class of drugs. Karyotype analysis showed that the parent WS had a chromosome content which was significantly higher than the WR. A number of chromosome marker bands were also distinguishable, indicative of distinct nuclear structural differences. A lack of collateral resistance to haloethylnitrosoureas was demonstrated for the WR cell line. In some cases the sensitivity of the WR to nitrosoureas was greater than that of WS. In addition, the WR could be sensitized to NM by a concomitant addition of a water-soluble carbamoylating agent, N,N'-bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea, which possessed no intrinsic alkylating activity. Since NM and nitrosoureas differ pharmacologically, mainly by the latter's potential to carbamoylate, this reaction would appear to be critical to the cytotoxic properties of nitrosoureas against WR cells. Heretofore, carbamoylation has been considered of little importance to the antitumor properties of nitrosoureas. Moreover, 1-(4-amino-2-methylpyrimidine-5-yl)-methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) has been reported as possessing only minimal carbamoylating potential, as measured in vitro by a lysine assay. While remaining an accurate assay for the modification of the psi-amino groups of lysine, it is possible that the quantitative lysine assay may not predict the physiological carbamoylating potential of ACNU in the Walker cells, since marked cytotoxicity was achieved in both WR and WS by ACNU.

Animals↗
PubMed1986

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↗
PubMed1993

Characterization of a lipophilic antifolate resistance provoked by treatment of mammalian cells with the antiparasitic agent pyrimethamine.

We describe the characterization of an antitumor drug resistance following multiple step selection of hamster cells to the 2,4-diaminopyrimidines (DAP) metoprine, pyrimethamine (Pyr), and trimethoprim (Tmp). Pyr and Tmp are DAP lipophilic antifolates currently used as antiparasitic and antibacterial antibiotics, respectively. Dihydrofolate reductase (DHFR) from hamster cells bore a low or poor affinity to these DAP as compared to the hydrophilic folate antagonist methotrexate (MTX). Metoprine-resistant cells over-expressed DHFR enzyme and consequently displayed a high level of resistance to both hydrophilic and lipophilic antifolates including DAP but maintained wild type sensitivity to pleiotropic drugs involved in multi-drug resistance (MDR). In contrast, although Pyr- and Tmp-resistant cells expressed parental levels of wild type DHFR, they displayed a high degree of resistance to DAP and, surprisingly, to the lipophilic MTX analogs piritrexim (PTX) and trimetrexate (TMTX), while maintaining sensitivity to MTX. These drug-resistant cells maintained wild type mRNA levels of the MDR gene product P-glycoprotein and showed collateral hypersensitivity to pleiotropic drugs. To study the underlying mechanism of this apparently new resistance phenotype, we have employed fluorescein-methotrexate (F-MTX) labeling of cells and its displacement by different antifolates. Parental AA8 and Pyr-resistant cells showed a similar level of F-MTX labeling, however, while DAP, TMTX, and PTX showed an efficient competitive displacement of F-MTX from AA8 cells, Pyr-resistant cells displayed a persistent retention of F-MTX labeling in the presence of high concentrations of these lipophilic antifolates. Pyr-resistant cells showed a wild type displacement of F-MTX with MTX. This DAP resistance phenotype was unstable as it was rapidly lost upon growth under nonselective conditions. Furthermore, when the antifolate resistance levels of Pyr-resistant cells were plotted versus the ratios of the 50% F-MTX displacement values obtained with resistant and parental AA8 cells, a good correlation (r2 > 0.98) was obtained. We conclude that Pyr-resistant cells possess a novel phenotype that derives its resistance to lipophilic antifolates solely from a predominant decrease in the accumulation of DAP and lipid-soluble analogs of MTX.

Animals↗
PubMed1992

Collateral resistance or sensitivity of human larynx carcinoma HEp2 cells resistant to cis-dichlorodiammineplatinum (II) or vincristine sulfate.

Human larynx carcinoma HEp2 cells in tissue culture were repeatedly treated with two chemotherapeutic agents which exhibit distinct mechanisms of action and which differ in mechanisms underlying resistance: cis-dichlorodiammineplatinum (II) (cis-DDP) and vincristine sulfate (VCR). Two schedules of resistance development were used: Acute (cells repeatedly treated with drug for 1 hour in serum-free medium: CA15 and VA15 cells), and continuous (repeatedly treated for 24 hours in complete medium: CK15 and VK15 cells). The sensitivity of cis-DDP resistant (CA15 and CK15 cells) and VCR resistant (VA15 and VK15 cells) sublines to cis-DDP VCR, methotrexate (MTX) and gamma rays was determined by survival assay. The results showed that all sublines became resistant to MTX. Cis-DDP resistant cells became cross-resistant to VCR too. Of VCR resistant sublines, only VK15 cells changed (increased) their sensitivity to cis-DDP. Resistant sublines (except CA15) became sensitive to gamma rays. The degree of resistance or collateral resistance/sensitivity depended on the chemotherapeutic agent used for selection and on the schedule of resistance development. The present data support the idea of complexity of resistance phenomenon. They also emphasize the difficulty and importance of judicious choice of agents that should be given in combined therapy of tumors.

Cell Survival↗
PubMed1986

Approaches to overcome in vivo anti-cancer drug resistance.

Therapeutic efficacy of anticancer drugs against malignant diseases is limited because of the selection and regrowth of drug resistant cells. This problem is compounded by the development of cross-resistance to other useful chemotherapeutic agents which severely limits treatment alternatives. Development of approaches to overcome and/or circumvent drug resistance will depend on the precise understanding of the mechanism(s) of resistance not only at the target tumor cell level (in vitro) but also in vivo. The data on L1210 sensitive to araC transplanted s.c. demonstrated that although target cells are highly sensitive to araC, the lack of in vivo response of solid L1210 cells (s.c.) is primarily due to limited drug delivery to the target. Approaches that would modify these processes should improve on the therapeutic selectivity of this agent. In contrast, in cells where the mechanism of resistance is deletion of a key anabolic enzyme (e.g. CdR kinase), these cells are collaterally sensitive in vitro and in vivo to DAUR. This type of resistance, however, could not be overcome by liposome encapsulation of araC or araCTP. With respect to AM resistance, the concentration of VRP for in vitro reversal of resistance of P-388/AM was difficult to achieve in vivo without significant host toxicity. Continuous infusion of VRP, however, demonstrated that at the maximally tolerated doses of VRP it was not possible to achieve any significant therapeutic effects against P-388/AM. The use of liposomes or modulation by VRP does not appear to be a fruitful approach in overcoming AM resistance, especially in cells which possess a high degree of resistance. Metabolic modulation of FU by dLCF appears to be a promising area of investigation and deserves further investigation concerning quantitation of the intracellular pools of folate and ways to modulate them.

3-Deazauridine↗
PubMed1984

The use of a fluorescent methotrexate probe to monitor the effects of three vinca alkaloids on a mixed population of parental L1210 and gene-amplified methotrexate-resistant cells by flow cytometry.

Cells resistant to methotrexate (L1210/R7A) and possessing an increased level of dihydrofolate reductase due to gene amplification can be detected by the technique of flow cytofluorimetry using a new fluorescent derivative of methotrexate (F-MTX) based on a putrescine linker. Comparative studies of dihydrofolate reductase enzyme and cell growth inhibition following treatment with methotrexate and F-MTX suggest that the two agents possess similar modes of action. In an artificially mixed population of cells sensitive and resistant to methotrexate it is possible, using F-MTX, to recognise and separate distinct cell subpopulations showing differential fluorescence using a fluorescence-activated cell sorter (FACS IV). The selective removal of the resistant cells within a mixed population of sensitive and resistant cells has been demonstrated for 5 X 10(-8) M vinblastine by means of flow cytometry. The effectiveness of the vinca alkaloids decreases in the order vinblastine greater than vindesine greater than vincristine, which previously was shown to be the order of effectiveness in producing collateral sensitivity.

Animals↗
PubMed2005

Potent reversal of multidrug resistance by ningalins and its use in drug combinations against human colon carcinoma xenograft in nude mice.

PURPOSE: To evaluate the pharmacological properties and the possible therapeutic applications of a series of synthetic marine natural product analogs, ningalins (N1-N6), in terms of cytotoxicity, MDR-reversing activity, and enhancement of drug combinations with antitumor agents in vitro and in vivo. METHODS: XTT assays, [3H]azidopine binding to P-glycoprotein (Pgp), cellular accumulation and efflux of labeled drugs were carried out in vitro. Drug combinations using combination index, dose-reduction index, and isobologram were performed in vitro and enhancement of efficacy in drug combinations against human colon carcinoma HCT-116 xenografts were conducted with nude mice. RESULTS: N3 at sub-IC50 cytotoxic concentration (10 microM) was capable of enhancing vinblastine (VBL) cytotoxicity toward human leukemic CCRF-CEM cells about 50,000-fold as measured by the decrease of IC50 of VBL. For CCRF-CEM/VBL1000 (1,500-fold resistant to VBL and overexpressing Pgp), N3 and N5 enhanced VBL cytotoxicity as much as 6.2 million-fold and 210,000-fold, respectively. Moreover, N3 and N5 collaterally made CCRF-CEM/VBL1000 cells 4,000-fold and 130-fold, respectively, more susceptible to VBL than the parent CCRF-CEM cells. In human mammary carcinoma cells MX-1/paclitaxel which were 170-fold resistant to taxol and 38-fold resistant to VBL, N3 was capable of enhancing VBL effect as much as 6,000-fold. Combination therapy on murine P388/doxorubicin (DX) leukemia with DX+N3 or taxol+N3 achieved greater efficacy than the therapy with each drug alone. Impressively, nude mice, bearing human colon carcinoma HCT-116 cells, treated with a suboptimal dosage of taxol in combination with N3, N5 or N6 led to shrinkage of established tumor and achieved total tumor remission, while taxol alone had no tumor disappearance in this xenograft model. Furthermore, the enhancement of antitumor effect by ningalins, at least in parts, are due to inhibiting Pgp which was supported by the observation that the ningalins compete for [3H]azidopine binding to Pgp, increase the cellular accumulation of VBL or taxol, and inhibit drug efflux from the tumor cells. CONCLUSION: The profound enhancement of antitumor cytotoxicity of vinblastine and taxol in vitro by ningalins may have multiple mechanisms including the MDR-reversing effects. The mechanisms for collateral sensitivity by ningalins against sensitive (parent) cells are not yet clear. The marked enhancement of therapeutic effect of taxol by ningalins against xenograft tumors in nude mice suggests potential applications of therapeutic use of ningalins.

Animals↗
PubMed2003

Doxorubicin-resistant, MRP1-expressing U-1285 cells are sensitive to idarubicin.

A doxorubicin-resistant subline (U-1285dox(900)) was derived from the human small cell lung carcinoma cell line U-1285. U-1285dox(900) was exposed to a wide range of anticancer agents to determine its resistance profile. In contrast to U-1285 cells, the resistant subline U-1285dox(900) expressed elevated MRP1 mRNA detected by reversed transcriptase-polymerase chain reaction (RT-PCR) and MRP1 protein analyzed with Western blot. Neither MDR1 mRNA nor P-glycoprotein could be detected in the parental cell line or resistant subline. U-1285dox(900) exhibited high resistance to doxorubicin, epirubicin, daunorubicin, and vincristine, an intermediate resistance to mitoxantrone, and a low resistance to etoposide. A collateral sensitivity to cytosine arabinoside, chlorodeoxyadenosine, and melphalan was observed. The resistance could be reversed by buthionine-sulphoximine and verapamil for all tested drugs. Compared with daunorubicin, resistance to idarubicin was very low, 14-fold and 2.6-fold, respectively. This was associated with a higher accumulation due to a slower transport of idarubicin out of U-1285dox(900) cells.

Area Under Curve↗
PubMed2000

Growth inhibitory effect of a new camptothecin analog, DX-8951f, on various drug-resistant sublines including BCRP-mediated camptothecin derivative-resistant variants derived from the human lung cancer cell line PC-6.

DX-8951f, a new water-soluble camptothecin (CPT) derivative, has been reported to show potent antitumor effects against various tumors in vitro and in vivo. We further evaluated the cytotoxic effect of DX-8951f against eight drug-resistant sublines derived by stepwise exposure of human oat cell carcinoma PC-6 to various drugs. In paclitaxel-, adriamycin-, vincristine- and etoposide-resistant cells, overexpression of P-glycoprotein (P-gp) and a correlative reduction in drug accumulation and typical drug-sensitivity pattern were confirmed. The etoposide-resistant line with the highest P-gp level was cross-resistant also to SN-38, CPT-11 and topotecan (TPT), but not to 9-aminocamptothecin (9-AC), CPT and DX-8951f. SN-38- and CPT-11-resistant cells, of which topoisomerase I activities and levels were similar to those of the parent cells, showed cross-resistance clearly to TPT, 9-AC and mitoxantrone, but hardly to DX-8951f. In these two resistant sublines, the intracellular topotecan level was significantly lower than that in parental PC-6 and the reduced accumulation was found to be mediated by breast cancer resistant protein (BCRP). The cisplatin-resistant variant, which had a 2-fold increase in glutathione content, showed no cross-resistance and the 5-fluorouracil-resistant variant, which had a 50% decrease in glutathione content, exhibited collateral sensitivity to most of the other anticancer agents including DX-8951f. We concluded that DX-8951f showed a potent cytotoxic effect on various types of drug-resistant cells.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1994

Collateral sensitivity of human melanoma multidrug-resistant variants to the polyamine analogue, N1,N11-diethylnorspermine.

Certain N-alkylated analogues of the natural polyamine spermine, such as N1,N11-diethylnorspermine (DENSPM), rapidly deplete intracellular polyamine pools by down-regulating the biosynthetic enzymes, ornithine decarboxylase and S-adenosylmethionine decarboxylase, and by potently up-regulating the polyamine catabolizing enzyme, spermidine/spermine N1-acetyltransferase. On the basis of previously reported antitumor activity in human tumor xenograft model systems, DENSPM is currently undergoing Phase I clinical trials against human melanoma and other solid tumors. The antiproliferative activity of this analogue against the multidrug resistance (MDR) phenotype was examined in three MDR sublines of human melanoma RPMI-7932 cells, which were shown to be 2-to 10-fold resistant to classical MDR agents. These MDR lines had been separately derived using different selecting agents (Lemontt et al., Cancer Res., 48: 6344-6353, 1988). Subline functional resistance due to P-glycoprotein was confirmed by decreased retention of rhodamine 123 relative to parent cells as detected by flow cytometry. Although the three sublines were 2- to 10-fold less sensitive than the parent line to classical MDR-type agents, they were found in dose-response studies to be significantly more sensitive to DENSPM than the parent line. In addition, they showed a distinct cytotoxic response after a 48-h treatment with 10 microM DENSPM, which was not apparent in the parent line. Growth sensitivity of the sublines to the ornithine decarboxylase inhibitor, alpha-difluoromethylornithine, or the S-adenosylmethionine decarboxylase inhibitor, CGP-48664, was found to be similar to parent cells. The ratio of the key biosynthetic enzyme activities for ornithine decarboxylase and S-adenosylmethionine decarboxylase was found to be 3.5- to 5-fold higher in all three sublines, due mainly to increases in the former enzyme. This imbalance produced unusually high putrescine pools. Although DENSPM down-regulation of decarboxylase activities and potent up-regulation of spermidine/spermine N1-acetyltransferase activity occurred similarly in both parent and variant lines, polyamine depletion was greater in the variant lines. Collateral sensitivity of the MDR sublines to DENSPM is partially attributable to the finding that analogue (and spermidine) uptake in the sublines was about 2-fold higher (after 2 h) than in the parent cells. The presence of disturbances in polyamine homeostasis and increased sensitivity to DENSPM in three independently selected cell line variants suggests that they may be generally associated with the MDR phenotype in human melanoma and possibly other tumor cells. The collateral sensitivity of human melanoma MDR variants to DENSPM represents a possible therapeutic indication which should be considered during the ongoing clinical evaluation of this drug.

ATP Binding Cassette Transporter, Subfamily B, Mem↗