Original Paper Oncology 1992:49:173 179

Toshiya Misawa Fumitaka Kikkawa Hidenori Oguchi Yoshimitsu Morikawa Michiyasu Kawai Osamu Maeda Mitsumasa Iwata Takeo Kano Yoshihito Furuhashi Yutaka Tomoda

Accumulation of c/s-Diamminedichloroplatinum (II) and Its Analogues in Sensitive and Resistant Human Ovarian Carcinoma Cells

Department o f Obstetrics and Gynecology. Nagoya University School o f Medicine. Nagoya. Japan

Abstract

Human ovarian carcinoma cell line (NOS2). established from a patient with serous cystadenocarcinoma of the ovary, has been exposed to a stepwise in­ crease in m-diamminediehloroplatinum (11) (CDDP) concentration to pro­ duce a CDDP-resislant cell line NOS2CR) as an experimental model for resis­ tance to CDDP. NOS2CR cells showed a 7-fold resistance to CDDP and a les­ ser degree of cross-resistance to diammine (1,1-cyclobutanedicarboxylato)platinum (II) (CBDCA) and (-)-(R)-2-aminomethylpyrrolidine (1,1-cyclobutanedicarboxylato) platinum (II) (DWA2114R). In the absence of CDDP. cross-resistance to DWA2114R was reduced to the original level by 2 months, although 83% resistance to CDDP remained up to 6 months. To investigate CDDP-resistant mechanisms, alterations in the intracellular accumulation of CDDP and analogues were assayed by atomic absorption. In both NOS2 and NOS2CR cells, accumulation of CDDP increased linearly with time and was concentration-dependent. NOS2CR cells demonstrated 71,52 and 12% reduc­ tion in accumulation of CDDP, CBDCA, and DWA2II4R, respectively. These reductions did not seem to be due to P-glycoprotein, because expression of multidrug-resistant I gene was not detected in either NOS2 or NOS2CR cells. These studies indicate that the mechanisms of resistance to CDDP and analogues in NOS2CR cells are related in the main to reduced intracellular ac­ cumulation of drugs. DWA2II4R might be helpful to treat CDDP-resistant and recurrent tumors which were treated by CDDP.

Introduction

CDDP [m-diamminedichloroplatinum (II)] is an anti­ cancer drug widely used in the therapy of a broad spectrum of cancers. For the treatment of ovarian cancer, it has

proven to be the most useful anticancer drug, and the clini­ cal complete response rate increased from 30 to 50% in stage III and IV ovarian carcinoma since combination therapy of CDDP was introduced to treat ovarian cancer [1], Development of resistance often limits the clinical use-

Dr. Toshiya Misawa Department o f Obstetrics and Gynecology Nagoya University School of Medicine Tsurumai-cho 65. Showa-ku Nagoya 466 (Japan)

r 1992 S. Karger AG. Basel 0030 2414/92, 0493 0173 S 2.75, 0

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KeyWords Cisplatin Carboplatin DWA21I4R Ovarian carcinoma Drug resistance

Materials and Methods Chemicals. C D D P. CBDCA. and D W A 2II4R were obtained from Nippon Kayaku Ltd. (Tokyo, Japan). Bristol Myers Squibb Ltd. (Tokyo. Japan), and Chugai Pharmaceutical Co. Ltd. (Tokyo. Japan), respectively. A C N U (nimustine) and carboquone were ob ­ tained from Sankyo Ltd. Adriamycin was obtained from Kyowa Hakko Kogyo Ltd. All anticancer drugs were used in clinically avail­ able formulations. Tetrazolium salt (MTT) and deoxycytidine 5'-(uP)-triphosphate were purchased from Sigma and Amersham Japan Ltd. (Tokyo, Japan), respectively. Cell Lines. The NOS2 cell line was established from a patient with serous cystadenocarcinoma o f the ovary. By continuous exposure to

174

C D D P while slowly escalating the concentration for 18 months, this cell line acquired C D D P resistance, and was designated NOS2CR. By continuous exposure to adriamycin for 12 months, we also estab­ lished an adriamycin-resistant cell line (NOS2AR) which has a 23fold resistance to adriamycin. These cell lines were maintained in RPMI 1640 medium supplemented with 10% (v/v) fetal bovine serum and 2 mM L-glutamine Cultures were equilibrated with hu­ midified 5% CO; in air at 37 C. M TT Assay. Sensitivity to anticancer drugs was measured by MTT assay as described in our previous report [13]. Cells were cul­ tured for 4 days in a medium containing drugs at various concentra­ tions. After the addition o f MTT. incubation was continued for a further 4 h. The supernatant was aspirated, and then the resulting pigment was dissolved in dimethyl sulfoxide. The absorbance was measured at 550 nm by an easy plate reader (EA R 400 FW. SLT-Lab instruments). Each point was the mean o f 6 values, and the resistance factor was calculated by dividing the IG® value for NOS2CR cells by the IC,„ value for NOS2 cells. Accumulation o f Platinum Drui;s. Exponentially growing cells were incubated in freshly changed RPMI 1640 medium containing 10% fetal bovine serum and each platinum drug at various con­ centrations. After washing with phosphate-buffered saline twice, cells were collected by trypsinization and were stored at —20 C for use. Analysis for intracellular platinum accumulation was performed by a modified method o f Peraar.d Harder [14]. Cell pellets were mixed with concentrated H N O , and then evaporated until dry. Each sample was dissolved in 0.1 N H N O , and determined for platinum by flame­ less atomic absorption spectrophotometry (AA-8500 MK II, N ip­ pon Jarrell-Ash Co. Ltd.). The intracellular platinum accumulation was normalized to the cellular protein content estimated by BCA pro­ tein assay kit. Northern Hybridization. Total R NA s were obtained from NOS2, NOS2CR and NOS2AR cells by a method o f CsCl [15], Ten micro­ grams o f the total R NA s were elcctrophoresed on 1% agarose gel containing 0.66 M formaldehyde and were then transferred to a nyl­ on filter. rRNA was used as a size marker. The probe for multidrug resistant 1 gene was labelled with (a-}:P) dCTP by random primer translation. Hybridization w as performed at 65 C overnight. The fil­ ter was washed with 2 x SSC containing 0.5% SDS 4 or more times, whereupon autoradiography was performed.

Results

NOS2 and NOS2CR cells grow as a uniform monolayer culture on plastic and there was no significant change in morphology. The effects of CDDP. CBDCA, and DWA2114R in inhibiting cellular growth in sensitive and resistant NOS2 cells are shown in figure 1. The results re­ vealed a 7-fold increase in the concentration of CDDP re­ quired to cause a 50% reduction in the percentage of con­ trol cell growth in NOS2CR cells compared to NOS2 cells (fig. 2A). Recently, new CDDP analogues have been de­ veloped with expectations to diminish the severe side ef­ fects of CDDP and to overcome the resistance [ 16-19], To investigate the effectiveness of CBDCA and DWA2114R

Misawa/Kikkawa/Oguchi Morikawa/ Kawai/Maeda/Iwata/Kano Furuhashi/ Tomoda

Accumulation of CDDP and Its Analogues

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fulness of CDDP for cancer treatment. Mechanisms of re­ sistance to CDDP have been investigated in CDDP-rcsistant cell lines to prevent the resistance and improve the sen­ sitivity to CDDP [2-4]. Several possible mechanisms of the resistance to CDDP are proposed. First, decreased in­ tracellular accumulation of CDDP was observed in resis­ tant cells [5-7]. Second, increased intracellular glutathione levels and enhanced activity of glutathione S transferase (GST) were reported [8-10], Glutathione and GST are thought to play a main role in detoxification. Sensitivity to alkylating agents, such as chlorambucil, melphalan, and CDDP, was not altered, however, in this enzyme transfectant cells which showed more than 3 times activity of GST [11], Third, increased removal of DNA-bound CDDP was reported [12]. Several approaches have been followed to overcome resistance, such as enhancement of intracellular CDDP accumulation by verapamil and depiction of in­ tracellular glutathione by /),L.-buthionine sulfoximine [2, 3], However, these attempts have met with limited success because the resistant mechanism is multifactorial and dif­ fers from cell line to cell line. Recently, several CDDP analogues have been de­ veloped. Carboplatin (1,1-cyclobutanedicarboxylato) platinum (II) (CBDCA) - is the first available analogue with lower emetic potential and nephrotoxicity, but it causes severe thrombocytopenia. (-)-(R)-2-aminomethylpyrrolidine (1.1-cyclobutanedicarboxylato) plati­ num (II), (DWA 2114R), a new platinum anticancer drug, causes lower nephrotoxicity and less thrombocytopenia. The clinical effectiveness of this drug on ovarian cancer was demonstrated in phase II and III trials in Japan. NOS2CR cells were established by exposing NOS2 cells, derived from ovarian serous cystadenocarcinoma, to CDDP for 18 months to investigate the mechanisms of re­ sistance to CDDP and cross-resistance to other CDDP an­ alogues. The results of this study indicate which drugs are useful for treating CDDP-resistant tumors.

o II

N

Fig. 1. Chemical structures o f C D D P. CBDCA, and D W A2II4R.

H

^

/ - Cl

NHi \

^

NH / Pt\ 0_ c A y

a

CDDP

on resistant cells, we examined the efficacy of two an­ alogues on NOS2CR cells. Figure 2B and C indicates that a lesser degree of cross-resistance to CBDCA and no sig­ nificant cross-resistance to DWA2114R were present. We examined cross-resistance to alkylating agents and adriamycin to investigate possible mechanisms of resistance to CDDP in NOS2CR cells, since it is thought that platinum drugs, alkylating agents, and adriamycin induce DNA damage. Platinum drugs arc converted to an aquated and charged intermediate that interacts with the 7N of adenine and guanine base of DNA in cells [20,21]. IC^ values and resistance factors are shown in table I. NOS2CR cells had various degrees of cross resistance to all drugs except for adriamycin. The resistance factor for DWA2114R was the lowest among the 3 platinum drugs and 2 alkylating agents, suggesting that DWA2114R could be useful to CDDP-resistant cancer. The stability ofNOS2CR cells is presented in table 1. In the absence of CDDP selection, the resistance to CDDP gradually declined over the course of 6 months from 7-fold to 5.8-fold. The resistance to CDDP was very stable, in­ dicating that the mechanism could be attributable to herit­ able genetic alterations. The resistance to two alkylating agents and CBDCA remained in 6 months revertant cells (NOS2CR6M), while that to DWA2114R was observed only little even in 2-month revertant cells (NOS2CR2M). Differences of the rate of losing cross-resistance to the dif­ ferent agents suggests that there were plural mechanisms in the resistance to CDDP. One of the most important mechanisms of resistance is decreased intracellular accumulation of anticancer drugs in cells. Thus, we measured intracellular platinum ac­ cumulation of each platinum drug by atomic absorption. Attempts to measure intracellular platinum accumulation at low concentrations were not successful, since the amount found in cells after the short time of exposure was below the detection limit. Both cell lines were exposed at high concentrations. These concentrations were relatively non toxic to the cells because of the short time of exposure

/ ' 0—

" \ A

CBDCA

A

rN H % / 0_ cy \ ■i*y—

N H ^

K>

^ 0 —

C '\/

8 DWA2114R

Fig. 2. Inhibition o f cell growth by C D D P (A). CBDCA (B ). and DW A2114R (C) in N O S 2 (O la n d NOS2CR cells ( # ) as determined by MTT assay. Points are the mean values for 6 independent experi­ ments. Bars indicate the SD.

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NH)\

Fig. 3. Accumulation o f intracellular C D D P in NOS2 ( O ) and NOS2CR cells ( • ) as measured by atomic absorp­ tion. A Accumulation o f intracellular C D D P after 2 h o f treatment with various concentrations. B Accumulation o f intracellular C D D P after treatment with 200 \iM C D D P for various times. Points are the mean values for 3 indepen­ dent experiments. Bars indicate the SD.

Table 1. Sensitivity o f NOS2. NOS2CR. and revenant cells to anticancer drugs 1C», ng/ml NOS2 C DD P

1.6

CBDCA

28.0

DW A2I14R

23.0

Carboquon A CN U Adriamycin

0.0023 15.0 0.33

NOS2CR

NOS2CR 1 M

N O S2C R 2 A/

NOS2CR 4 M

NOS2CR 6 M

11.2 (7.0) 82.8 (3.0) 36.8 (1.6) 0.009 (3.9) 63.8 (4.3) 0.27

11.2 (7.0) 58.8 (2.1) 27.6 (1.2) 0.0094 (4.1) 62.3 (4.2)

10.9 (6.8) 53.2 (1.9) 25.3 (1.1) 0.0076 (3.3) 59.5 (4.0)

9.3 (5.8) 44.8 (1.6)

9.3 (5.8) 42.0 (1.5)

0.0067 (2.9) 35.7 (2.4)

0.003 (1.3) 34.4 (2.3)

Values in parenthesis are resistance factors defined as I C » o f respective cells, 1C» o f NOS2 cells.

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tieth of that of CDDP by exposure to the same concentra­ tion in NOS2 cells. However, reduction of this drug in NOS2CR cells was only 13% (fig. 4B). It is well known that P-glycoprotein is closely related to adriamycin resistance [22, 23]. Thus, we examined the ex­ pression of MDR 1 gene,encoding for P-glycoprotein, in NOS2, NOS2CR, and NOS2AR cells (fig. 5). Messenger RNA for MDR 1 gene was detected in NOS2AR cells but not in NOS2 and NOS2CR cells. This suggests that de­ creasing accumulation of CDDP was not due to the M DR 1gene, and that other transport systems exist.

Misawa Kikkawa/Oguchi'Morikawa, Kawai Maeda, Iwata Kano Furuhashi Tomoda

Accumulation of CDDP and Its Analogues

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to the drugs. The accumulation of CDDP was linear over a 3-hour incubation time and concentrations from 50 to 300 \xM in both sensitive and resistant NOS2 cells (fig. 3). NOS2C R cells demonstrated a 71 % decrease in accumula­ tion of CDDP over NOS2 cells. This indicated that de­ creased intracellular accumulation of CDDP contributed partially to the resistance to CDDP. Accumulation of CBDCA was lower than that of CDDP by exposure of the same concentration in NOS2 cells. NOS2CR cells demon­ strated a 50% reduction in accumulation of CBDCA (fig. 4A). Accumulation of DWA2114R was only one-twen­

Fig. 4. Accumulation o f intracellular CBDCA (A) and DW A2114R (B ) after 2 h treatment at various concentra­ tions in NOS2 (O) and NOS2CR cells ( • ) as measured by atomic absorption. Points are the mean values for 3 or 4 independent experiments. Bars indicate the SD.

Discussion 2

3

Fig. 5. Northern blot analysis o f M DR 1 m R NA . Ten micro­ grams o f total RN As extracted from NOS2 (lane 1). NOS2CR (lane 2), and NOS2AR cells (lane 3) were electrophoresed on 1% agarose gel containing 0.66 M formaldehyde. A M DR 1 gene was used as a probe. B The ethidium bromide-stained gel indicates the degree o f loading equivalence.

The objective of this study was to investigate mecha­ nisms underlying resistance to CDDP in NOS2CR cells and to find an effective anticancer drug on CDDP-resistant tumors. NOS2CR cells show a 7-fold resistance to CDDP over NOS2 cells. Many CDDP resistant cell lines have been established, but there have been only a few re­ ports of resistance being examined in revertant cells. Frei et al. [24] established a CDDP-resistant cell line derived from squamous cell carcinoma of the tongue. These resis­ tant cells, generated by exposure to CDDP for 2 months, rapidly lost the resistant phenotype. Further selection pressure for over 9 months caused more stability and the resistance was one-third the original level 3 months after removal of CDDP pressure. In the absence of CDDP selec­ tion, the resistance of COLO B cells, derived from ovarian carcinoma, gradually declined over the course of 6 months from 14-fold to 5-fold [25]. Developing stable resistant cell lines seems to require a long time of selection pressure. Thus, we cultured NOS2 cells in a medium while slowly escalating the concentration of CDDP for 18 months. The resistance remained in NOS2CR6M cells, which werecultured in the absence of CDDP for 6 months, and the resis­ tance factor was reduced slightly from 7 to 5.8. The resis­ tance in NOS2CR cells was stable enough and suitable for our purposes, because most recurrent tumors which were treated with CDDP previously have stable resistance to CDDP.

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1

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but other mechanisms may also exist. A decrease in ac­ cumulation of CDDPcould indicatean altered influx and/ or efflux, but these studies did not address this question. Expression of MDR1 gene, encoding for P-glycoprotein, was not detected in NOS2 and NOS2CR cells, although this expression was observed in NOS2AR cells. This showed that the altered transport system was not due to P-glycoprotein. There were several reports that the de­ crease in accumulation of CDDP in resistant cells is due to a decreased influx [30. 31]. We also examined the ac­ cumulation of CDDP analogues. Intracellular accumula­ tions of CBDCA and DWA2114R showed 63 and 87% of those in NOS2 cells, respectively. The degree of resistance and the intracellular platinum level correlated reversely, suggesting that an altered transport system mainly causes resistance to CDDP and its analogues. In NOS2 cells, in­ tracellular accumulation of DWA2114R was only onetwentieth that of CDDP at exposure of the same con­ centration. while in NOS2CR cells, it was one-fifth. How­ ever, a 10-fold dose of DWA2114R caused a lesser degree of side effects, such as leukopenia, thrombocytopenia, and nephrotoxicity, than CDDP [32], In conclusion, DWA2114R is the most effective on NOS2CR cells of the 3 platinum anticancer drugs, and thereisonly a littledifferencein intracellularaccumulation between NOS2 and NOS2CR cells. This sugests that DWA2114R could be a helpful new platinum anticancer drug to CDDP-resistant tumors.

Acknowledgements This work was supported in part by a grant to Y .T. (02404067) from the Ministry o f Education, and by a grant to Yoshihito Furuhashi from the Japan Association o f Gynecological Malignant Tu­ mor.

Misawa Kikkawa/Oguchi/Morikawa/ Kawai Maeda Iwata Kano/ Furuhashi, Tomoda

Accumulation of CDDP and Its Analogues

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Multiple drug resistance is often encountered in vivo and in vitro. Since mechanism of cytotoxicity of CDDP is to interact with cellular DNA like alkylating agents and adriamycin. cross-resistances to these drugs were exam­ ined (table 1). Although the cytotoxic mechanism of these drugs is thought to be roughly the same. IC,0 values of carboquone and ACNU increased approximately 4-fold, while that of adriamycin was not altered. A lesser degree of cross-resistance to alkylating agents was observed in previous papers [26,27], suggesting that a common action mechanism works between CDDP and alkylating agents. Resistance factors to carboquone and ACNU decreased more in NOS2CR6M than that to CDDP, suggesting that there exist specific mechanisms to CDDP resistance. Although much effort has been made to date to over­ come resistance to CDDP, no effective methods or agents have been developed. Several CDDP analogues, however, have been developed and tried in clinical studies [16-19], CBDCA and DWA2114R were developed to keep po­ tency and to reduce side effects, in particular nephrotoxic­ ity of CDDP. hvata et al. [21] reported that both CDDP and DWA2114R bind specific sequences of DNA, such as deoxy guanine-guanine and deoxy adenine-guanine. However, the resistance factor of DWA2114R was the smallest among CDDP and its analogues, and rapidly de­ creased in revertant cells. Kraker et al. [7] established 2 CDDP-resistant cell lines derived from L1210and 1from P388. Their cells had 39,35 and 22% cross-resistance to CBDCA, respectively, of their resistance to CDDP. In CDDP-resistant BE cells de­ rived from human colon carcinoma, there was 34% of cross-resistance [9], In NOS2CR cells, 43% cross-resis­ tance was observed. However, cross-resistance to DWA2114R was only 23% and no cross-resistance was observed in NOS2CR2M. showing the possibility of effec­ tiveness on recurrent and CDDP-resistant tumors clini­ cally. DNA interstrand cross-link formation by CDDP has been examined recently [28, 29], Bungo et al. [5] observed that the decreased accumulation was paralleled by the de­ creased level of DNA interstrand cross-link formation [5], They concluded that the decrease in the intracellular ac­ cumulation of CDDP might be the main cause of CDDP resistance. Thus, accumulations of CDDP and analogues were assayed by atomic absorption. Accumulation of CDDP increased in a time and concentration dependent manner in NOS2 and NOS2CR cells (fig. 2). The ac­ cumulation in NOS2CR cells was only 29% of that in NOS2 cells. Resistance to CDDP in NOS2CR cells were mediated in part by a decrease in accumulation of CDDP,

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Accumulation of cis-diamminedichloroplatinum (II) and its analogues in sensitive and resistant human ovarian carcinoma cells.

Human ovarian carcinoma cell line (NOS2), established from a patient with serous cystadenocarcinoma of the ovary, has been exposed to a stepwise incre...
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