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Results for “Drug Collateral Sensitivity”

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PubMed1991

Folate transport and the modulation of antifolate sensitivity in a methotrexate-resistant human breast cancer cell line.

The mechanism of acquired methotrexate-resistance in an estrogen-receptor positive human breast cancer cell line (MTX(R)ZR-75-1) was studied. MTX(R) ZR-75-1 cells are 250-fold resistant to methotrexate when grown in the presence of 1 microM folinic acid and 2,400-fold resistant in the presence of 1 microM folic acid. This drug resistant cell line also showed collateral sensitivity (10-fold) to trimetrexate (TMQ), when grown in the presence of folinic acid. Using fluoresceinated methotrexate (F-MTX), FACS analysis indicated that there is no intracellular accumulation of methotrexate into MTX(R) ZR-75-1 cells, as determined by competition of F-MTX and methotrexate binding to dihydrofolate reductase. These characteristics strongly indicate that the mechanism of resistance involved down regulation of the reduced-folate transporter. To investigate this further, the transport kinetics of parental and MTX(R) ZR-75-1 cells were examined. Although the V(max) for methotrexate transport in wild-type (WT) ZR-75-1 breast cancer cells was 1-2 orders of magnitude lower than that in the well characterized leukemia cell lines, such as L1210 and CCRF-CEM cells, kinetic analysis indicated that transport of methotrexate into WT ZR-75-1 cells involved a mechanism that was similar if not identical to the reduced folate transporter. In contrast, no specific uptake of methotrexate was detected in MTX(R) ZR-75-1cells. Furthermore, neither cell line expressed detectable levels of folate binding protein, a binding protein with high affinity for folic acid as well as for reduced folates and antifolates. These results indicate that the level of expression of the reduced-folate carrier may be an important factor in determining the sensitivity of breast cancer cells as well as leukemia cells to antifolate compounds.

Animals↗

PubMed1988

Differential patterns of anti-tumour drug responses and mechanisms of resistance in a series of independently-derived VP-16-resistant human tumour cell lines.

Resistance to etoposide, which was expressed following exposure of a human tumour cell line (HN-I) to fractionated X-irradiation (II fractions to a total dose of 50Gy), was found to be exhibited after delivery of only 5 fractions (total dose of 22.5Gy). In addition, 2 new etoposide-resistant sublines of these HN-I cells have been developed by continuous exposure in vitro to sublethal drug concentrations. No significant differences in growth characteristics were shown between all these resistant sublines and the parental line. The drug-treated line, HN-I/VP-2, expressed cross resistance to vincristine, adriamycin and daunomycin, and marginal cross resistance to vinblastine and cisplatin. The X-irradiation-treated subline (HN-I/DXR-II) also proved cross-resistant to vincristine and marginally cross-resistant to vinblastine, but showed unaltered responses to adriamycin and daunomycin, and expressed marginal collateral sensitivity to cisplatin. Comparisons of drug-uptake characteristics showed that only the HN-I/VP2 cells and not the HN-I/DXR-II cells had reduced uptake of vincristine, vinblastine and daunomycin. However, etoposide uptake was not altered in either resistant subline. Further investigations have shown that the approximately 4-fold level of resistance to etoposide in these HN-I/VP-2 and HN-I/DXR-II cells was associated with a reduction in etoposide-induced DNA single-strand breakage. However, repair of these lesions, after drug removal, was rapid and similar in the parental and drug-resistant sublines, with 50% having resealed within 20-26 min. Resistance to etoposide was also associated with significantly elevated (p less than 0.01) glutathione peroxidase activity in both sublines, whilst glutathione S-transferase activity was marginally elevated (117%) only in the HN-I/DXR-II cells. There were no significant alterations in total glutathione levels. These results suggest that not only do patterns of response to anti-tumour drugs differ depending upon the agent employed to "induce" resistance, but that multiple mechanisms appear to be associated with these altered responses.

Antineoplastic Agents↗

PubMed1984

Biochemical pharmacology of the lipophilic antifolate, trimetrexate.

Trimetrexate is a novel lipophilic folate antagonist that causes growth inhibition, inhibition of nucleic acid biosynthesis, and cytotoxicity at nanomolar concentrations in tissue cultures. The potency of trimetrexate cytotoxicity against most cell lines is greater than that of methotrexate. Trimetrexate has antitumor activity in vivo in several murine leukemia and solid tumor systems, including tumors in which methotrexate is inactive. Antitumor activity was seen following oral, intravenous, or intraperitoneal administration. Trimetrexate causes a pronounced and early depression in incorporation of deoxyuridine into DNA. In tumor cell lines resistant to methotrexate because of a drug transport defect, trimetrexate retains activity. In many such cases the methotrexate-resistant tumors show collateral sensitivity to trimetrexate. In methotrexate-resistant cells with impaired drug transport, trimetrexate sensitivity was even more pronounced when cells were grown in folate-free medium supplemented with physiological levels of tetrahydrofolate cofactor. In the human tumor stem cell colony assay, trimetrexate, at concentrations achievable in vivo, gave activity against many human tumors, including samples that were unresponsive to methotrexate. Trimetrexate crosses the blood-brain barrier, and at very high doses may cause neurotoxicity. At conventional doses the primary toxic effects in mice are gastrointestinal. This toxicity is reversible at therapeutic doses. Unlike earlier lipophilic antifolates, trimetrexate has rapid plasma clearance (t1/2 in mice of 45 minutes). Trimetrexate is a tight-binding competitive inhibitor of dihydrofolate reductase. The Ki,slope for inhibition of the human enzyme was 4 X 10(-11) M. A dose-dependent decrease in cellular purine ribonucleotide pools is given by trimetrexate. Pyrimidine ribonucleotide pools tend to increase in treated cells. Trimetrexate caused a marked depression of cellular pools of dTTP and dGTP, and a lesser depression in dATP. Cytotoxicity of trimetrexate in vitro was prevented by leucovorin. Leucovorin also protected mice from trimetrexate toxicity. Thymidine protected cells from lethal effects of low concentrations of trimetrexate, but not from high concentrations. The combination of thymidine and hypoxanthine completely protected cells from low and high concentrations of trimetrexate. A new, stable and highly water-soluble formulation of trimetrexate has been developed. Because of the interesting biochemical and pharmacological properties of trimetrexate, and its experimental antitumor activity, clinical trials are planned.

Animals↗

PubMed1989

Equilibrium, kinetic and photoaffinity labeling studies of daunomycin binding to P-glycoprotein-containing membranes of multidrug-resistant Chinese hamster ovary cells.

The binding of daunomycin and its Bolton-Hunter derivative iodomycin to plasma membranes isolated from multidrug-resistant Chinese hamster ovary cells (CHO B30) and their drug-sensitive parents (B1) was investigated. The thermodynamics and kinetics of equilibrium binding monitored by fluorescence titrations and temperature-jump relaxation spectrometry were compared with the specificity of covalent photolabeling with [3H]daunomycin and [125I]iodomycin. The facts that the uptake of anthracycline from aqueous solution into the CHO membranes was not accompanied by any substantial increase of fluorescence anisotropy nor by any spectral shift of the fluorescence emission spectrum and that the partition ratio into the membrane was 20-30-fold higher when compared to a lecithin bilayer, provided evidence that the non-covalent drug binding sites are constituted by polar protein domains without any substantial contribution from the surrounding lipids. Photoaffinity labeling with nanomolar concentrations of anthracycline and equilibrium binding curves independently showed that a 150-170-kDa plasma membrane glycoprotein (P-glycoprotein), whose overexpression is the major difference between B1 and B30 membranes, provides the binding sites of highest affinity for daunomycin and iodomycin (K approximately equal to 4 x 10(7) M-1). Comparison of photolabeling and equilibrium data suggested that the same binding sites on P-glycoprotein were most probably being monitored. The photolabeling of P-glycoprotein by iodomycin was inhibited in a dose-dependent manner by other compounds to which multi-drug-resistant cells are either resistant or collaterally sensitive with the following orders of effectiveness: vinblastine greater than verapamil greater than nitrendipine greater than daunomycin much greater than colchicine. Temperature-jump experiments covering the time range of 1 microseconds to 1 s revealed a single concentration-dependent relaxation time of 10-30 microseconds. The association of daunomycin with its binding sites in the membranes was found to be a diffusion-controlled process with kon rates of 2-4 X 10(9) M-1 s-1. Therefore, the selectivity of drug binding was entirely reflected in the dissociation rates.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

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↗

PubMed2004

Gene expression profiles in the cellular response to a multinuclear platinum complex.

We used cDNA arrays to monitor modulation of mRNA expression after exposure to a multinuclear platinum complex (BBR3464) in a human cervix squamous cell carcinoma cell line (A431) and in a cisplatin-resistant subline (A431/Pt) exhibiting collateral sensitivity to BBR3464. In parental A431cells, the drug induced at least twofold up-regulation of 15 genes including cell cycle and growth regulators, tumor suppressors and signal transduction genes. In cisplatin-resistant A431/Pt cells, BBR3464increased the expression of 15 genes such as apoptosis regulators and genes involved in the DNA damage response. Interestingly, BBR3464induced up-regulation of anti-metastatic factors together with down-regulation of several pro-metastatic factors. Cell cycle analysis indicated a marked G2arrest in treated A431cells, whereas an apoptotic response was documented in A431/Pt cells. These differential patterns of transcriptional profile in sensitive and resistant cells are consistent with a role for cell cycle regulation in the response to BBR3464.

Antineoplastic Agents↗

PubMed1997

Multienzyme-mediated stable and transient multidrug resistance and collateral sensitivity induced by xenobiotics.

BACKGROUND: Determinants of cellular sensitivity to anticancer drugs include enzymes that catalyze their biotransformation. Coordinated induction of some of these enzymes is known to be caused by a number of dietary constituents, environmental contaminants, pharmacological agents and other xenobiotics, e.g. 3-methylcholanthrene and catechol. Despite the potential for inducing simultaneous changes in tumor cell sensitivity to a wide range of drugs, scant attention has been paid to the impact that dietary constituents and other xenobiotics might have on the therapeutic outcome of cancer chemotherapy. PURPOSE: The aim of this investigation was to demonstrate the potential of xenobiotic-induced multienzyme-mediated stable and transient multidrug resistance/collateral sensitivity in a model system. METHODS: Human breast adenocarcinoma MCF-7/0 cells and a stably oxazaphosphorine-resistant subline thereof, MCF-7/OAP, were grown in the presence of 3-methylcholanthrene (3 microM), catechol (30 microM), or vehicle for 5 days. Spectrophotometric and spectrofluorometric assays were used to quantify catalytic activities and thus cellular levels of cytosolic class 3 aldehyde dehydrogenase, glutathione S-transferase, DT-diaphorase, UDP-glucuronosyl transferase and cytochrome P450 1A1. A colony-forming assay was used to quantify cellular sensitivities to several anticancer drugs. RESULTS: Relative to their untreated counterparts, MCF-7/0 and MCF-7/OAP cells treated with 3-methylcholanthrene or catechol transiently expressed elevated levels of cytosolic class 3 aldehyde dehydrogenase, glutathione S-transferase, DT-diaphorase and UDP-glucuronosyl transferase, and were transiently, more resistant to mafosfamide, melphalan, and mitoxantrone, and more sensitive to EO9. Further, MCF-7/0 and MCF-7/OAP cells treated with 3-methylcholanthrene, but not those treated with catechol, transiently expressed elevated levels of cytochrome P450 1A1 and were transiently more sensitive to ellipticine. Relative to MCF-7/0 cells, MCF-7/OAP cells stably overexpressed all but cytochrome P450 1A1 and were stably, more resistant to mafosfamide, melphalan and mitoxantrone, and more sensitive to EO9. Inclusion of relatively specific inhibitors of, or alternative substrates for, the enzymes of interest during drug exposure negated the influence of enzyme overexpression on cellular sensitivities to these agents. Untreated, and 3-methylcholanthrene- or catechol-treated, MCF-7/0 and MCF-7/OAP cells were equisensitive to vincristine and nearly so to doxorubicin. CONCLUSIONS: Collectively, these experiments illustrate the potential for both stable and transient xenobiotic-induced multienzyme-mediated multidrug resistance/collateral sensitivity that, although also the result of a single event, is mechanistically different from, and pertains to a largely different group of anticancer agents than does, the multidrug resistance caused by cell surface multidrug transporters.

Adenocarcinoma↗

PubMed1995

Establishment and characterization of non-small cell lung cancer cell lines resistant to mitomycin C under aerobic conditions.

To elucidate the mechanisms of acquired resistance to mitomycin C (MMC) in non-small cell lung cancer (NSCLC), we established two MMC-resistant NSCLC sublines by continuous exposure to MMC, using PC-9 as a parent cell line. The sublines, PC-9/MC2 and PC-9/MC4, were 6.4- and 10-fold more resistant to MMC than their parent cell line, respectively, at the IC50 value as determined by MTT assay. They exhibited cross-resistance to EO9, but were not resistant to cisplatin, vindesine, etoposide, carboquone, or KW-2149, a novel MMC derivative. They were collaterally sensitive to adriamycin and menadione. Accumulation of the drug was decreased in the resistant sublines to about 60% of that in the parent cells. Cytosolic DT-diaphorase (DTD) activities were decreased to 13.5 +/- 3.2 in PC9/MC2 and 1.3 +/- 0.6 in PC-9/MC4 from 261.5 +/- 92.7 nmol/min/mg protein in the parent PC-9. NADH:cytochrome b5 reductase activities in both of the resistant cell lines were significantly decreased as compared to that in the parent cell line. Addition of dicumarol resulted in a two-fold increase in IC50 value in PC-9, whereas the IC50 value showed no change in PC-9/MC4. Moreover, dicumarol did not affect the sensitivities to KW-2149 but decreased the sensitivities to EO9 in both the parent and the resistant cell lines. Formation of an alkylating metabolite was significantly decreased in the resistant cells, in parallel to the degree of resistance. We concluded that deficient drug activation due to decreased DTD activity was important as a mechanism of resistance to MMC in PC-9, a relatively DTD-rich NSCLC cell line.

Aerobiosis↗

PubMed1982

Biochemical correlates of responsiveness and collateral sensitivity of some methotrexate-resistant murine tumors to the lipophilic antifolate, metoprine.

The M5076 murine "ovarian" tumor which is naturally refractive to methotrexate was found to be highly responsive to the lipophilic antifolate, metoprine. M5076 cells were markedly deficient in mediated entry of methotrexate. This was in contrast to the L1210 leukemia, a tumor highly responsive to methotrexate but poorly responsive to metoprine. Two L1210 leukemia sublines, with acquired resistance to methotrexate by virtue of a deficiency in mediated entry of drug similar to that seen for M5076 cells, were found to be collaterally sensitive to metoprine. The insensitivity to methotrexate of the M5076 tumor and the two L1210 sublines is associated with low saturability (high Km) and reduced capacity (low Vmax) for mediated influx of drug. 5-Methyltetrahydrofolate, the major circulating folate in blood but not metoprine, shares this mediated route for entry. Therefore, a relatively low level of accumulation of this natural folate in these methotrexate-resistant tumors, in the face of a metoprine-induced blockade at the level of dihydrofolate reductase, probably accounts for the high sensitivity of these tumors to this lipophilic agent. Evidence for this notion was derived during transport and growth experiments in vitro using 5-formyltetrahydrofolate as a model folate coenzyme. The value for influx Vmax of this folate compound in a transport-deficient methotrexate-resistant subline compared to the parental L1210 was reduced to the same extent as that shown for methotrexate. Growth of this resistant L1210 subline showed a greater requirement for this model compound than did the parental line. Also, the concentration necessary for 50% inhibition by metoprine in the presence of this reduced folate was lower in the resistant subline. Inhibition of each cell line by metoprine, on the other hand, was the same when folic acid was used as the folate source. The implications of these findings for the use of lipophilic antifolates as alternative therapy for some methotrexate-resistant tumors are discussed.

Animals↗

PubMed2000

Selection of human leukemic CEM cells for resistance to the DNA topoisomerase II catalytic inhibitor ICRF-187 results in increased levels of topoisomerase IIalpha and altered G(2)/M checkpoint and apoptotic responses.

ICRF-187 is a bisdioxopiperazine anticancer drug that inhibits the catalytic activity of DNA topoisomerase (topo) II without stabilizing DNA-topoII cleavable complexes. To better understand the mechanisms of action of and resistance to topoII catalytic inhibitors, human leukemic CEM cells were selected for resistance to ICRF-187. The clones CEM/ICRF-8 and CEM/ICRF-18 are approximately 40- and 69-fold resistant to ICRF-187, and 12- and 67-fold cross-resistant to ICRF-193, respectively, but are sensitive to other topoII catalytic inhibitors (merbarone and aclarubicin), as well as collaterally sensitive to the DNA-topoII complex-stabilizing drug etoposide (VP-16). Both the number of VP-16- induced DNA-topoII complexes formed and the amount of in vitro topoII catalytic activity are enhanced in the drug-resistant cells. The ICRF-187-resistant clones contain approximately 5-fold increase in topoIIalpha protein levels and approximately 2.2-fold increase in topoIIalpha mRNA levels. Furthermore, CEM/ICRF-8 expresses approximately 3.5-fold increase in topoIIalpha promoter activity, suggesting that up-regulation of topoIIalpha in this clone occurs at the transcriptional level. Treatment of the drug-resistant or -sensitive cells with equitoxic doses of merbarone or teniposide results in a G(2)/M arrest. In marked contrast, when treated with equitoxic ICRF-187 doses, the drug-resistant clones exhibit either a transient arrest or completely lack the G(2)/M checkpoint compared with the drug-sensitive cells. This aberrant cell cycle profile is associated with a 48-h delay in drug-induced apoptotic cell death, as revealed by fluorescent-end labeling of DNA and poly (ADP-ribose) polymerase cleavage. In summary, resistance to ICRF-187 in CEM cells is associated with increased levels of catalytically active topoIIalpha and altered G(2)/M checkpoint and apoptotic responses.

Antigens, Neoplasm↗

PubMed1997

Analysis in yeast of antimalaria drugs that target the dihydrofolate reductase of Plasmodium falciparum.

Pyrimethamine and cycloguanil are competitive inhibitors of the Plasmodium enzyme dihydrofolate reductase (DHFR). They have been effective treatments for malaria, but rapid selection of populations of the parasite resistant to these drugs has compromised their effectiveness. Parasites resistant to either drug usually have point mutations in the dhfr gene, but the frequency of these mutations is unknown. To study drug resistance more effectively, we transferred the DHFR domain of the dhfr-thymidylate synthase gene from a drug-sensitive line of P. falciparum to a strain of the budding yeast, Saccharomyces cerevisiae, that lacks endogenous DHFR activity. Expression of the P. falciparum dhfr is controlled by the yeast dhfr 5' and 3' regulatory regions and the heterologous enzyme provided all of the functions of the yeast dhfr gene. These yeast were susceptible to pyrimethamine and cycloguanil at low concentrations that inhibit P. falciparum (IC50 about 10(-8) and 10(-7) M, respectively). Yeast expressing constructs with dhfr alleles from pyrimethamine-resistant strains were resistant to both pyrimethamine and cycloguanil (IC50 > 10(-6) M); resistance of the yeast depended on the dhfr allele they expressed. The experimental drug WR99210 efficiently killed all three yeast strains (IC50 about 10(-8) M) but the pyrR strains showed collateral hypersensitivity to drug. The yeast transformants carrying the drug-sensitive allele can now be screened quickly and quantitatively to identify new drugs or combinations of drugs and determine which drugs select resistant parasites least efficiently. Such compounds would be excellent candidates for development of treatments with a longer life in clinical practice.

Animals↗

PubMed1983

Establishment of cross-resistance profiles for new agents.

Sublines of murine leukemias (L1210 and P388) and solid tumors selected for resistance to representatives of all of the chemical and functional classes of clinically useful anticancer drugs have been isolated and established in serial in vivo passage and, in some cases, in vitro culture. Extensive resistance, cross-resistance, and collateral-sensitivity patterns have been established with most of the sublines of the drug-resistant murine leukemias under treatment with greater than 100 different established and clinically useful anticancer drugs or new candidate anticancer drugs currently under study. Patients selected for inclusion in phase I-II trials usually have tumors that have failed to respond to treatment with established clinically useful drugs, either from the start of treatment or during continuing treatment after initial useful response. These treatment failures are no doubt due, in many cases, to drug-resistant tumors if initially unresponsive or to the overgrowth of drug-resistant mutant tumor stem cells in initially responding patients who ultimately failed under continuing treatment. Therefore, the cross-resistance profiles of drug-resistant murine tumors to treatment with new drugs going into phase I-II trials should provide useful guides for patient selection for those trials. Also, these cross-resistance profiles will provide useful information indicating likely biochemical mechanism of action of new drugs with promising anticancer activity, thus guiding drug selection for combination chemotherapy trials in animals or man. Numerous examples of all of the above indications for useful application of such information derived from chemotherapy trials with drug-resistant murine tumors are reported.

Animals↗

PubMed2004

Acquired resistance of human T cells to sulfasalazine: stability of the resistant phenotype and sensitivity to non-related DMARDs.

BACKGROUND: A recent study from our laboratory showed that induction of the multidrug resistance related drug efflux pump ABCG2 contributed to acquired resistance of human T cells to the disease modifying antirheumatic drug (DMARD) sulfasalazine (SSZ). OBJECTIVES: To investigate the duration of SSZ resistance and ABCG2 expression after withdrawal of SSZ and rechallenging with SSZ, and to assess the impact of SSZ resistance on responsiveness to other DMARDs. METHODS: Human CEM cells (T cell origin) with acquired resistance to SSZ (CEM/SSZ) were characterised for (a) SSZ sensitivity and ABCG2 expression during withdrawal and rechallenge of SSZ, and (b) antiproliferative efficacy of other DMARDs. RESULTS: ABCG2 protein expression was stable for at least 4 weeks when CEM/SSZ cells were grown in the absence of SSZ, but gradually declined, along with SSZ resistance levels, to non-detectable levels after withdrawal of SSZ for 6 months. Rechallenging with SSZ led to a rapid (<2.5 weeks) resumption of SSZ resistance and ABCG2 expression as in the original CEM/SSZ cells. CEM/SSZ cells displayed diminished sensitivity to the DMARDs leflunomide (5.1-fold) and methotrexate (1.8-fold), were moderately more sensitive (1.6-2.0 fold) to cyclosporin A and chloroquine, and markedly more sensitive (13-fold) to the glucocorticoid dexamethasone as compared with parental CEM cells. CONCLUSION: The drug efflux pump ABCG2 has a major role in conferring resistance to SSZ. The collateral sensitivity of SSZ resistant cells for some other (non-related) DMARDs may provide a further rationale for sequential mono- or combination therapies with distinct DMARDs upon decreased efficacy of SSZ.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

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↗

PubMed1996

Are the major effects of P-glycoprotein modulators due to altered pharmacokinetics of anticancer drugs?

Agents (modulators) that reverse the in vitro resistance of tumor cells to anticancer drugs that are substrates for P-glycoprotein (Pgp, the product of the MDR1 gene) have been given to patients concurrently with anticancer drugs in an attempt to improve therapeutic response. The vast majority of investigations into these drugs indicate that Pgp modulators decrease the systemic clearance of anticancer drugs, thus potentially nonselectively increasing exposure to normal and malignant cells and thereby potentially increasing the severity and/or incidence of adverse effects associated with the anticancer therapy. Mechanisms by which Pgp modulators could alter the pharmacokinetics of the anticancer agent include competition for cytochrome P450 intestinal or liver metabolism, inhibition of Pgp-mediated biliary excretion or intestinal transport, or inhibition of renal elimination. It is suggested that administration of Pgp modulators is unlikely to improve the therapeutic index for anticancer drugs unless agents that lack significant pharmacokinetic interactions are found. Moreover, it will likely be required that there be some cancer-tissue selectivity for modulators in order to avoid collaterally increasing the sensitivity of normal Pgp-expressing tissues to the anticancer drug.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1984

Establishment of an etoposide-resistant human epithelial tumour cell line in vitro: characterization of patterns of cross-resistance and drug sensitivities.

A human tumour cell line resistant to etoposide ( VP16 -213) has been produced by fractionated X-irradiation exposure in vitro. Characterization of this line, derived from an epithelioid carcinoma of the tongue, revealed no significant differences in terms of several cytological and kinetic parameters compared with the parent line. Patterns of cross-resistance and drug sensitivities were determined by colony formation in soft agar after 24 h drug exposures. Three patterns of response were observed with the VP16 -213-resistant cells showing: marked cross-resistance to vincristine and teniposide , collateral sensitivity to 5- fluorouracil , hydroxyurea and cis-platinum, and comparable responses to the parent line for adriamycin, bleomycin, dibromodulcitol and methotrexate. This is the first demonstration that specific drug resistance can be induced by prior exposure to X-irradiation in vitro. This cell line appears to show a unique lack of cross-resistance between adriamycin and vincristine or etoposide. Preliminary investigations into possible mechanisms of etoposide resistance demonstrated similar DNA sedimentation profiles after etoposide exposure in both tumour cell lines, implying no differential effects of this drug on DNA of resistant cells. These data raise the possibility that the expression and mechanism of resistance may differ, depending on the manner in which drug resistance is induced.

Carcinoma, Squamous Cell↗

PubMed1982

Mechanism of action of 2-crotonyloxymethyl-4,5,6-trihydroxycyclohex-2-enone, a SH inhibitory antitumor antibiotic, and its effect on drug-resistant neoplastic cells.

An inhibitor of alkaline phosphodiesterase was isolated from a soil Streptomyces. The agent was identified with 2-crotonyloxymethyl-4,5,6-trihydroxycylohex-2-enone (COTC) by UV, IR, 1H HMR and 13C NMR spectrometry. The mechanism of tumor-inhibitory action of COTC was studied with murine lymphoblastma L5178Y cells. COTC blocked alkaline phosphodiesterase; IC 50 was 60 micrograms/ml by the method employed. The growth of L5178Y cells was inhibited by COTC; IC50 was 4.4 micrograms/ml. DNA biosynthesis was preferentially prevented by COTC over RNA and protein syntheses; IC50 of DNA synthesis was 7 or approximately 25 micrograms/ml. COTC significantly inhibited DNA polymerase alpha even in the presence of dithiothreitol. The mitosis was markedly blocked by COTC; complete inhibition was observed at a drug concentration of 20 microgram/ml. Adriamycin-, aclarubicin- and bleomycin-resisant cell subline showed collateral sensitivity to COTC. COTC and aclarubicin exhibited synergistic activity on aclarubicin-resistant cells, but not on the parental cells. COTC increased uptake of [3H]adriamycin or blocked the drug efflux in the resistance cells, but not in the parental cells. The effects of COTC on macromolecular syntheses, mitosis and membrane functions may be attributed to the interaction with the sulfhydryl group of various enzymes. Although COTC is multifunctional drug, the inhibition of DNA polymerase alpha and a certain mitotic process seems to be related to the lethal action.

Animals↗

PubMed1982

[General observation on drug resistance of cancer cells].

General discussions on the drug resistance of cancer cells were made from various points of view: (1) drug resistance as an unhereditary phenotype, (2) changes in the cell population during drug treatment, (3) acquired resistance and natural resistance, (4) general concepts on biochemical and pharmacological mechanisms for drug resistance, (5) common mechanism for concurrent resistance to DNA-intercalators and vinca-alkaloids, and (6) collateral sensitivity on a cellular basis.

Animals↗