Yonago Acta medica 2013;56:43–50

Review Article: Special Contribution

New Strategy for Overcoming Resistance to Chemotherapy of Ovarian Cancer
Junzo Kigawa
Tottori University Hospital Cancer Center, Yonago 683-8504, Japan

ABSTRACTThe incidence of ovarian cancer in 2008 was projected
to be 225,500 new cases and 140,200 deaths worldwide,
representing 3.7% of all female cancers and 4.2% of allcancer deaths in women.1 Ovarian cancer, one of the
major causes of death from cancer in women, is commonly diagnosed at advanced stage. Cytoreductive
surgery followed by platinum and taxane-based combination chemotherapy is currently the standard treatment
for ovarian cancer.2 Ovarian cancer is one of the mostsensitive solid tumors, with objective responses ranging
from 60 to 80% even in patients with advanced stage.3
However, most patients ultimately recur and develop
chemo-resistance.
An international study, GOG 182-ICON 5, sought toimprove the efficacy of standard platinum-taxane therapy by incorporating newer cytotoxic agents (gemcitabine,
pegylated liposomal doxorubicin and topotecan).4 Unfortunately, the combination of these agents used instandard therapy has not improved overall survival (OS).
Furthermore, the most effective regimen for second line
chemotherapy has not yet been determined. The secondline chemotherapies have achieved objective responses
in about 10 to 30% of patients and even lower percentage of complete response.5 As a result, the survival rate
for patients with ovarian cancer has not improved overthe past 20 years.6 A new strategy is needed to improve
the prognosis of patients with ovarian cancer.
Resistance to chemotherapy presents a major obstacle to attempt to improve the prognosis of patientswith ovarian cancer. Accordingly, it is important for the
management of ovarian cancer to elucidate the mechanisms of chemoresistance and to get over the resistance.
Recently, the biological characteristics of ovarian cancer
have been clear and molecular-targeted agents including
signal-transduction inhibitors and anti-angiogenesis havedeveloped. Here, a new strategy for treatment of ovariancancer is discussed from the viewpoint of the conquestof chemoresistance based on our data.

Background

Ovarian cancer is one of the most sensitive solid tumors, with objective responses ranging
from 60 to 80% even in patients with advanced stage.
However, most patients ultimately recur and develop
resistance to chemotherapy. As a result, the survival rate
for patients with ovarian cancer has not improved overthe past 20 years. Resistance to chemotherapy presents
a major obstacle to attempt to improve the prognosis ofpatients with ovarian cancer. A new strategy is necessary to improve the prognosis of patients with ovariancancer.
Methods The mechanism of chemoresistance wasreviewed to get over the resistance. Additionally, the biological characteristics of ovarian cancer and moleculartargeted agents including signal-transduction inhibitors
and anti-angiogenesis were discussed.
Results
Genetic diagnosis for chemosensitivity withdrug-resistance genes may be a useful predictor. Unfortunately, molecular-targeted therapy alone has been
insufficient to improve the prognosis for patients withadvanced ovarian cancer. Molecular molecular-targeted
therapy should be carried out together with conventional
cytotoxic agents. On the occasion of the use of the molecular targeted-agents, care of the appearance of theunexpected adverse effect should be important.
Conclusion The future research in this field will enable to develop an effective strategy for conquest of chemoresistance in ovarian cancer.
Key words chemotherapy; molecular targeted agent;ovarian cancer; resistanceCorresponding author: Junzo Kigawa, MD
kigawa@med.tottori-u.ac.jp
Received 2012 December 10
Accepted 2013 March 22
Abbreviations: CDDP, cisplatin; CPT-11, 7-ethyl-10-[4-(1piperidino)-1-piperidino] carbonyloxycamptothecin; ERK, extracellular signal-regulated kinase kinase; FIGO, International
Federation of Gynecology and Obstetrics; GOG, Gynecologic
Oncology Group; ICON, International Collaborative Groupfor Ovarian Neoplasia; KFr, cisplatin-resistant KF; MDR-1,
multidrug-resistance-1; MEK, mitogen-activated protein kinasekinase; MRP, multidrug resistance-associated protein; OS, overall
survival; PDGF, platelet-derived growth factor; PFS, progressionfree survival; PI3K, phosphatidylinositol 3'-kinase; PMA, phorbol
12-myristate 13-acetate; PTX, paclitaxel; topo, topoisomerase;
VEGF, endothelium growth factor

CHEMORESISTANCE MECHANISMS AND
SECOND LINE CHEMOTHERAPY
Anticancer drugs interfere indiscriminately with DNA
synthesis, DNA repair systems and mitosis. Many mechanisms have been postulated to explain chemoresistance,
including decreased drug accumulation inside tumor
43

J. Kigawa

Fig. 1. Many mechanisms of anticancer
agents have been proposed, including
decreased drug accumulation, increased
cellar detoxification by proteins such as
glutathione, decreased the induction of
apoptosis and increased DNA repair.
GCS, glutamylcysteine synthetase;
GSH, glutathione; MDR-l, multidrugresistance-1; MRP, multidrug resistanceassociated protein.

cells, increased cellular detoxification and increased
DNA repair activity.7, 8, 9 Apoptosis and survival signal
pathway also contribute to sensitivity to anti-cancer
agents10, 11 (Fig. 1). Platinum and taxane agents are key
drugs for first line chemotherapy of ovarian cancer.3
Second line chemotherapy should be chosen in consideration of chemoresistance mechanisms.
Platinum agent such as cisplatin (CDDP) is one of
the most active anticancer agents now used. The lengthof the progression free interval following the first platinum-based chemotherapy is the most important predictive factor of response to second line chemotherapy.12, 13,
14, 15The patients who relapse after over 24 months havethe highest chance of responding to the first platinumbased chemotherapy. In contrast, patients who recur
within 6 months show low response rate.13
Despite its broad clinical applications, however, intrinsic or acquired resistance to CDDP often culminatesin chemotherapeutic failure. Of the several approaches
used to overcome the resistance to CDDP, the use ofother drugs given in combination seems to be essential.
Experimental studies on the combined effects of CDDP
and other anticancer agents can provide information on
the most appropriate sequence.
Multidrug resistance-associated protein (MRP)
gene functions as an ATP-dependent pump for cytotoxic
drugs and MRP plays the significant role for platinum
resistance in ovarian cancer.8 Interestingly, topoisomerase (topo) I enzymatic activity was 2- to 4-fold higher
in the CDDP-resistant cell lines compared with theirrespective parent cell lines. Additionally, topo II protein
contents in resistant ovarian cancer cells were significantly greater compared with those of their parent celllines.11 It is reported that the expression levels of topoisomerase were associated with sensitivity to topoisomerase inhibitors.16, 17
DNA topo inhibitors are of interest as targets forcancer chemotherapy.18 7-Ethyl-10-[4-(1-piperidino)-

1-piperidino] carbonyloxycamptothecin (CPT-11) inhibits topo I through the formation of stable topo I-DNA
cleavable complexes.19 CPT-11, a semisynthetic watersoluble derivative of camptothecin, has a potent antitumor activities.19 CPT-11 is known as an effective against
pleiotropic drug-resistant tumors in vitro and in vivo andshows some lack of cross resistance with CDDP.20, 21, 22,
23
Furthermore, the synergism between CDDP and CPT11 has been demonstrated and clinical studies showedthat the CPT-11/CDDP combination was more efficacious than CPT-11 alone.24
KF cells, epithelial ovarian carcinoma cell line anda CDDP resistant subline, KFr were used as an acquired
CDDP-resistant model. The effects of CDDP in combination with SN-38, an active metabolite of CPT-11,
on KF and KFr cells were analyzed using an improved
isobologram method (Fig. 2). For KF cells, the combined data points fell within an envelope surroundedby three lines, indicating an additive effect. In contrast,
for KFr, CDDP-resistant cell line, the data points were
below the envelopes, indicating a supra-additive (synergistic) effect. These results suggest that the combinationof CDDP and SN-38 may be more effective in CDDPresistant cells than in the parent cells. To determine thebiological factors involved in the sensitivity to the combination of CDDP and SN-38, we compared topo I catalytic activity between KF and KFr cells (Fig. 3). Topo I
activity in KFr was greater than in KF cells; the increase
was 4-fold for KFr cells versus KF cells. A potential
mechanism to explain the synergism between CDDP
and topo I inhibitors has been proposed; an increased
DNA interstrand cross-linking by the simultaneous
exposure to CDDP and topo I inhibitor and an enhancement of the activity of topo I inhibitors by high doses ofCDDP.25 Although these findings do not explain why theenhancement of CDDP cytotoxicity by a topo I inhibitor
was observed only in the CDDP-resistant cells, the enhanced topo I activity could, at least in part, contribute44New treatment strategy for ovarian cancer

Fig. 2. Isobolograms of cisplatin (CDDP)
at IC50, based on dose response curves incombination with SN-38 in KF and KFrcell lines. The abscissa shows the ratio ofconcentration to the IC50 for CDDP, andthe ordinate represents that for SN-38.
The solid line represents mode I, and thetwo broken lines represent mode II. The
exposure of CDDP combined with SN-38
to KF cells produces only additive effects. In contrast, for KFr cells the combination of CDDP and SN-38 is synergistic. IC50, half maximal inhibitory concentration; KFr, cisplatin-resistant KF.

Additionally, 60 mg/m2 CDDP was infused intravenously over a 120- min period on day 1. Of the 30 patients,
18 responded to CPT-11 and CDDP (complete response= 2; partial response = 16) and 12 did not (no change =8; progressive disease = 4). There were no significant
differences in patient characteristics and performancestatus between the responders and the nonresponders to
the second line chemotherapy. The minimum amount of
extracted nuclear protein after platinum-based chemotherapy showing complete DNA relaxation ranged from15 to 388 ng. The amount of nuclear protein required forcomplete DNA relaxation was significantly greater in
responders than in nonresponders (201.7 ± 92.5 versus
124.1 ± 59.4 ng, P = 0.0164; Fig. 4). This result reflects
our in vitro finding that topo I activity was enhancedby exposure to CDDP and related to chemosensitivity.
Therefore, the combination chemotherapy consisting of
CPT-11 and CDDP may be an effective second line chemotherapy for CDDP resistant ovarian cancer.

to the enhancement of CDDP cytotoxicity in CDDP-resistant cells more effectively than in the parent cells. Additionally, a significant correlation between the sensitivity for SN-38 and topo I activity was observed. Fukuda
et al. demonstrated that the sensitivity of tumor cells to
topo I inhibitors was associated with intracellular topo
I level.26 Topo I expression reflects sensitivity to topo I
inhibitor.26, 27 Hochster et al.27 found a negative correlation of topo I protein level with area under the curve of
topo I inhibitor, and Subramanian et al.28 demonstrated
that topo I activity measured by ICE bioassay related toresponse to topo I inhibitor. Those findings including
our study mentioned above suggest topo I activity may
be a useful predictor of resistance or sensitivity to CPT11 based chemotherapy.
Next, we examined the relationship between topo I
activity and the sensitivity to chemotherapy consisting of
CDDP and CPT-11 in patients with relapsed ovarian cancer.29 A total of 30 subjects were selected from patientsfor recurrent epithelial ovarian cancer with measurable
lesions. All patients had initially undergone platinumbased chemotherapy. All patients underwent surgery to
remove recurrent tumor before second line chemotherapy consisting of CPT-11 and CDDP, but did not receive
complete resection. Tumor samples were obtained at thesurgery. All patients received 50 to 60 mg/m2 CPT-11
intravenously over a 90-min period on days 1, 8 and 15.

Genetic diagnosis for chemosensitivity with drug-resistance genes
In previous chemosensitivity assays, cancer cells wereisolated from the tumor, and these cultured cells were
exposed to chemotherapeutic agents for evaluating theeffectiveness of agents. The assays are complex and dif-

Fig. 3. Topo I catalytic activity
in KF and KFr cells. Topo I
catalytic activity in KFr cells
is 4-fold of that in KF cells.
KFr, cisplatin-resistant KF;
topo, topoisomerase.

45

J. Kigawa

and the expression levels of topo IIalpha were lower in
etoposide-resistant cell lines than in their parent celllines that contained fewer copies than their parent cells.
The expression of topo I was significantly higher in CPT11/CDDP responders and topo IIalpha was also higher
in etoposide responders, suggesting that the expression
level of topoisomerase contributes to sensitivity to topoisomerase inhibitor.31
As a result, the accuracy of the present genetic diagnosis for chemosensitivity was 85.7 % for taxane/carboplatin therapy, 77.8% for etoposide /cisplatin and 100.0%
for CPT-11/CDDP therapy.

Fig. 4. The amount of
the extraction is significantly greater innonresponders thanin responders (201.7± 92.5 versus 124.1 ±59.4 ng).

Molecular-targeted therapy
Recent advances in our understanding of the molecularbiology of cancer and carcinogenesis have led to a variety of targeted agents. Targeted agents affect tumor cells,
tumor stroma, tumor vasculature and cellular signalingmechanisms that are aberrant in tumor tissue. They are
now entering clinical trials and are expected to become
attractive treatment options for malignancies.33, 34 Now,
molecular-targeted therapies for ovarian cancer including signal-transduction inhibitors and anti-angiogenesis
have developed and several clinical trials have been
performed for ovarian cancer.33, 35, 36 Unfortunately,
molecular-targeted agent alone has been insufficient
to improve the prognosis for advanced ovarian cancer.
Therefore, molecular-targeted therapy should be carriedout together with conventional cytotoxic agents.
Angiogenesis is a process critical for continuous
tumor growth, invasion and metastasis. The new bloodvessels created by angiogenesis from existing vasculature (neovascularization) is a complex process regulated
by a number of growth factors and cytokines, such as
vascular endothelium growth factors (VEGFs), fibroblast
growth factors, angiopoietin, platelet-derived growth
factors (PDGFs), tumor necrosis factor-alpha and interleukin 6 and 8 receptor pathways. The VEGF family andits receptors (VEGFRs) are one of the major pathways
involved in tumor neovascularization. In ovarian cancer,
overexpression of VEGF is often observed and has been
associated with increased poor prognosis.37
Bevacizumab is a recombinant, humanized, monoclonal immunoglobulin G1 antibody targeted at VEGFA. This antibody binds to and neutralizes all biologically active forms of VEGF-A (e.g., VEGF-A165) which
suppresses growth of tumors and inhibits progression ofmetastatic disease.38, 39 Additionally, anti-VEGF drugs
are thought to enhance the effects of chemotherapeutic
agents by improving the structure and function (normalization) of tumor vessels.40 Two phase III studies,

ficult. In contrast, genetic diagnosis for chemosensitivity
is more convenient because cell culture is unnecessary
and the transportation of specimen is easy for genetic
diagnosis. cDNA microarray analysis of non-small celllung cancers after laser-capture microdissection of cancer cells from primary tumors, showing a significant association between expression levels of genes and chemosensitivity.30 The reference of the gene, which is peculiar
to each anticancer agent, may be useful in determining
sensitivity.
Although chemoresistance is a multifactorial phenomenon, on the occasion of the clinical application,
several candidate agents must be tested and validated on
small specimens of the patient’s tumor to select effective
agents for that individual. Accordingly, it is important tolimit the number of examined genes for the cost benefit
on the occasion of the clinical application. Anticancer
agents against epithelial ovarian cancer are still limited
to a few drugs, such as platinum agents, taxane compounds and DNA topoisomerase inhibitors.
The expression of multidrug-resistance-1 (MDR1) gene encoding P-glycoprotein gene was significantly
higher in non-responders of taxane and carboplatintherapy.31 Due to the hydrophilic nature of taxane compound, resistance to taxane agent is associated with
MDR-1. MDR-1 gene expression is related to sensitivity
to taxane compounds in ovarian cancer.32 In contrast,
there were no differences in the level of MRP between
responders and non-responders prior to chemotherapy.8
After chemotherapy, however, MRP gene expression
was significantly higher in non-responders than in responders. MRP gene expression, at least before chemotherapy, may not relate to chemoresponse. MDR-1 genemight be a useful predictor for combination taxane andcarboplatin therapy.
Copy number of topo I gene inversely correlatedwith sensitivity to SN38. Additionally, the expression
levels of topo I were lower in CPT-resistant cell lines,
46

New treatment strategy for ovarian cancer

the Gynecologic Oncology Group (GOG) 218 and theInternational Collaborative Group for Ovarian Neoplasia(ICON) 7, examined the combined effects with bevacizumab and standard chemotherapy [paclitaxel (PTX) +carboplatin] in a first-line/adjuvant chemotherapy setting.41, 42 The GOG218 trial was a 3-arm, double-blind,placebo-controlled, randomized, phase III study of 1873
patients with macroscopic residual stage III or any stage
IV ovarian, fallopian tube and peritoneal cancer.41 Patients who received bevacizumab (15 mg/kg) plus chemotherapy with 16 cycles of maintenance bevacizumab
had significantly longer progression-free survival (PFS)
than those who received chemotherapy alone (median
PFS, 14.1 versus 10.3 months). However, no significant
difference in OS was observed. The rate of hypertension
requiring medical therapy was higher in the chemotherapy plus bevacizumab arm compared to chemotherapy
alone, though gastrointestinal events above grade 2
were observed in less than 3 % of patients. ICON7 had
a similar design as a double-armed phase III study thatenrolled 1528 patients with newly diagnosed high-riskstage I/IIA and stage III/IV ovarian, fallopian tube andperitoneal cancer, who were assigned randomly to chemotherapy alone or chemotherapy plus bevacizumab (7.5mg/kg) with 12 cycles of maintenance bevacizumab.42
Although the dose of bevacizumab used in this trial was
half of that used in GOG218, it significantly prolonged
PFS (median PFS, 17.4 versus 19.8 months). Hypertension of grade 2 or higher was observed more often in thebevacizumab arm (18 versus 2 % with chemotherapy
alone). Among patients at high risk for progression (i.e.,
FIGO stage IV disease or stage III disease and > 1.0 cm
of residual disease after debulking surgery), the medianPFS (15.9 versus 10.5 months) and median OS (28.8 versus 36.6 months) were significantly longer in the bevacizumab arm.
The Ovarian Cancer Education Awareness Network
trial evaluated the efficacy of bevacizumab in combination with carboplatin and gemcitabine in patientswith recurrent, platinum-sensitive ovarian, primary
peritoneal, or fallopian tube cancers after front-line,
platinum-based therapy.43 A taotal of 484 patients wereassigned randomly to a group administered 6 cycles ofchemotherapy combined with bevacizumab (15 mg/kg)
or to placebo followed by maintenance bevacizumab
or placebo until their disease progressed or unacceptable toxicity developed. PFS for the bevacizumab arm
was significantly longer than for the placebo arm (median PFS, 12.4 versus 8.4 months). Grade 3 or higher
hypertension and proteinuria occurred more frequently
in the bevacizumab arm. Another study, GOG213, isenrolling a targeted 660 patients with platinum-sensitive
recurrent ovarian, primary peritoneal, or fallopian tube
cancer. This randomized, phase III trial is comparing
chemotherapy (PTX + carboplatin) every 3 weeks for 6
to 8 cycles and chemotherapy plus bevacizumab (15 mg/kg) with maintenance bevacizumab every 3 weeks. The
surgical candidates among these patients will undergo
secondary randomization to surgery or no surgery.
Chemotherapy-induced activation of cell-survival
pathways is observed frequently when conventional
anticancer drugs are used, and targeting these survival
signals will be invaluable in designing rational and novel
combination therapies. A number of agents designed
to inhibit the kinase components of those signaling
pathways, including mitogen-activated protein kinasekinase (MEK)-extracellular signal-regulated kinase kinase (ERK) and phosphatidylinositol 3'-kinase (PI3K)/
Akt, have been developed and clinically tested in cancer
treatment, such as lung, breast cancer and melanoma.44,
45
PTX functions by binding to intracellular beta-tubulin, thus stabilizing microtubules. This action blocks
normal cell-cycle progress when the mitotic metaphaseand anaphase merge, preventing chromosome segregation and tumor-cell death. PTX also has the potential tomodulate various signaling pathways, such as the MEK/ERK signaling cascade and a PI3K–Akt pathway, which
are proliferation and cell-survival pathways.46, 47, 48 Ac-

Fig. 5. The receiver operating characteristic (ROC)
curve according to chemoresponse for TC (A), EP (B)and CPT-11/CDDP therapy(C). The optimal cut points
are 80 for MDR-1, 90 for
topo IIalpha and 200 for
topo I by selecting the pointon the ROC curve that maximized both sensitivity and specificity. CDDP, cisplatin; CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin; EP, combination with etoposide and CDDP; MDR-1, multidrug-resistance-1; TC, combination with paclitaxel and carboplatin;
topo, topoisomerase.

47

J. Kigawa

Fig. 6. The effects of paclitaxel(PTX) combined with mitogen-activated protein kinase kinase (MEK)and phosphatidylinositol 3'-kinase(PI3K) inhibitors on ovarian cancer
cells. Cell proliferation was significantly suppressed by PTX combinedwith MEK and PI3K inhibitors
compared with other treatment conditions. LY294002, PI3K inhibitor;
PD98059, MEK inhibitor.

tivating these pathways leads to phosphorylated Bc12
antagonist of cell death and B-cell leukemia/lymphoma(Bcl)-2, and inhibits apoptosis. Amplified PI3K andactivated Akt have been found in 30 to 40% of ovariancarcinomas and could represent the mechanism of drug
resistance in patients with ovarian cancer.49
Kawaguchi et al. reported that the additive effect of
MEK inhibitor combined with PTX in ovarian cancer
cell lines tested with a range of pMEK protein expression
levels after PTX treatment. Enhanced PTX-induced cell
death in the presence of MEK inhibitor may relate to suppression of the survival-signaling function of the MEK–ERK pathway, although the exact mechanism is unclear50(Fig. 5). The additive effect of PI3K inhibitor and PTX
in all ovarian cancer cell lines was studied, regardless ofthe pAkt expression levels. Interestingly, upregulation ofpAkt protein expression levels was seen after treating thecells with MEK inhibitor and PTX. Overexpression ofactivated Akt may decrease the sensitivity to the combination of MEK inhibitor and PTX. Inhibiting MEK and
ERK upregulates Akt kinase activity.51 Inhibiting MEK
pharmacologically does not only activate Akt, but also
prolongs cell survival in normal cells. These findings
suggest that simultaneously suppressing the MEK–ERK
and PI3K–Akt pathways could dramatically intensify
PTX-induced apoptosis in ovarian cancer cells.
Targeting these MEK–ERK and PI3K–Akt pathways may be important in treating ovarian cancer.
Nonaka et al. treated ovarian cancer cell lines with
CDDP and any of a PI3K inhibitor (LY294002), a MEK
inhibitor (PD98059), or a MEK/ERK activator [phorbol
12-myristate 13-acetate (PMA)], and assessed cell viability, expression of MEK/ERK and PI3K/Akt, cell cycle
distribution and apoptosis.52 CDDP and LY294002 hadan additive effect on inhibiting cell growth, and CDDP
and PD98059 had and antagonistic effect on cell growthin all cell lines (Fig. 6). In CDDP-resistant cells, CDDP
and PMA dramatically suppressed the cell growth, up-

regulated the expression of phosphorylated ERK andcleaved caspase-9, down-regulated the expression ofcheckpoint kinases, and increased the proportion ofcells in the synthesis-phase fraction and apoptotic cells.
Those findings indicate that further study is warranted
to determine the effectiveness of combination treatment
with anticancer agents and molecular targeting therapy
for platinum-resistant ovarian carcinoma.
On the occasion of the use of the molecular targeted-agents, we must take care of the appearance of theunexpected adverse effect.53 Additionally, the cost-effectiveness should be an important issue. Because tailor
made treatment based on the characteristic of the cancer
cell is expected, translational research for biomarker isnecessary.
The author declares no conflict of interest.
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