Cancer Research Prevention Award Metabolism
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Marchini, S.
Right arrow Articles by Geroni, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Marchini, S.
Right arrow Articles by Geroni, C.
[Cancer Research 61, 1991-1995, March 1, 2001]
© 2001 American Association for Cancer Research

Experimental Therapeutics

4-Demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548), a Novel Anticancer Agent Active against Tumor CellLines with Different Resistance Mechanisms1

Sergio Marchini2, Giovanna Damia, Massimo Broggini, Giulia Pennella, Marina Ripamonti, Aurelio Marsiglio and Cristina Geroni

Laboratory of Molecular Pharmacology, Istituto di Ricerche Farmacologiche "Mario Negi," 20157 Milan [S. M., G. D., M. B.], and Pharmacia Corporation, Pharmacology Department, Discovery Research Oncology, 20014 Milan [G. P., M. R., A. M., C. G.], Italy


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The activity of 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548), a new alkycycline with high antitumor activity against a broad range of cancer cells, was evaluated in vitro and in vivo in cells selected for resistance to different anticancer agents. Both in vitro and in vivo, PNU-159548 did retain its activity in cells expressing the multidrug resistance (MDR) phenotype, associated to MDR-1 gene overexpression or with an alteration in the topoisomerase II gene (altered MDR), independently on the drug used for the selection of the resistant cell line. According to these data, the intracellular uptake of PNU-159548 is not influenced by the presence of MDR-1. PNU-159548 was also active, both in vitro and in vivo, against cells showing resistance to various alkylating agents (including cisplatin, cyclophosphamide, and melphalan) and topoisomerase I-inhibitors. Cells defective in nucleotide excision repair, which did show hypersensitivity to treatment with UV irradiation and alkylating agents, showed only a marginally increased sensitivity to PNU-159548. Similarly, the activity of the drug was not influenced by the mismatch repair system, as assessed in two different cellular systems deficient in hMLH1 expression and in which hMLH1 activity was restored by chromosome 3 transfer. The results obtained clearly indicate that the new anticancer agent PNU-159548 is able to overcome the classical mechanisms of resistance emerging after treatment with the most clinically used anticancer agents, and it could represent an alternate choice in the treatment of those tumors refractory to conventional therapy.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
One of the major goals for developing new anticancer agents is to overcome the resistance to drug treatment that almost invariably arises with conventional chemotherapy, even after an initially good tumor response.

Alkycyclines are a new class of compounds with alkylating substituents introduced at positions C-3' of the aminosugar of anthracyclines such as IDA3 , an anthracycline of the second generation used in clinical practice (1, 2, 3) . In vitro, alkycyclines showed a higher cytotoxic potency than the parent drug, being active on cell lines with high levels of expression of the MDR-1 gene that are resistant to doxorubicin and idarubicin.

PNU-159548, the lead compound of this new class of antitumor agents and currently in Phase II clinical trial, is an idarubicin analogue bearing an aziridinyl moiety at position C-3' and the substitution, at position C-4', of a methylsulphonic group. Previous studies (4) showed that the compound was more cytotoxic than idarubicin in a panel of murine and human cell lines growing in vitro and in vivo. DNA interaction studies showed that PNU-159548 is able to alkylate guanines at the N7 position and adenines at the N3 position of the DNA (5) .

Here we report on the activity of PNU-159548 in tumor cell lines with well-defined mechanisms of sensitivity and resistance to classical anticancer agents.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Drugs.
PNU-159548, DX, and IDA were synthesized by the Pharmacia Corporation (Milan, Italy). The chemical structure of PNU-159548 is reported in Fig. 1Citation .



View larger version (17K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. Chemical structure of PNU-159548.

 
The compounds were dissolved and diluted just before use, and concentrations were adjusted spectrophotometrically according to their coefficient of extinction: PNU-159548 {lambda}max 482 nm; E% 181.95 (CH3OH), DX {lambda}max 496 nm; E% 200 (H2O) and IDA {lambda}max 484 nm; E% 174 (H2O).

DDP was obtained from Bristol Myers Squibb and dissolved in medium just before use. MNNG and L-PAM were purchased from Sigma, dissolved in DMSO, and subsequently diluted in medium.

Cell Lines.
The murine P388 leukemia and its subline resistant to DX (P388/DX), the murine reticulum cell sarcoma M5076 and its subline resistant to CTX (M5076/CTX), the murine L1210 leukemia and sublines resistant to alkylating agents (L1210/DDP, L1210/L-PAM, L1210/CTX, and L1210/ BCNU), camptothecins (L1210/CPT and L1210/9-AC), anthracyclines (L1210/DX), or taxanes (L1210/TAX), were grown in RPMI 1640 (Life Technologies, Inc.) supplemented with 10% FCS.

The human coloncarcinoma cell line LoVo and its subline resistant to DX (LoVo/DX) were grown in F12 medium (Life Technologies, Inc.) supplemented with 10% FCS. The human lymphoblastic leukemia CEM and its sublines resistant to VM-26 (CEM-VM-1) or VLB (CEM/VLB100) were grown in DMEM (Life Technologies, Inc.) supplemented with 10% FCS. Resistant cells were grown in vitro without drug for a minimum of 5 days before treatment.

The hMLH1-deficient human colorectal adenocarcinoma cell line HCT-116 and the subline into which a wild-type copy hMLH1 on chromosome 3 has been introduced by microcell fusion (HCT-116+ch3; Ref. 6 ) were obtained from Dr. G. Marra (University of Zurich, Zurich, Switzerland). Both cell lines were grown in Iscove’s modified Dulbecco’s medium (Life Technologies, Inc.). The DDP0-resistant subline A2780/CP70 (derived from the human ovarian cancer cell line A2780), which has lost hMLH1 expression, and the A2780/CP70+ch3 clone [obtained from A2780/CP70 by introducing chromosome 3 by microcell-mediated chromosome transfer (7) ] were grown in RPMI 1640 supplemented with 10% FCS.

The CHO parental cell line AA8, and the UV-sensitive DNA repair deficient mutant cell lines UV47 and UV96, lacking functional ERCC4/XPF and ERCC1 genes respectively, were used. All these cell lines were grown in Ham-F10 medium (Life Technologies, Inc.) supplemented with 10% FCS.

In Vitro Cytotoxicity.
For clonogenic assay, cells were plated at 250 cells/well (HCT-116 and HCT-116+ch3, A2780/CP70 and A2780/CP70+ch3), or 150 cells/cm2 (AA8, UV47, and UV96). After 1-h treatment with different drug concentrations, plates were incubated for 10–14 days in drug-free medium, and the number of colonies formed were counted after staining with 10% crystal violet in 20% ethanol and automatically counted on a image analyzer (Immagini & Computer, Italy). The data of the survival curves are expressed as the percentage of untreated controls. Concentrations inhibiting colony formation by 50% (IC50) were determined by interpolation from the concentration-response curves. In vitro drug sensitivity was determined for all of the other cell lines by counting surviving cells using a ZBI Coulter Counter apparatus. Exponentially growing cells were seeded and exposed to various concentrations of drug immediately after seeding. The antiproliferative activity of the drug was evaluated after 48-h treatment and calculated from dose-response curves and expressed as IC50.

IC50 values were calculated from two to three independent experiments, each consisting of at least three replicates.

Animals and Tumor Lines.
DBA/2, inbred BALB/cAnNoxDBA/2No (CD2F1) and C57Bl/6xDBA/2 (B6D2F1) adult female mice (Charles River, Calco, Como and Harlan Nossan, Milan, Italy) were used to evaluate the antitumor activity. Mice were 2–3 months of age, weighed 20–22 g, and were kept under standard laboratory conditions.

The mouse colony was routinely tested monthly for the absence of antibodies to a panel of pathogens including mouse hepatitis, Sendai Virus, and Mycoplasma pulmonis.

P388, L1210, L1210/DX, L1210/L-PAM L1210/DDP, L1210/CTX, L1210/BCNU, L1210/CPT, and L1210/9AC murine leukemias were maintained in DBA/2N mice by weekly i.p. passages of 106cells/mouse. L1210/TAX leukemia was transplanted by weekly i.p. passages of 105 cells/mouse. For experiments, 105 cells/mouse were injected i.v. in CD2F1 mice. P388/DX murine leukemia was transplanted by weekly i.p. injections of 106cells/mouse and, for experiments, 105 cells/mouse were injected i.v. in B6D2F1 mice.

Drug Administration and Evaluation of Antitumor Activity and Toxicity.
Treatment was administered i.v. in a volume of 10 ml/kg of body weight. Treatment schedules are reported in each table.

Drug activity was determined by comparing the MST of the treated group with that of the control group and results are expressed as ILS%:

Toxicity was evaluated on the basis of weight loss and the gross autopsy findings, mainly in terms of reduction of spleen and liver size.

Intracellular Uptake.
Intracellular drug content was determined in L1210, L1210/DX, P388, and P388/DX cells treated with 100 ng/ml PNU-159548 and incubated at 37°C for up to 60 min. Aliquots of 1 x 106 cells were harvested at different times of incubation and washed twice in ice-cold PBS. For drug-efflux determinations, cells incubated with PNU-159548 for 60 min were washed as described above, then incubated in drug-free medium and harvested after 60-min incubation. Cell pellets were stored at -20°C before the extraction.

Pellets of PNU-159548 were diluted with saline and sonicated for 15 s. Then the suspension was mixed vigorously (30 s) with 1 M HCOONH4 (pH 8.5) and CHCl3:Propanol (5:1) was added before stirring for 15 min. Samples were centrifuged at 3000 rpm/10 min to obtain two fractions. The organic phase was collected, and the dried material diluted with methanol:H2O (75:25) and analyzed. Samples were analyzed by high-performance liquid chromatography using C18 reverse-phase column and a spectrofluorometer as detector (excitation and emission wavelengths were 479 and 593 nm, respectively).

Each sample was run in triplicate. Experiments were carried out at least twice. Cell number was determined with a ZBI Coulter Counter apparatus on an aliquot of the cell suspension before centrifugation. The intracellular accumulation of the drug is reported as ng/106 cells.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
In Vitro Studies.
We initially evaluated the activity of PNU-159548 against human and murine tumor cell lines expressing the MDR-1 and at-MDR phenotypes. Table 1Citation reports the IC50 of PNU-159548 in the resistant cell lines and in their respective parental cell lines. In all of the four systems tested, PNU-159548 was equally active in parental and MDR-1-expressing sublines, independently of the drug used to select the resistant clones. For comparison, Table 1Citation reports the cytotoxicity of DX and of the closest structural relative of PNU-159548, IDA. Both DX and IDA showed cross-resistance in all of the MDR-1 and at-MDR sublines. In the L1210, L1210/DX, P388, and P388/DX cell lines, we measured the intracellular uptake of PNU-159548. As shown in Fig. 2Citation , PNU-159548 rapidly accumulated in the cells with no differences between the parental and the MDR-1 gene-expressing subline in both systems.


View this table:
[in this window]
[in a new window]

  		Table 1 Cell growth inhibition of PNU-159548 against parental and MDR-1 and at-MDR tumor cells

 


View larger version (18K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 2. Intracellular accumulation of PNU-159548 in L1210 and L1210/DX cells (A) and in P388 and P388/DX (B). Intracellular drug content was evaluated as described in "Materials and Methods." Parental ({circ}) and DX-resistant (•) cells were treated continuously up to 60 min (uptake), then the drug was withdrawn and cells were incubated in drug-free medium for 60 min (efflux). Values, mean ± SE of at least two independent experiments each consisting of three replicates.

 
We then tested the activity of PNU-159548 against cell sublines made resistant to different agents (Table 2)Citation . PNU-159548 was only slightly less active in sublines resistant to alkylating agents, with a resistance index ranging from 1.2 to 2.5 (a range similar to that of the two anthracyclines, DX and IDA). When PNU-159548 was tested against sublines made resistant to topoisomerase I inhibitors (L1210/CPT and L1210/9-AC), no decreased activity, but rather a slight collateral sensitivity, was found.


View this table:
[in this window]
[in a new window]

  		Table 2 Cell growth inhibition of PNU-159548 on alkylating agents and campthotecin-resistant tumor cells (comparison with DX and IDA)

 
By using the human colocarcinoma cell line HCT-116 and a subline derived from it by chromosome 3 transfer, we investigated the effect of PNU-159548 on MMR-deficient and -proficient cells. As can be seen from Table 3Citation , the restoration of MMR ability by chromosome 3 transfer does not change significantly the IC50 of the compound compared with the MMR-deficient HCT-116 cells (22 versus 32 ng/ml) under conditions in which, for both DDP and MNNG, the restoration of MMR functions is associated with an increased cytotoxicity. Likewise, in another human-derived cellular system, in A2780/CP70 cells (defective in MMR) and A2780/CP70+ch3 cells (proficient in MMR), PNU-159548 was similarly cytotoxic in MMR-proficient and -deficient cells in conditions under which a methylating agent (MNNG) and an alkylating agent (DDP) showed a higher activity upon restoration of MMR function (Table 3)Citation .


View this table:
[in this window]
[in a new window]

  		Table 3 In vitro cytotoxic activity of PNU-159548 in MMR-deficient and -proficient cell lines

 
We then investigated the influence of NER on the activity of PNU-159548. We selected the CHO system in which parental (AA8) or NER-deficient (UV47 and UV96) mutant cells were available. The IC50s obtained after the treatment of cells with different drug concentrations are reported in Table 4Citation . In parental AA8 cells, PNU-159548 showed an IC50 of 65 ng/ml. In UV47 cells presenting a NER defect that can be complemented by the ERCC4/XPF gene, PNU-159548 was ~2-fold more active, with an IC50 of 30 ng/ml. The drug was even more active in the UV96 cells, which have a defect that can be complemented by the ERCC1 gene. In fact, in this cell line, PNU-159548 was 3.5-fold more active than in the parental cell line. By comparing the activity of PNU-159548 in NER defective cells with that of other alkylating agents, it can be seen that PNU-159548 behaves differently from classical alkylating agents, such as L-PAM and DDP, which did show a marked increase in cytotoxicity (>74-fold and >24-fold, respectively) in cells lacking a functional ERCC1 or ERCC4/XPF gene.


View this table:
[in this window]
[in a new window]

  		Table 4 In vitro cytotoxic activity of PNU-159548 in CHO parental cell line (AA8) and in UV-sensitive strains (UV47 and UV96)

 
In Vivo Studies.
The activity of PNU-159548 observed in vitro against MDR-1 gene-expressing cells was confirmed in vivo in animals receiving transplants of the parental P388 or L1210 murine leukemias and their resistant sublines. PNU-159548 did show dose-dependent activity against L1210- and P388-bearing mice and, more importantly, did retain activity in the MDR-1-expressing resistant sublines, with an ILS% ranging from 66 to 104% (Table 5)Citation . As already observed in vitro, both P388/DX and L1210/DX showed cross resistance in vivo to DX and IDA. Similarly, PNU-159548 maintained in vivo antitumor activity against alkylating agent-resistant L1210 sublines (Table 6)Citation . In all of the four sublines tested, in fact, the compound was able to increase ILS% by 42% or more and was always more active when compared with the drug used to select the resistant subline.


View this table:
[in this window]
[in a new window]

  		Table 5 Antitumor activity of PNU-159548 against disseminated MDR-1 resistant leukemias (comparison with DX and IDA)

 

View this table:
[in this window]
[in a new window]

  		Table 6 Antitumor activity of PNU-159548 against disseminated leukemias resistant to alkylating agents and campthotecins

 
Finally PNU-159548 was equally active against L1210 parental and topoisomerase I-resistant sublines in vivo (Table 6)Citation , independently of which drug was used to select the resistance.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
PNU-159548 is a new antitumor agent with alkylating properties. The drug has shown promising preclinical antitumor activity (8) and is now in Phase II clinical trial (4) . Its mechanism of action is still unknown, although in vitro experiments clearly demonstrated its ability to bind and alkylate DNA (9) . However, cell lines selected for resistance to classical alkylating agents did not show cross-resistance with PNU-159548, suggesting that the compound could preferentially bind covalently to DNA regions different from those alkylated by conventional alkylating agents, or that other intracellular targets could be responsible for its mechanism of action. Moreover, PNU-159548 maintains its activity on MDR-1-expressing resistant cells, again suggesting that the simultaneous presence of an anthracycline backbone and an alkylating moiety could lead to a mechanism of action and resistance different from that of anthracyclines. The fact that in all of the MDR-1 tumor models used here, DX and IDA, the latter being anthracycline the most closely structurally related to PNU-159548, have shown a clear cross-resistance, further supports the idea that this compound behaves differently from anthracyclines. In line with these findings are the observations that PNU-159548 does not interact, at least at pharmacologically relevant concentrations, with topoisomerase II (4) , a classical target of anthracyclines (10 , 11) , and that the intracellular levels of PNU-159548 are similar in MDR-1-positive and -negative cells.

Although theoretically one could expect no cross resistance between PNU-159548 and topoisomerase I-inhibitors, it was important to verify that this was the case. Indeed, a slight in vitro collateral sensitivity, which has not yet been explained, was found in two sublines with different mechanisms of alteration of topoisomerase I activity, i.e., reduction of catalytic activity of topoisomerase I (L1210/CPT) and mutations at amino acid aa621 N-T and aa361 G-W (L1210/9-AC; Ref. 12 ).

To get some insight into the mechanism of action of PNU-159548, we investigated its cytotoxicity in cell lines defective in NER and MMR systems. It has been reported that cells defective in ERCC1 and ERCC4/XPF, two rate-limiting step proteins belonging to the NER system, have an increased susceptibility to treatment with classical alkylating agents, including DDP and L-PAM (13 , 14) . Even if PNU-159548 showed a little increase in activity in the two NER-defective cell lines selected, this was well below the effect observed after DDP and L-PAM treatment and much more similar to that observed after treatment with minor-groove-alkylating agents (14) . The results are in contrast with its strong alkylation observed in vitro with naked DNA, suggesting the possibility that, in vivo, in intact cells, PNU-159548 alkylation could be quantitatively modest. Such a possibility is supported by the data obtained with DNA-minor-groove-alkylating agents which, beside alkylating the minor groove (as opposed to major-groove alkylation produced by DDP and L-PAM), have been reported to produce a lower number of alkylations as compared with classical alkylating agents (5 , 15) . An additional possibility is that other repair enzymes could be responsible for the removal of adducts induced by PNU-159548 treatment. Regarding the MMR system, the loss of its activity is associated with a reduced activity of some alkylating agents, including DDP and minor-groove binders, DX, and, recently, also aphidicolin (6 , 16, 17, 18, 19, 20) . In addition, not only cell lines selected for resistance to DDP, but also several tumors, have been reported to lack in MMR (17 , 20) , supporting the importance of this repair system in the response to treatment with different anticancer agents. PNU-159548 showed no differences in activity between MMR-proficient or -deficient cells. This could have an important consequence, considering that the activity of the different drugs used in the clinic is influenced by defects in the MMR, and, therefore, a compound with similar or higher activity against MMR-defective cells could represent an important alternative in tumors known to have such a defect. In addition, using isogenic cellular systems, we found that other sensors of DNA damage, such as p53 and DNA-PK, which are known to influence the activity of DNA damaging agents, including alkylating agents and anthracyclines (22, 23, 24, 25) , also did not influence the activity of PNU-159548 (data not shown).

In conclusion the new anticancer agent PNU-159548 shows strong activity in a panel of murine and human cancer cell lines with different mechanisms of resistance. The observed non-cross-resistance in vitro, confirmed in vivo, indicates that the compound has a new mechanism of action different from both anthracyclines and alkylating agents. PNU-159548 could represent a good alternative in the treatment of tumors refractory to treatment with the anticancer agents commonly used in the clinic.


   ACKNOWLEDGMENTS
 
We thank Drs. Giancarlo Marra (Zurich, Switzerland) and Robert Brown (Glasgow, United Kingdom) for the HCT116+ch3 and A2780/CP70+ch3 cells, respectively.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 S. M. is the recipient of a fellowship from the Federazione Italiana Ricerca Cancro. Back

2 To whom requests for reprints should be addressed, at Laboratory of Molecular Pharmacology, Instituto di Ricerche Farmacologiche "Mario Negri," via Eritrea 62, 20157 Milan, Italy. Fax: 39-02-3546277; E-mail: marchini{at}marionegri.it Back

3 The abbreviations used are: IDA, idarubicin, 4-demethoxydaunorubicin; PNU159548, 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin; DDP, cis-dichloro-diammine platinum; MNNG, N-methyl-N-nitro-N-nitrosoguanidine; L-PAM, melphalan; DMSO, dimethylsulfoxide; FCS, fetal calf serum; CHO, Chinese Hamster Ovary; MST, median survival time; ILS%, percent increase in life span; DX, doxorubicin; NER, nucleotide excision repair; MMR, mismatch repair; MDR, multidrug resistance; at-MDR, altered MDR; TAX, taxol; CPT, camptothecin; 9-AC, 9-amino-camptothecin; CTX, cyclophosphamide; BCNU, Lomustine, 1,3-bis-(2-chloroethyl)-1-nitrosourea; VLB, vinblastine; VM-26, teniposide; IC50, concentration inhibiting colony formation by 50%; DNA-PK, DNA dependent protein kinase. Back

Received 7/ 5/00. Accepted 1/ 2/01.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Fields S. M., Koeller J. M. Idarubicin: a second-generation anthracycline. DICP, 25: 505-517, 1991.[Abstract]
  2. Arcamone F. Properties of antitumor anthracyclines and new developments in their application: Cain memorial award lecture. Cancer Res., 45: 5995-5999, 1985.[Abstract/Free Full Text]
  3. Capranico G., Riva A., Tinelli S., Dasdia T., Zunino F. Markedly reduced levels of anthracycline-induced DNA strand breaks in resistant P388 leukemia cells and isolated nuclei. Cancer Res., 47: 3752-3756, 1987.[Abstract/Free Full Text]
  4. Geroni C., Ripamonti M., Marsiglio A., Pastori A., Caruso M., Bargiotti A. PNU-159548 (4-demethoxy-3'-deamino-3'-aziridinyl-4'methylsulphonyl-DNR), a novel cytotoxic agent with wide spectrum of activity. Proc. Am. Assoc. Cancer Res., 39: 221 1998.
  5. Marchini S., Cozzi P., Beria I., Geroni C., Capolongo L., D’Incalci M., Broggini M. Sequence-specific, DNA alkylation of novel tallimustine derivatives. Anticancer Drug Des., 13: 193-205, 1998.[Medline]
  6. Koi M., Umar A., Chauhan D. P., Cherian S. P., Carethers J. M., Kunkel T. A., Boland C. R. Human chromosome 3 corrects mismatch repair deficiency and microsatellite instability and reduces N-methyl-N'-nitro-N- nitrosoguanidine tolerance in colon tumor cells with homozygous hMLH1. Cancer Res., 54: 4308-4312, 1994.[Abstract/Free Full Text]
  7. Durant S. T., Morris M. M., Illand M., McKay H. J., McCormick C., Hirst G. L., Borts R. H., Brown R. Dependence on RAD52 and RAD1 for anticancer drug resistance mediated by inactivation of mismatch repair genes. Curr. Biol., 9: 51-54, 1999.[Medline]
  8. Geroni C., Ripamonti M., Arrigoni C., Fiorentini F., Capolongo L., Moneta D., Marchini S., Della Torre P., Albanese C., Lamparelli M. G., Ciomei M., Rossi R., Caruso M. Pharmacological and toxicological aspects of PNU-15948: a novel antineoplastic agent. Cancer Res., 61: 1983-1990, 2001.[Abstract/Free Full Text]
  9. Marchini S., Gonzalez Paz O., Ripamonti M., Geroni C., Bargiotti A., Caruso M., Todeschi S., D’Incalci M., Broggini M. Sequence-specific, DNA interactions by novel alkylating anthracycline derivatives. Anticancer Drug Des., 10: 641-653, 1995.[Medline]
  10. Binaschi M., Farinosi R., Austin C. A., Fisher L. M., Zunino F., Capranico G. Human DNA topoisomerase II{alpha}-dependent DNA cleavage and yeast cell killing by anthracycline analogues. Cancer Res., 58: 1886-1892, 1998.[Abstract/Free Full Text]
  11. Gewirtz D. A. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics Adriamycin and daunorubicin. Biochem. Pharmacol., 57: 727-741, 1999.[Medline]
  12. Capolongo L., Albanese C., Ciomei M., Geroni C., Isacchi A., Magistrelli G., Marsiglio A., Ripamonti M., Grandi M. Characterization of L1210 murine leukemia cell lines resistant to camptothecins. Proc. Am. Assoc. Cancer Res., 39: 217 1998.
  13. Grant D. F., Bessho T., Reardon J. T. Nucleotide excision repair of melphalan monoadducts. Cancer Res., 58: 5196-5200, 1998.[Abstract/Free Full Text]
  14. Damia G., Imperatori L., Stefanini M., D’Incalci M. Sensitivity of CHO mutant cell lines with specific defects in nucleotide excision repair to different anticancer agents. Int. J. Cancer, 66: 779-783, 1996.[Medline]
  15. Broggini M., Coley H. M., Mongelli N., Pesenti E., Wyatt M. D., Hartley J. A., D’Incalci M. DNA sequence-specific adenine alkylation by the novel antitumor drug tallimustine (FCE 24517), a benzoyl nitrogen mustard derivative of distamycin. Nucleic Acids Res., 23: 81-87, 1995.[Abstract/Free Full Text]
  16. Colella G., Marchini S., D’Incalci M., Brown R., Broggini M. Mismatch repair deficiency is associated with resistance to DNA minor groove alkylating agents. Br. J. Cancer, 80: 338-343, 1999.[Medline]
  17. Aebi S., Kurdi-Haidar B., Gordon R., Cenni B., Zheng H., Fink D., Christen R. D., Boland C. R., Koi M., Fishel R., Howell S. B. Loss of DNA mismatch repair in acquired resistance to cisplatin. Cancer Res., 56: 3087-3090, 1996.[Abstract/Free Full Text]
  18. Fink D., Nebel S., Aebi S., Zheng H., Cenni B., Nehme A., Christen R. D., Howell S. B. The role of DNA mismatch repair in platinum drug resistance. Cancer Res., 56: 4881-4886, 1996.[Abstract/Free Full Text]
  19. Moreland N. J., Illand M., Kim Y. T., Paul J., Brown R. Modulation of drug resistance mediated by loss of mismatch repair by the DNA polymerase inhibitor aphidicolin. Cancer Res., 59: 2102-2106, 1999.[Abstract/Free Full Text]
  20. Fink D., Aebi S., Howell S. B. The role of DNA mismatch repair in drug resistance. Clin. Cancer Res., 4: 1-6, 1998.[Abstract]
  21. Brown R., Hirst G. L., Gallagher W. M., McIlwrath A. J., Margison G. P., van der Zee A. G., Anthoney D. A. hMLH1 expression and cellular responses of ovarian tumor cells to treatment with cytotoxic anticancer agents. Oncogene, 15: 45-52, 1997.[Medline]
  22. Muller C., Christodoulopoulos G., Salles B., Panasci L. DNA-dependent protein kinase activity correlates with clinical and in vitro sensitivity of chronic lymphocytic leukemia lymphocytes to nitrogen mustards. Blood, 92: 2213-2219, 1998.[Abstract/Free Full Text]
  23. Christodoulopoulos G., Muller C., Salles B., Kazmi R., Panasci L. Potentiation of chlorambucil cytotoxicity in B-cell chronic lymphocytic leukemia by inhibition of DNA-dependent protein kinase activity using Wortmannin. Cancer Res., 58: 1789-1792, 1998.[Abstract/Free Full Text]
  24. Waldman T., Zhang Y., Dillehay L., Yu J., Kinzler K., Vogelstein B., Williams J. Cell-cycle arrest versus cell death in cancer therapy. Nat. Med., 3: 1034-1036, 1997.[Medline]
  25. Ko L. J., Prives C., Maki C. G., Huibregtse J. M., Howley P. M. p53: puzzle and paradigm. Genes Dev., 56: 2649-2654, 1996.



This article has been cited by other articles:


Home page
 Pharmacol. Rev.Home page
G. Minotti, P. Menna, E. Salvatorelli, G. Cairo, and L. Gianni
Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity
Pharmacol. Rev., June 1, 2004; 56(2): 185 - 229.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Marchini, S.
Right arrow Articles by Geroni, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Marchini, S.
Right arrow Articles by Geroni, C.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online