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PubMed1997

Annamycin circumvents resistance mediated by the multidrug resistance-associated protein (MRP) in breast MCF-7 and small-cell lung UMCC-1 cancer cell lines selected for resistance to etoposide.

Annamycin (Ann) is a highly lipophilic anthracycline antibiotic that has been shown to circumvent MDR-1 both in vitro and in vivo. A liposomal formulation of Ann is currently in phase I clinical trials. The multidrug resistance-associated protein (MRP) has been found to be over-expressed in some human leukemias at relapse and to be a poor prognostic factor in neuroblastoma. We studied the in vitro cytotoxicity and the cellular uptake and efflux of Ann and doxorubicin (Dox) in 2 pairs of human cell lines, breast carcinoma MCF7 and small-cell lung cancer UMCC-1, and their MRP-expressing counterparts, MCF-7/VP and UMCC-1/VP. Resistance indexes were 1.1 and 1.4 for Ann vs. 6.9 and 11.6 for Dox. Ann cellular accumulation was 3- to 5-fold higher than that of Dox in both sensitive and resistant cells. No changes in drug efflux between sensitive and resistant cells were observed in the case of Ann, while Dox efflux at 1 hr was 20-25% higher in resistant than in sensitive cells. By confocal microscopy, the subcellular distribution of Ann was identical in sensitive and resistant cells, localizing mostly in the perinuclear structures, while that of Dox was exclusively nuclear in sensitive cells and nuclear and in the cell membrane in resistant cells. There was a good correlation between the extent of DNA breaks induced by each drug in the different cell lines and cytotoxic effect. Our results indicate that Ann may be effective in the treatment of malignancies in which MRP is a relevant mechanism of clinical resistance.

ATP-Binding Cassette Transporters↗
PubMed1993

Multidrug-resistant human KB carcinoma cells are highly resistant to the protein phosphatase inhibitors okadaic acid and calyculin A. Analysis of potential mechanisms involved in toxin resistance.

In this study we show that multidrug-resistant (MDR) human KB-V1 cells are highly resistant to the cytotoxicity of okadaic acid and calyculin A, 2 toxins from marine sponges that are potent inhibitors of type-1 and type-2A protein phosphatases (PP1 and PP2A). Cytotoxicity and colony-forming assays indicated that, relative to parental drug-sensitive KB-3 cells, KB-V1 cells are 35-fold more resistant to okadaic acid and 70-fold more resistant to calyculin A. Cytotoxicity of the toxins was associated with mitotic arrest characterized by chromosome scattering and over-condensation, with KB-3 cells being more sensitive than KB-V1 cells and calyculin A being more potent than okadaic acid. The resistance of KB-V1 cells to both okadaic acid and calyculin A was completely reversed by verapamil, suggesting that the toxins may be transported by P-glycoprotein (P-gp). To further assess the possibility of an interaction with P-gp, the toxins were employed as potential modulators of the photoaffinity labeling of P-gp by [3H]azidopine. Relative to vinblastine, which effectively competed with [3H]azidopine for P-gp photolabeling, calyculin A was 100-fold less potent and okadaic acid did not inhibit photolabeling at concentrations up to 50 microM. To determine whether the resistance mechanism involved differences in toxin-sensitive phosphatase activity, the activity was assayed in extracts from both cell lines and found to be slightly higher (1.6-fold) in KB-V1 than in KB-3 cells. Our results demonstrate a novel, marked resistance of MDR KB-V1 cells to these phosphatase inhibitors and suggest that a major mechanism of resistance may involve toxin transport by P-gp at sites apparently different from those which bind azidopine.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Melphalan resistance and photoaffinity labelling of P-glycoprotein in multidrug-resistant Chinese hamster ovary cells: reversal of resistance by cyclosporin A and hyperthermia.

The multidrug resistance phenotype is often associated with overexpression of P-glycoprotein, an energy-dependent efflux pump responsible for decreased intracellular accumulation of chemotherapeutic agents. The role of P-glycoprotein in the mechanism of cross-resistance to melphalan in multidrug-resistant Chinese hamster ovary cells (CH(R)C5) was investigated by photoaffinity labelling of P-glycoprotein using [3H]azidopine. We investigated whether the chemosensitiser cyclosporin A and hyperthermia, either used alone or combined, could reverse melphalan resistance and alter transport processes for [14C]melphalan in CH(R)C5 cells. Melphalan inhibited azidopine photolabelling of P-glycoprotein, implicating drug efflux mediated by P-glycoprotein in the mechanism of melphalan resistance in CH(R)C5 cells. Azidopine photolabelling also was inhibited by the chemosensitiser cyclosporin A, which binds to P-glycoprotein. Cyclosporin A alone reversed melphalan resistance in CH(R)C5 cells, but had no effect in drug-sensitive AuxB1 cells. Hyperthermia (40-45 degrees) alone increased melphalan cytotoxicity in both cell lines. When hyperthermia was combined with cyclosporin A, a large increase in melphalan cytotoxicity occurred, but only in CH(R)C5 cells. This effect increased with temperature and exposure time. Sensitisation to melphalan cytotoxicity by heat and cyclosporin A in CH(R)C5 cells appeared to be explained by altered drug transport processes. Lower accumulation of melphalan occurred in CH(R)C5 cells than in drug-sensitive cells. At 37 degrees, cyclosporin A increased drug accumulation in CH(R)C5 cells, but not in AuxB1 cells, by slowing drug efflux from cells. Heat alone increased both melphalan uptake and drug efflux for both cell lines. Our findings suggest that the combination of cyclosporin A and hyperthermia could be very useful in overcoming melphalan resistance by increasing intracellular drug accumulation in multidrug-resistant cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Drug-resistance enables selective killing of resistant leukemia cells: exploiting of drug resistance instead of reversal.

Drug resistance is a well recognized problem in cancer therapy. Despite the current dogma that drug resistance is always an obstacle for treatment, here I show that it provides opportunities for selective protection of non-resistant cells with killing of drug-resistant cancer cells. According to the proposed 'two-drug' strategy, the first drug should be ineffective against a target drug-resistant cell (ie the drug is a substrate of MRP or Pgp pumps). In addition, it must be cytostatic but not cytotoxic. The second drug, which is applied in sequence, must be a cycle-dependent apoptotic drug to which the target cell is not cross-resistant. Thus, low doses of adriamycin, etoposide and actinomycin D, used as the first drugs, were cytostatic to parental HL60 cells. Therefore, these drugs precluded Bcl-2/Raf-1 phosphorylation, PARP cleavage and cell death which are otherwise induced by paclitaxel, a mitosis-selective apoptotic drug for HL60 cells. In contrast, HL60/ADR cells which express MRP, a transporter which pumps out the first drugs from a cell, were insensitive to the first drugs and therefore readily underwent apoptosis following the second drug. This strategy also allowed a selective killing of HL60/TX cells which express MDR-1, with the only difference being that the second drug, paclitaxel, was substituted for epothilones, non-Pgp substrates. Lack of protection by the first drug, a Pgp substrate, resulted in HL60/TX killing by the second drug, whereas parental HL-60 cells were fully protected. Therefore, drug resistant cells can be selectively killed by a combination of drugs not killing sensitive cells. Lack of toxicity against normal cells will be clinically translated in reduction of adverse side-effects of chemotherapy against drug-resistant malignancies.

Apoptosis↗
PubMed2006

The molecular mechanism of resistance to methotrexate in mouse methotrexate-resistant cells by cancer drug resistance and metabolism SuperArray.

Drug resistance is often a limiting factor in successful chemotherapy. Understanding of the molecular mechanism of resistance to methotrexate is important for optimal use as well as for the development of new drugs. Using standard cytogenetic techniques, double minutes (DMs) were detected in mouse methotrexate-resistant cell lines inducted in vitro in this study. Moreover, functional SuperArray, determining the regulation of gene expression corresponding to 96 genes involved in the metabolism of and the development of resistance to cancer drugs was used to study in detail the molecular mechanism of resistance to methotrexate. Significant higher expressions of many genes especially dhfr, mrp5, atm and p53 were detected in methotrexate-resistant cells than in normal mouse cells by SuperArray analysis and corresponding excessive expressions of DHFR, MRP5, ATM, and P53 proteins in methotrexate-resistant cells were also confirmed by Western blot analysis. The results in this study indicated that DHFR, MRP5, ATM, and P53 could play important roles in resistance to methotrexate and some of them would be new potential drug targets.

Animals↗
PubMed2004

Analysis of the drug resistance profile of multidrug resistance protein 7 (ABCC10): resistance to docetaxel.

The multidrug resistance protein (MRP) family consists of nine members that can be categorized according to whether or not a third (NH(2)-terminal) membrane-spanning domain is present. Three (MRP1, MRP2, and MRP3) of the four members that have this structural feature are able to confer resistance to natural product anticancer agents. We previously established that MRP7, the remaining family member that has three membrane-spanning domains, possesses the cardinal biochemical activity of MRPs in that it is able to transport amphipathic anions such as 17beta-estradiol 17-(beta-d-glucuronide). However, the drug resistance profile of the pump has not been determined. In this study, the drug resistance capabilities of MRP7 are evaluated by analyzing the resistance profiles of two clones of HEK293 cells in which the pump was ectopically expressed. MRP7-transfected HEK293 cells exhibited the highest levels of resistance toward docetaxel (9-13-fold). In addition, lower levels of resistance were observed for paclitaxel (3-fold), vincristine (3-fold), and vinblastine (3-4-fold). Consistent with the operation of an ATP-dependent efflux pump, MRP7-transfected cells exhibited reduced accumulation of radiolabeled paclitaxel compared with HEK293 cells transfected with parental plasmid. These results indicate that MRP7, unlike other MRPs, is a resistance factor for taxanes.

Antineoplastic Agents, Phytogenic↗
PubMed1980

Effect of nosiheptide as a feed additive in chicks on the quantity, duration, prevalence of excretion, and resistance to antibacterial agents of Salmonella typhimurium; on the proportion of Escherichia coli and other coliforms resistant to antibacterial agents; and on their degree and spectrum of resistance.

In the first experiment two groups (B and D) each of ten, 15-day-old chicks were fed for 33 days a diet supplemented with nosiheptide (20 g/t) and 2 groups (A and C) of 10 each a diet without medication. Groups A and B were inoculated with Salmonella typhimurium, var. copenhagen (variant resistant to nalidixic acid of the strain DVR 101) 5 days after treatment was started. At intervals of 2, 4, 6, 8, 10, 12, 14, 21, and 28 days postinoculation the following data were collected: the number of salmonella excreted per gram of feces, their duration and prevalence of excretion, and the proportion of salmonella resistant to 9 antibacterial agents commonly used in human and veterinary medicine, as well as their degree and spectrum of resistance. In the second experiment two groups of 10 chicks each were fed either a basal diet (control group) or a diet supplemented with nosiheptide at 20 g/t (treated group). Immediately before and at the end of treatment, the proportions of fecal coliforms, particularly E. coli, which were resistant to 11 commonly used antibacterial agents, and their degree and spectrum of resistance were determined in the 2 groups of chicks. All the strains isolated before treatment started were E. coli sensitive to the 11 antibacterial agents. The strains isolated at the end of treatment were coliforms otherthan E. coli (40% in the control group, 32% in the treated group) and E. coli (60 and 68%, respectively). Coliforms other than E. coli were, as is usual, resistant to ampicillin and sensitive to the other antibacterial agents. The E. coli strains were either sensitive to all the antibacterial agents or resistant to tetracycline and furazolidone (51.8% in the control group, 34.1% in the treated group), or resistant to furazolidone alone (3.7% in the control group, 5.8% in the treated group). In both experiments these determinations showed no appreciable differences between treated and untreated chicks.

Animal Feed↗
PubMed1974

Carbamate resistance in Anopheles albimanus. Cross resistance spectrum and stability of resistance.

Carbamate resistance induced in a field strain of A. albimanus from El Salvador by laboratory selection with propoxur remained fairly stable on relaxation of selection pressure for 12 generations. Studies on cross and multiple resistance showed that this strain was not resistant to the pyrethroids bioresmethrin, bioallethrin, and CRC 11451, although resistance to cismethrin was 2.3-fold. Resistance to 10 carbamates of various structural configurations covered a broad spectrum, being for example >100x to Bay 38799, Ciba 17474, and Ciba 18107, 74.8x to carbaryl, 20.57x to carbanolate, and 2.27x to Stauffer R 15396. The possible causes of the presence or absence of cross resistance and the implications of stability of resistance and cross resistance are discussed.

Animals↗
PubMed1998

In vitro activity of LY333328 against vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, and penicillin-resistant Streptococcus pneumoniae.

We report the activity of LY333328 against 35 clinical isolates of vancomycin-resistant enterococci (including organisms carrying the vanA, vanB, vanC-1, and vanC-2/3 genes, as determined by PCR), 33 clinical isolates of methicillin-resistant S. aureus, and 29 clinical isolates of high-level penicillin-resistant S. pneumoniae. All isolates of vancomycin-resistant enterococci were inhibited by 2 micrograms/mL LY333328, and 8 micrograms/mL LY333328 was bactericidal against all isolates tested. All isolates of methicillin-resistant S. aureus were inhibited by 1 microgram/mL LY333328, and 4 micrograms/mL LY333328 was bactericidal against all methicillin-resistant S. aureus isolates tested. All isolates of penicillin-resistant S. pneumoniae were inhibited by < 0.125 microgram/mL LY333328, and 0.25 microgram/mL LY333328 was bactericidal against all S. pneumoniae isolates tested. LY333328 is a promising new glycopeptide antimicrobial agent.

Anti-Bacterial Agents↗
PubMed1999

In vitro activity of linezolid against vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae.

We report the activity of the new oxazolidinone antimicrobial agent linezolid against 37 clinical isolates of vancomycin-resistant enterococci (including organisms carrying the vanA, vanB, vanC-1, and vanC-2/3 genes), 26 clinical isolates of methicillin-resistant S. aureus and 20 clinical isolates of high-level penicillin-resistant S. pneumoniae. All isolates of vancomycin-resistant enterococci were inhibited by < or = 4 ug/ml of linezolid. All isolates of methicillin-resistant S. aureus were inhibited by < or = 8 ug/ml of linezolid. All isolates of penicillin-resistant S. pneumoniae were inhibited by < or = 2 ug/ml of linezolid. Linezolid inhibits strains of multidrug resistant Gram-positive cocci in vitro at concentrations < or = 8 ug/ml.

Acetamides↗
PubMed2001

Sequential gene expression of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and lung resistance protein: functional activity of P-gp and MRP present in the doxorubicin-resistant human K562 cell lines.

Previous studies have reported that P-glycoprotein (P-gp), a transmembrane efflux pump involved in multidrug resistance (MDR), was overexpressed in the doxorubicin (Dox)-resistant human erythroleukemia cell line K562. Nevertheless, several results suggested that P-gp was not the only mechanism involved in these resistant cells. Sequential co-expression of other MDR-associated proteins was sometimes reported, as MDR-associated protein (MRP) and lung resistance protein (LRP), in different MDR cell lines. Thus, mRNA expression and stability of P-gp, MRP and LRP were analyzed, while their corresponding protein levels were quantified in correlation with functional assay, in the K562 cell line and two Dox-resistant variants (K562/R). Their P-gp content was in accordance with their degree of resistance, but not as much in the level of mRNA expression, suggesting a post-transcriptional regulation. On the other hand, MRP could play a minor role in MDR because of an unchanged expression in K562/R sublines. A surprising progressive disappearance of LRP in both resistant cells suggested that the original mechanism of drug redistribution may be operative, involving a negative role for LRP.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Evaluation of a mutation test using S49 mouse lymphoma cells and monitoring simultaneously the induction of dexamethasone resistance, 6-thioguanine resistance and ouabain resistance.

A test for the detection of chemically induced mutants in S49 mouse lymphoma cells is described. These cells can be plated in parallel in several selective media; the induced frequencies of dexamethasone-resistant, 6-thioguanine-resistant and ouabain-resistant mutants were compared. The first two selection systems permit the detection of all kinds of mutation that result in alteration or partial or complete loss of the gene product concerned, whereas ouabain-resistant mutants can only be induced with strong point mutagens in these cells. Dexamethasone resistance is the marker induced at the highest frequency among these three. Data obtained from this selection system are therefore the most amenable to statistical analysis. Dexamethasone resistance is expressed within a short time after mutagenesis (3 days), and because S49 cells do not display metabolic co-operation, large numbers of cells can be screened. A metabolizing system in vitro with rat-liver homogenate may be included in tests of indirectly acting mutagens. These features make the S49 mutation test system using dexamethasone resistance as the main marker and other markers as internal controls an attractive tool in mutation testing in somatic cells in vitro.

Animals↗
PubMed2002

High-level ivermectin resistance in a field isolate of Haemonchus contortus associated with a low level of resistance in the larval stage: implications for resistance detection.

The IVPro isolate of Haemonchus contortus was isolated in 1999 after significant numbers of the parasite survived an ivermectin capsule treatment of grazing sheep acquiring a natural infection at Prospect, NSW, Australia. The isolate shows high-level resistance to ivermectin (faecal egg count is unaffected by ivermectin oral treatment at 0.2mg kg(-1)). The larval LC(50), as assessed by larval development assays (LDAs), is only approximately two-fold higher than several susceptible isolates, making it difficult to detect the resistance using larval LC(50) as an indicator. However, the isolate shows the presence of a small proportion of the population (<20%) able to develop at significantly higher drug concentrations than the susceptible isolates. Hence, if the IVPro and susceptible isolates are compared at the LC(99) level, the IVPro isolate is readily identifiable as resistant. This degree of distinction at the LC(99) allows the IVPro isolate to be identified as resistant by simply observing the highest drug concentration in the development assay at which some larvae develop relative to the susceptible isolates. Assessing the development assay using this criterion allows a distinction between IVPro and the susceptible isolates equivalent to 10-fold differences in drug concentration, greatly increasing the likelihood of detecting the resistant isolate in routine resistance tests. This study highlights the need to examine this aspect of LDAs in order to detect the type of resistance displayed by IVPro H. contortus.

Animals↗
PubMed1994

Trimethoprim resistance in urinary pathogens in northern Scotland: epidemic spread of a resistance plasmid encoding the type Ib trimethoprim-resistant dihydrofolate reductase.

The prevalence of trimethoprim resistance in enterobacterial urinary pathogens from hospitalised patients in the Angus district of northern Scotland (22.8%) was twice that found in similar isolates from patients attending general practitioners (11.2%). Thirty-three of the 143 trimethoprim-resistant strains were shown to harbour transferable plasmids conferring high-level trimethoprim resistance. In total, 17 different plasmid types were distinguished. Two plasmids, pUK1184 and pUK1185, accounted for 36% of the trimethoprim resistance plasmids and were shown by restriction endonuclease digestion fingerprints to be closely related to plasmid pUK28, previously demonstrated to be endemic in urinary pathogens in the Edinburgh area. Only 21% of the plasmids were shown to encode the type Ia trimethoprim-resistant dihydrofolate reductase, whereas 70% of the trimethoprim resistance plasmids were found to encode the type Ib dihydrofolate reductase. Hybridisation of the trimethoprim resistance plasmids identified in this study with gene probes specific for the integrase genes of transposons Tn7 and Tn21 indicates that the dhfrIa is rarely present within Tn7 or related transposons in these plasmids and may be more prevalent within Tn21-like transposons. In contrast, with the exception of the two endemic plasmids that harboured the dhfrIb gene within a Tn7-like transposon, the majority of dhfrIb genes were not found to be associated with either Tn7- or Tn21-like structures.

Bacteriuria↗
PubMed1975

Drug-resistant Leptomonas: cross-resistance in trypanocide-resistant clones.

A Leptomonas of insect origin was highly susceptible to several standard trypanocides and leishmanicides in vitro. Resistance was induced to some of these drugs; clones were isolated from each strain. Cross-resistance patterns of the clones were derived for diamidines, quinapyramine (Antrycide), acriflavin, phenanthridines, and other drugs active against trypanosomes and leishmanias. Clones tested included two each that were resistant to acriflavin, Antrycide, diminazene aceturate (Berenil), and pentamidine and one that was resistant to stilbamidine. Appreciable cross-resistance was evident for all clones. Differences were observed between clones from the same parent strain. Collateral susceptibility towards isometamidium and oxophenarsine was detected in most clone-derived populations. In clones passaged without drug to test for drug fastness, acriflavin and pentamidine clones lost resistance within 10 transfers, whereas Berenil and Antrycide clones retained considerable resistance after 20 to 30 subcultures without drug. Considerations of differences in life cycles suggest that the clone collection may be useful in screening for agents effective against leishmanias and stercorarian trypanosomes rather than against salivary trypanosomes.

Clone Cells↗
PubMed2006

Association between mutations in Plasmodium falciparum chloroquine resistance transporter and P. falciparum multidrug resistance 1 genes and in vivo amodiaquine resistance in P. falciparum malaria-infected children in Nigeria.

This study investigated the association between Plasmodium falciparum chloroquine resistance transporter (pfcrt) T76 and P. falciparum multidrug resistance gene 1 (pfmdr1) Y86 alleles and in vivo amodiaquine (AQ) resistance, as well as the clearance of parasites harboring these two alleles in children treated with AQ in southwest Nigeria. One hundred one children with acute uncomplicated P. falciparum malaria infections were treated with the standard dosage of AQ and followed-up for 28 days. Blood samples were collected on filter paper samples at enrollment and during follow-up for identification of parasite genotypes and pfcrt and pfmdr1 mutations using polymerase chain reaction and restriction fragment length polymorphism approaches. Parasitologic assessment of response to treatment showed that 87% and 13% (RI) of patients were cured and failed treatment, respectively. Although infections in patients were polyclonal (as determined by merozoite surface protein 2 genotyping), the presence of both mutants pfcrtT76 and pfmdr1Y86 alleles in parasites is associated with in vivo AQ resistance (odds ratio = 7.58, 95% confidence interval = 1.58-36.25, P = 0.006) and is selected by the drug in children who failed AQ treatment. Treatment failure with the combination of mutant pfcrtT76 and pfmdr1Y86 alleles as well as the ability of patients to clear these resistant parasites is dependent on age, suggesting a critical role of host immunity in clearing AQ-resistant P. falciparum. The combination of mutant pfcrtT76 and pfmdr1Y86 alleles may be useful markers for monitoring the development and spread of AQ resistance, when combining this drug with other antimalarials for treatment of malaria in Africa.

Age Factors↗
PubMed1989

Insect growth regulators: I. Biological activity of some IGR's against the susceptible and resistant strains of Culex pipiens larvae. II. Pattern of cross resistance to IGR's in carbaryl-resistant strain.

The biological activity and cross-resistance of some IGR's, Dimilin, BAY SIR 8514 and Chlorofluzuron against susceptible and carbaryl-resistant strains of Culex pipiens were determined. The results indicated that these compounds are highly effective against the larvae of C. pipiens but more potent larvicides against the susceptible larvae than against the resistant ones. The pattern of cross-resistance to the used IGR's in the carbaryl-resistant strain were obtained. The data revealed no three IGR's as larvicides against the susceptible and resistant Culex pipiens. The pattern of cross resistance to other potent IGR's was also studies.

Animals↗
PubMed1978

In vivo characteristics of resistance and cross-resistance of an adriamycin-resistant subline of P388 leukemia.

A subline of P388 leukemia resistant to adriamycin (P388/ADR) was developed by exposure to the drug in vivo. Resistance to adriamycin proved to be a stable characteristic of P388/ADR. There was no significant inhibition of nucleic acid synthesis in P388/ADR cells in vivo following a dose of 10 mg/kg of adriamycin in contrast to a prolonged and complete inhibition, particularly of DNA synthesis, observed in parental sensitive P388 leukemia cells. P388/ADR proved to be completely cross-resistant to a spectrum of anthracycline derivatives. Cross-resistance was observed to nonanthracycline DNA intercalating agents (with the exception of anthramycin), to agents which interfere with mitotic spindle function, and to antineoplastic inhibitors of protein biosynthesis (with the exception of bruceantin). P388/ADR was sensitive to antimetabolites and alkylating agents. Cross-resistance was also observed to several agents (ICRF-159, a terephthalanilide, taxol, lymphosarcin, bouvardin, and a crude extract of Ervatamia hyneana) whose mechanisms of action have not yet been clearly defined. This observation has proved useful in providing a lead for determination of mechanism of action of some of these drugs. The pattern of cross-resistance of a subline of P388 leukemia resistant to daunorubicin, though not studied extensively, appears to be similar to that of P388/ADR.

Animals↗