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PubMed1993

Evidence of in vitro development of drug resistance to azidothymidine in T-lymphocytic leukemia cell lines (Jurkat E6-1/AZT-100) and in pediatric patients with HIV-1 infection.

Clinical reports indicate that the development of drug resistance to AZT after chronic administration is common. In order to study this phenomenon, the T-cell line Jurkat E6-1 was treated continuously in vitro with low, gradually increased, concentrations of azidothymidine (AZT). Initially, 1 microM AZT significantly retarded the cell line from reaching confluence. However, after 10 weeks the T-cell line was able to grow in 10 microM AZT without any evidence of growth inhibition. Subsequently, cell isolates could grow continuously in the presence of 20, 50, and 100 microM AZT without growth inhibition. These T-cell lines (Jurkat E6-1/AZT-10, Jurkat E6-1/AZT-20, Jurkat E6-1/AZT-50, and Jurkat E6-1/AZT-100) were tested for AZT anabolism using purified [3H]AZT, and the results were compared to the wild-type untreated Jurkat E6-1 cell line. Similar intracellular AZT anabolites concentrations were determined in all cell lines. However, a four- to sixfold lower cellular concentration of mono-, di-, and triphosphate anabolites of AZT was determined in the Jurkat E6-1/AZT-10 cell line after 1 microM AZT incubation and 6.5-fold lower after 10 microM AZT treatment. In general, a five- to sixfold reduction in the phosphorylation rates were estimated in the AZT resistant T-cell line. Pharmacology studies of [3H]AZT in the Jurkat E6-1/AZT-100 cell line showed a much lower level of activation of the pro-drug (28-fold), due to lack of thymidine kinase (TK) activity when compared to the Jurkat E6-1/AZT-10 T-cell line. A similar level of resistance was obtained at the thymidylate (dTMP) kinase level. Concurrently an additional mode of resistance (407-fold) was seen on the incorporation of the AZT triphosphate anabolite (AZTTP) into cellular DNA. The formation of this cell line in a period of < or = 4 months coincides with the evidence of the clinical development of "resistance" to AZT in patients who receive the drug continuously. In addition, these T-cell lines have been infected with HIV, and studies on the development of collaterally sensitive regimens are under way.

Adolescent↗
PubMed1989

Drug selectivity and membrane transport properties of normal human lymphocytes.

This study used Interleukin (IL)-stimulated normal human lymphocytes in culture as a model system to examine membrane transport systems and drug cytotoxicity. Normal peripheral blood mononuclear cells were stimulated with either purified IL-1 or phytohemagglutinin (PHA) and maintained for several months in IL-2. Only 'T' lymphocytes grew in culture. Amino acid transport was compared in PHA-stimulated cells and IL-stimulated cells. Both the PHA- and IL-stimulated lymphocyte cell lines had similar generation times and similar uptake and efflux of cisplatin and methotrexate. Yet, PHA-stimulated cells proved 3- to 5-fold more sensitive to the cytotoxic effects of these drugs. The greater drug sensitivity of the PHA-stimulated cell line was associated with enhanced sodium-dependent methionine transport and altered amino acid transport systems. Differences in the nutrient transport systems are comparable to those previously observed between drug sensitive and resistant cells, and may provide the biochemical basis for cisplatin and methotrexate collateral resistance.

Amino Acids↗
PubMed1995

Relationships between resistance to cisplatin and antifolates in sensitive and resistant tumour cell lines.

Possible relationships between tumour resistance to cisplatin and the folate-based thymidylate synthase (TS) inhibitors, CB3717 and ZD1694 (tomudex), have been investigated in vitro using a panel of tumour cell lines (predominantly human ovarian), either parental or possessing acquired resistance to cisplatin or ZD1694. Across eight parent human tumour cell lines, ZD1694 was the most potent drug (mean IC50 of 1.9 x 10(-8) M), being over 250 times as potent as its prototype CB3717 (mean IC50 of 4.8 x 10(-6) M). In five pairs of acquired cisplatin-resistant human tumour cell lines (three ovarian, one cervical and one testicular) which encompass all of the main known mechanisms of platinum drug resistance, ZD1694, CB3717 and the DHFR inhibitor, methotrexate, all exhibited non-cross-resistance. The cervical line, HX/155cisR, showed collateral sensitivity to ZD1694, CB3717, 5-fluorouracil (FUra) and fluorodeoxyuridine (FdUrd). One cell line, A2780cisR, showed a low level of cross-resistance to FUra (resistance factor, RF, of 1.5) and FdUrd (RF of 3.8). A2780cisR, in common with two other cisplatin-resistant lines, did not possess elevated TS activity compared with its parent. Cisplatin retained activity in four acquired ZD1694-resistant cell lines (encompassing reduced folate transport, elevated TS and defective polyglutamation mechanisms of resistance). Furthermore, combinations of ZD1694 with each of the platinum-based drugs, cisplatin, carboplatin and the recently introduced orally administrable, JM216, all showed additive growth inhibitory effects by median effect analysis. These data suggest that the tumour inhibitory properties of the recently introduced highly potent TS inhibitor, ZD1694, and cisplatin, and, moreover, their respective mechanisms of resistance, do not overlap. Therefore, these drugs may be considered for combination in the clinic.

Antineoplastic Agents↗
PubMed1987

Detection of murine S180 cells expressing a multidrug resistance phenotype using different in vitro test systems and a monoclonal antibody.

Doxorubicin (adriamycin) preconditioned S180 cells were more resistant to doxorubicin. The resistance was detected by three different methods (short-term test, colony assay, tissue culture assay). The doxorubicin-resistant S180 cells express the pleitrop drug resistance phenotype. There exists a multidrug resistance to doxorubicin, dactinomycin (actinomycin D), vincristine and colchicine. In addition, collateral sensitivity was found to fluorouracil (5-fluorouracil) and methotrexate. This multidrug phenotype is in accordance with the pleiotropic phenotype of colchicine-resistant CHO cells. Resistant S180 cells express a glycoprotein of Mr 170 kd determined by indirect immunofluorescence using a monoclonal antibody (Mab 265/F4) to the P-glycoprotein of colchicine-resistant CHO-cells. The P-glycoprotein could be an important prognostic factors for tumors with multidrug resistance.

Animals↗
PubMed1985

Selective toxicity of a new lipophilic antifolate, BW301U, for methotrexate-resistant cells with reduced drug uptake.

Three methotrexate (MTX)-resistant cell lines and their MTX-sensitive counterparts have been used to examine 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methyl-pyrido[2,3-d]pyrimidine (BW301U), a novel lipophilic antifolate, and compare its cytotoxicity with MTX and metoprine. Collateral sensitivity for both BW301U and metoprine was observed in CCRF-CEM/MTX R-cells, where MTX resistance appeared to be primarily due to a deficiency in drug uptake. This was particularly pronounced with BW301U which proved to be as effective in killing CCRF-CEM/MTX R as was MTX with the parental CCRF-CEM cell line. This effect was not seen in other cell lines, L5178Y/MTX or L1210/MTX R, where resistance to MTX was correlated with either an overproduction of 5,6,7,8-tetrahydrofolate:nicotinamide adenine dinucleotide phosphate oxidoreductase EC 1.5.1.3 (DHFR) or with combined uptake defect and increased DHFR levels, respectively. In each case, however, BW301U and metoprine, especially at high concentrations, were more effective than MTX in treating MTX-resistant cells.

Antineoplastic Agents↗
PubMed1994

Multidrug resistance-associated protein gene overexpression and reduced drug sensitivity of topoisomerase II in a human breast carcinoma MCF7 cell line selected for etoposide resistance.

A human breast cancer cell line (MCF7/WT) was selected for resistance to etoposide (VP-16) by stepwise exposure to 2-fold increasing concentrations of this agent. The resulting cell line (MCF7/VP) was 28-, 21-, and 9-fold resistant to VP-16, VM-26, and doxorubicin, respectively. MCF7/VP cells also exhibited low-level cross-resistance to 4'-(9-acridinylamino)-methanesulfon-m-anisidide, mitoxantrone, and vincristine and no cross-resistance to genistein and camptothecin. Furthermore, these cells were collaterally sensitive to the alkylating agents melphalan and chlorambucil. DNA topoisomerase II levels were similar in both wild-type MCF7/WT and drug-resistant MCF7/VP cells. In contrast, topoisomerase II from MCF7/VP cells appeared to be 7-fold less sensitive to drug-induced cleavable complex formation in whole cells and 3-fold less sensitive in nuclear extracts than topoisomerase II from MCF7/WT cells. Although this suggested that the resistant cells may contain a qualitatively altered topoisomerase II, no mutations were detected in either the ATP-binding nor the putative breakage/resealing regions of either DNA topoisomerase II alpha or II beta. In addition, the steady-state intracellular VP-16 concentration was reduced by 2-fold in the resistant cells, in the absence of detectable mdr1/P-gp expression and without any change in drug efflux. In contrast, expression of the gene encoding the MRP was increased at least 10-fold in resistant MCF7/VP cells as compared to sensitive MCF7/WT cells. These results suggest that resistance to epipodophyllotoxins in MCF7/VP cells is multifactorial, involving a reduction in intracellular drug concentration, possibly as a consequence of MRP overexpression, and an altered DNA topoisomerase II drug sensitivity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Methotrexate and gamma-tert-butyl methotrexate transport in CEM and CEM/MTX human leukemic lymphoblasts.

In a continuing investigation of determinants of their 200-fold methotrexate resistance and their collateral sensitivity to gamma-tert-butyl methotrexate, the ability of CEM/MTX cells to transport the two drugs was analyzed and compared with that of CEM cells. The Km and Vmax values for the influx of methotrexate into CEM cells did not differ significantly from those of CEM/MTX cells, and this was the case for gamma-tert-butyl methotrexate as well. Surface binding and influx rates were proportional to cell surface area, but differences in efflux rates and methotrexate uptake were too large to be explained on this basis. Neither methotrexate nor trimetrexate competed with gamma-tert-butyl methotrexate influx in CEM cells. However, both drugs perturbed the gamma-tert-butyl methotrexate steady state in CEM cells, resulting in slightly less uptake than with gamma-tert-butyl methotrexate alone. However, the major difference between the two cell types was in the methotrexate uptake plateau, which was much greater in the case of the parental cell line. A related observation was the more rapid efflux of methotrexate from CEM/MTX cells than from CEM cells. The poor uptake, the associated meager capacity to polyglutamylate methotrexate and the enhanced methotrexate efflux appear to be responsible for its decreased activity against CEM/MTX cells. Half-lives for gamma-tert-butyl methotrexate efflux were the same in both cell lines, allowing the drug to accumulate to cytotoxic levels despite its inability to form polyglutamates.

Cell Line↗
PubMed1986

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↗
PubMed1982

Drug synergy in experimental African trypanosomiasis.

The possibilities of trypanocidal drug synergy have been examined in vitro and in vivo using a monomorphic laboratory strain of Trypanosoma rhodesiense. Twenty-seven different drug pair combinations were chosen from among 12 representative trypanocides on the basis of surmized or reported synergy, evidence of collateral sensitivity in resistant strains, and known differences in modes of action or in field use. In vitro synergy test were made with a transfer plate technique which allows direct isobol determination by microtest tray superimposition. All pairs showing synergy in vitro were tested further in mice. Statistically significant synergy was shown only by suramin and tryparsamide, suramin and Puromycin, and suramin and Berenil. Although six other pairs, of which three contained suramin, showed higher than addictive cure rates, these rates fell short of statistical significance.

Animals↗
PubMed1995

Intracellular pharmacodynamic studies of the synergistic combination of 6-mercaptopurine and cytosine arabinoside in human leukemia cell lines.

Selective combinations of purine and pyrimidine analogs increase remission rates in pediatric patients with relapsed leukemias. The combination of 6-mercaptopurine (6-MP) and cytosine arabinoside (ara-C) may exhibit synergism similar to that observed for fludarabine and ara-C and may diminish the potential for development of resistance since the two drugs are activated by separate enzymatic pathways. To determine the efficacy of the combination against human leukemia cells, we investigated the time-concentration relationships of the drugs given alone or in combination to the resultant cytotoxicity. To determine whether the combination leads to enhanced activity of deoxycytidine kinase (dCk), the rate-limiting enzyme in ara-C activation, we characterized the cellular dCk in CCRF/CEM/0, CCRF/CEM/ara-C/7A, and CCRF/CEM/ara-C/3A monoclonal cells before and after treatment with 6-MP. CCRF/CEM/0 (wild type), CCRF/CEM/ara-C/7A (approximately 50% ara-C-resistant as determined by ara-C sensitivity assay and dCk characterization), and CCRF/CEM/ara-C/3A (approximately 90% resistant to ara-C) human leukemia cells were incubated with various concentrations of 6-MP and ara-C given alone or in combination. Cell survival, inhibition of DNA synthetic capacity (DSC), ara-CTP anabolism, and dCk enzymatic characteristics were studied. Incubation of CEM/0 cells with 6-MP for 24 h, followed by ara-C for 48 h, increased cell-growth inhibition by approximately 0.5-1 log10, corresponding to 5- to 10-fold synergism, as compared with ara-C alone after identical drug incubation in all cell lines. Simultaneous administration showed no synergism, whereas reversal of the sequence produced an antagonistic effect. The ara-CTP levels were 2- to 3.5-fold and 3- to 5-fold higher in CEM/0 and CEM/ara-C/7A cells, respectively, in cells exposed to 6-MP followed by ara-C than in those exposed to ara-C alone at the same concentrations. Furthermore, a progressive increase in ara-CTP levels was noted in CEM/0 cells exposed to increasing concentrations of 6-MP followed by 10 or 20 microM ara-C. A significant decrease in DSC was observed upon treatment of wild-type and ara-C-resistant cells with 6-MP and ara-C. The combination of 6-MP and ara-C exhibits significant sequence-specific synergism in both wild-type and partially ara-C-resistant leukemia cell lines. The combination also exerts collateral sensitivity in the ara-C-resistant cell lines. 6-MP pretreatment may play a role in enhancing ara-C activation, thus producing drug synergism in sensitive and resistant leukemia cell lines.

Arabinofuranosylcytosine Triphosphate↗
PubMed1986

Therapeutic synergism of tiazofurin and selected antitumor drugs against sensitive and resistant P388 leukemia in mice.

Tiazofurin is a synthetic "C" nucleoside analogue with a promising spectrum of experimental antitumor activity and a relatively novel mechanism of action. Previous work in our laboratories had revealed indications of collateral sensitivity and therapeutic synergism for selected murine tumor models treated with tiazofurin alone or in combination with an antimetabolite or an alkylating agent. Elucidation by others of biochemical indicators of tiazofurin activity provided the rationale for extending our studies to include the tiazofurin combinations reported here. Young, adult, female, BALB/c X DBA/2 F1 mice bearing body burdens of about 4 X 10(7) cells at the start of treatment were used. Cells were implanted either i.p. or s.c. Tiazofurin plus cisplatin or the 5'-palmitate of 1-beta-D-arabinofuranosylcytosine (ara-C) was evaluated against the parent P388/O leukemia line. Tiazofurin plus 6-thioguanine was evaluated against the ara-C-resistant P388. All drug treatments were i.p. injections given daily for 9 days. The experimental design permitted comparison of optimal nontoxic single-agent and two-drug combination regimens on the basis of the estimated log10 change in tumor cell burden at the end of treatment. Concurrent untreated control mice bearing tumor burdens ranging from approximately one to 10(7) cells permitted estimates of cells surviving treatment. Optimal treatment with each of these combinations afforded tumor burden reductions that were greater by 1 to 7 orders of magnitude than the effects of the respective single agents. Optimal single-agent and combination dosages (mg per kg per dose) were as follows: tiazofurin, 500; cisplatin, 2.0; the 5'-palmitate of ara-C, 25; 6-thioguanine, 0.8; tiazofurin, 330 plus cisplatin, 0.58; tiazofurin, 220 plus the 5'-palmitate of ara-C, 20; tiazofurin, 100 plus 6-thioguanine, 0.8. The observed therapeutic synergism of these drugs with tiazofurin in animal models suggests the possibility that treatment with tiazofurin combinations may yield clinical results superior to those obtained with the single agents alone. Therapeutic synergism can be most readily maximized when biochemical markers of drug action are available to provide appropriate clinical-laboratory correlations. Extension of these approaches to the use of tiazofurin, for which biochemical markers and experimental combination chemotherapy leads are now available, would support the rational clinical development of tiazofurin combinations.

Animals↗
PubMed1986

Characterization of a new drug-resistant human myeloma cell line that expresses P-glycoprotein.

Multiple myeloma is a disease with a high initial chemotherapeutic response but virtually no cures due to emergence of drug resistance. A doxorubicin-resistant human myeloma cell line (8226/Dox) has been selected from the myeloma cell line RPMI8226 by continuously exposing cells to gradually increasing doses of doxorubicin. The resistant phenotype has been retained for over 2 months despite growth in drug-free medium. The resistant subline was cross-resistant to mitoxantrone, acronycine, etoposide, and vincristine. The 8226/Dox cell line remained sensitive to melphalan but acquired collateral sensitivity to dexamethasone. Intracellular doxorubicin accumulation, as measured by [14C]doxorubicin and high-performance liquid chromatography, was decreased by 54% at 1 h for 8226/Dox compared to the sensitive line. Efflux of doxorubicin was significantly greater in the resistant subline as compared to the sensitive parent cell line. Membrane analysis using immunoblotting techniques detected increased expression of the integral membrane protein P-glycoprotein (Mr 170,000) in the resistant subline. Cytogenetic analysis of 8226/Dox revealed a 7q-anomaly not seen in the parent cell line. No double minutes or homogeneously staining regions were observed. The drug sensitivity/resistance pattern of the resistant cell line correlates well with clinical observations indicating the potential of this cell line as a model for resistance in multiple myeloma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

[The efflux of intracellular vincristine in drug-resistant human lung cancer cells is not mediated by P-glycoprotein].

A subline (PC-9/VCR) of the human lung adenocarcinoma cell line (PC-9), derived by in vitro exposure to vincristine (VCR), exhibited a 10-12-fold resistance to VCR by MTT and HTCA assay. Compared to the parental cell line (PC-9), PC-9/VCR-resistant cells displayed a reduced accumulation of VCR. The rate of VCR efflux was shown to be enhanced by PC-9/VCR. Unlike multidrug resistance, this efflux was independent of P-glycoprotein overexpression as determined by the Northern blotting method. In addition, PC-9/VCR showed no collateral sensitivity to verapamil. This resistant subline only showed 6.9-fold and 2.5-fold cross resistance to colchicine and vinblastine, respectively. This preliminary result indicates that defective drug accumulation in PC-9/VCR is due to other mechanisms possibly involving the microtubule assembly.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Paclitaxel-resistant human ovarian cancer cells have mutant beta-tubulins that exhibit impaired paclitaxel-driven polymerization.

Acquired resistance to paclitaxel can be mediated by P-glycoprotein or by alterations involving tubulin. We report two paclitaxel-resistant sublines derived from 1A9 human ovarian carcinoma cells. Single-step paclitaxel selection with verapamil yielded two clones that are resistant to paclitaxel and collaterally sensitive to vinblastine. The resistant sublines are not paclitaxel-dependent, and resistance remained stable after 3 years of drug-free culture. All cell lines accumulate [3H]paclitaxel equally, and no MDR-1 mRNA was detected by polymerase chain reaction following reverse transcription. Total tubulin content is similar, but the polymerized fraction increased in parental but not in resistant cells following the paclitaxel addition. Purified tubulin from parental cells demonstrated paclitaxel-driven increased polymerization, in contrast to resistant cell tubulin, which did not polymerize under identical conditions. In contrast, epothilone B, an agent to which the resistant cells retained sensitivity, increased assembly. Comparable expression of beta-tubulin isotypes was found in parental and resistant cells, with predominant expression of the M40 and beta2 isotypes. Sequence analysis demonstrated acquired mutations in the M40 isotype at nucleotide 810 (T --> G; Phe270 --> Val) in 1A9PTX10 cells and nucleotide 1092 (G --> A; Ala364 --> Thr) in 1A9PTX22 cells. These results identify residues beta270 and beta364 as important modulators of paclitaxel's interaction with tubulin.

Antineoplastic Agents, Phytogenic↗