World Applied Sciences Journal 12 (8): 1368-1373, 2011ISSN 1818-4952© IDOSI Publications, 2011

Corresponding Author: Prof. Cui Manhua, Department of Obstetrics and Gynecology ,Second Hospital, Jilin University,218 Zi Qiang Street, Nan Guang District ,Changchun 130041 China.Mob: +86 1584 302 45 85, E-mail: cuimanhua@yahoo.com.

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Drug Resistance and its Solution in Chemotherapyof Gynecologic Malignant Tumors

Haroon Sheikh, Cui Manhua, Tianimun Xu and Cui Li Xiao

Department of Obstetrics and Gynecology, Second Hospital Jilin University,Nan Guang District, Changchun City, China

Abstract: Drug resistance is the fundamental reason for tumor recurrence and treatment failure in gynecologicmalignant tumors. Drug resistance prevention requires familiarity with physicochemical properties ofchemotherapeutic drugs, characteristics of vivo metabolism, correctly chosen chemotherapeutic schemesincluding multi-drug combination chemotherapy, experimental for doubtful diagnosis and timely assessmentto find, treat and prevent serious toxic side effects. Patients should receive sufficient and timely normativechemotherapy as early as possible.

Key words: Chemotherapy Drug-resistance Gynecology Malignant Ovarian tumor

INTRODUCTION RESULTS AND DISCUSSION

Chemotherapy, a systemic therapeutic measure, Application of New Chemotherapy Medicine:effectively controls the growth, diffusion and metastasis Conventional chemotherapeutic drugs such as platinumof tumors and cures gynecologic malignant tumors which drugs, paclitaxel, doxorubicin and so on can produce neware highly sensitive after operations. At present, drug generation of chemotherapeutic drugs through a certainresistance to chemotherapy is one of the essential transformation, increasing drugs sensitivity, loweringreasons for tumor recurrence and treatment failure. In toxic side effects, which can be applied in treatingterms of the mechanism and reasons of its drug gynecologic malignant tumors with drug resistance, suchresistance, how to prevent, avoid and overcome drug as liposome doxorubicin, oxaliplatin, irinotecan and so on.resistance is an important issue in order to improve Additionally, phenoxodiol, a small molecularpatients’ long-term efficacy and raise their survival rate anticarcinogen, can be singly applied to treat hormoneand will be a long-term task in the research on refractory prostate cancer and is sensitizing agent ofgynecologic malignant tumors as well [1]. chemotherapy for advanced cervical cancer, vaginal

MATERIALS AND METHODS compound based on oxidized GSH, is protective agent of

Index Medicus/ MEDLINE and Science Citation approved a combination with chemotherapeutic drugs inIndex were searched for English publications between Russia to treat ovarian cancer and non-small cell lungthe years 2000 and 2010 where the studied population cancer [2].included women diagnosed of gynecologic malignanttumors. Anti-Angiogenesis Therapy: Inhibiting tumor vessels’

Retrospectively, records of 200 patients between the formation is one effective way to stop tumor growth. Anti-years 1998-2009 were reviewed including patients who did angiogenesis drug, a chemotherapeutic drug, has manynot receive timely post surgery chemotherapy for advantages, compared with other ordinary drugs with cellgynecologic malignant tumors or received non- toxicity: First, anti-angiogenesis drug does not depend onindividualized. tumor types and additionally has nothing to do with the

carcinoma and advanced ovarian cancer; NOV-002, a

chemotherapy and immunomodulator, which has been

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mechanism of drug resistance of tumor cells. Secondly, progression. (4) gemcitabine (gemzer): usually adoptamong adults, vessels form only under some specific weekly therapy, administrated together with platinum (oncircumstances, so toxic side effects happen rarely. At the first day platinum is added), 21d is one course ofpresent, there are more than 75 kinds of anti-angiogenesis treatment, on the first and eighth days gemzer 1000mg/m ,drugs having been under clinical experiment. Most of 30~60min input is administered, or on the first, eighth andthem are under Phase I and Phase II of clinical experiment. fifteenth days drugs are administrated, 28d is one course.12 kinds out of them are under Phase III of clinical Together administrated with platinum and paclitaxel inexperiment, such as avastin, vascular enzyme and so chemotherapy, clinical remission rate can reach 43%~70%.on [3]. (5) oxaliplatin (L-OHP): can be administrated alone or

Targeted Therapy: Input drugs with cell toxicity more recommended dosage is 100~130mg/m per day, onespecifically to tumor tissue expressing corresponding administration/ three weeks, when clinically administratedreceptor so as to selectively kill tumor cells; normal together with cyclophosphamide, administration intervaltissues without expressing this receptor will be exempt is the same with conventional PC scheme; or alwaysfrom being infringed to lower toxic side effects from administrated with gemcitabine, remission rate can reachsystematical chemotherapy; therapeutic dosage can be 15%~30%[4].raised, moreover, overcome some tumor cells’ inherenttolerance for chemotherapeutic drugs. Such as erlotinib, DISCUSSIONgefitinib and so on, because of their unique antitumormechanism, no toxic side effects occur in blood system, it Patients with gynecologic malignant tumors initiallyis convenient for administration. In cell line of ovarian have a reaction to chemotherapy. Patients with more thancancer vitro paclitaxel drug resistance, erlotinib not only six months’ cancer-free plastochron are sensitive tohas no cross drug resistance but also quite high sensitive chemotherapy. During the initial chemotherapy period, ifdegree. the disease progression happens, the best relief is the size

According to the feature of multi-drug resistance in of lesion has no change or cancer-free plastochron is lessovarian cancer, after the recurrence of ovarian cancer, than six months, which is considered as drug resistancechange chemotherapeutic drugs and formulate the to chemotherapy. The drug resistance to chemotherapy ofsecond line chemotherapeutic scheme, adopting the majority of patients with gynecologic malignantchemotherapeutic scheme without platinum or extending tumors is defined as acquired drug resistance.therapeutic interval without platinum to reverse partial Nevertheless multi-drug resistance (MDR) of tumor cellsacquired drug resistance. But for the patients with is one of the key factors for chemotherapy failure.acquired drug resistance who have recurrence within sixmonths after stopping chemotherapy, patients with Decrease inConcentration of Chemotherapy Medicine inpersistent and refractory ovarian cancer who have drug Tumor Cells:resistance, new chemotherapeutic drugs without crossdrug resistance or scheme should be adopted to the best, Related with MDR1 Gene and Amplification and Overtumor progression-free period should be extended as long Expression of P-gp Glycoprotein in Tumor Cells.as possible. At present it is reported about therapeuticdrugs and scheme as follows: (1) oral etoposide (VP-16): Relevant drugs of chemotherapy include such naturalfor ovarian cancer with drug resistance, usually adopt 21d source as anthracycline, vinblastine, epipodophyllotoxin,oral scheme, on average daily 50mg/m , more than 32% actinomycin D, paclitaxel and so on and some2

remission rate can be achieved. (2) Liposome adriamycin hydrophobic drugs of chemotherapy. MDR1 gene is the(caelyx): usually take a dosage of 50mg/m per day, three most potent index, which can foresee the drug resistance2

weeks is a course of treatment, single drug can reach 15% of tumor patients. Reversal Strategy: for the time being,remission rate for drug-resistance patients. (3) topotecan: the research on inhibitor of P-gp glycoprotein hasaccording to the standard scheme, 1.5mg/m per day, developed into the third generation. The first generation2

5d non-stop is a course, the total remission rate for of inhibitor of P-gp glycoprotein includes verapamil,platinum drug-resistance patients of ovarian cancer can cyclosporine, tamoxifen and some protein antagonist ofreach around 15%, successfully delaying tumor calcium regulation. In vitro experiment, multi-drug

2

administrated by combination with other drugs,2

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resistance of tumors can be reversed and even completely follows: nitroimidazoles, paracetamol, sodium selenate andreversed. While, in vivo test, the concentration required selenocystein. The researches proves that combinedin effective reversal of multi-drug resistance vitro cannot medication leads to a better reversal effect [9].be reached due to self dosage limitation toxicity. Thesecond generation of inhibitor of P-gp glycoprotein has Increase in DNA Repair in Cells: After tumor cells havebeen synthesized on the basis of structure reformation of formed drug resistance, DNA repair will be increased inthe first generation, mainly including dexverapamil, the cells so that impaired DNA by drugs will be correcteddexniguldipine, valspodar, biricodar and etc., among those with the aim to decrease cell toxicity and continue cellvalspodar and biricodar are representative. The third division. Reversal Strategy: at present inhibitors of DNAgeneration of inhibitor of P-gp glycoprotein has made up polymerase applied in the first phase clinical experimentthe disadvantages of the second generation through include aphidicolin, Lu103793 and so on, which inhibitstructure activity and combinatorial chemistry and its DNA repair by inhibiting DNA polymerase to reverserepresentative drugs include tariquidar and XR-9576. A drug resistance. Phase I clinical experiment indicates thatclinical experiment proves that tariquidar and XR-9576 aphidicolin only has local toxicity effect and its maximumhave decreased IC50 value of doxorubicin, paclitaxel and tolerant dosage can reach 4500mg/m . This kind of drugvinorelbine from 2.57, 27.4 and 15.5mmol/L to 1.67, 20.6 has a good clinical tolerance [10].and 9.5mmol/L [5,6].

Multi-drug Resistance Protein (MRP), Lung Topoisomerase is the enzyme needed for DNA replicationResistance Protein (LRP) and Breast Cancer and transcription. It has two subtypes. One of its mainResistance Protein (BCRP) are a group of protein function is to adjust and control DNA supercoiled staterelated with multi-drug resistance of tumor cells [7]. and knotting or unknotting DNA ring connecting body

Reversal Strategy: at present we haven’t found any of nucleic acid in cells. The other function is to directlylow-toxicity and effective MRP reversal agent. join in the cell process of breaking and reuniting DNAResearchers found that verapamil can reverse not only molecular chain and the process of DNA recombination,MDR1 but also MRP; cyclosporine A can reverse MDR1 repair, transcription and replication. The quantity ofbut not MRP; whether paclitaxel can reverse MRP or not, enzyme will be changed. Reversal Strategy: type Iwhich still needs a further study. One pyridine analogue inhibitor contains camptothecin, actinomycin D and soPAK-104P and anti-LRP antibody can increase adriamycin on. Type II inhibitor contains some acridine,accumulation in cell nucleus and inhibit adriamycin epipodophyllotoxin, anthracycline and anthraquinones.flowing from cell nucleus to cytoplasm. Therefore, it isconsidered that PAK-104P can be applied in reversing Increase in Protein Kinase C (PKC) Activity: PKC is aMDR mediated by LRP [8]. group of Ca /isoenzyme phospholipid dependent. Actual

Increase in Metabolic Detoxification of Chemotherapy or MRP phosphorylate and get activity, which is one ofMedicine in Cells: Increase of level and activity of the important mechanisms of multi-drug resistance.glutathione (GSH) and glutathione S transferase (GST) in Reversal Strategy: Present researches show that inhibitingcells is the possible mechanism for drug resistance of PKC activity can antagonize MDR. At present thetumor cells. Content increase of GSH and activity inhibitors of PKC include NA2382 (derivatives ofenhancement of GST on the one hand result in increasing staurosporine), CGP41251, K2252a, CalphostinC, H27 anddrug polarity, losing toxicity, on the other hand are more so on.easily transported out of cells after they are coupled withdrug, hence, cells show MDR phenotype. Reversal p53 Gene Mutation and So On: For the time being manyStrategy: buthioninesulfox imine (BSO) is one synthetic researchers suggest that p53 gene plays a very importantamino acid analogue and inhibitor of GSH synthase, by role in platinum-based drug resistance in ovarian cancer.inhibiting from synthesizing to reverse tumor drug- Platinum drugs can result in DNA damage. When theresistance, which is under the second phase clinical damage occurs, the defunctionalization of p53 is one ofexperiment abroad. The drugs with similar effect are as the main reasons resulting in tumor drug resistance.

2

Decrease in Topoisomerase Quantity Activity:

state in order to indirectly influence metabolism process

2+

researches suggest that PKC can make P-gp glycoprotein

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Reversal Strategy: at present p53 has become the main occurrence rate of drug resistance, being fully familiarorientation of gene therapy research. Transfect wide typep53 to tumor cell strains without p53 expression,producing tumor inhibition and molecule change,synchronizing with stagnation and apoptosis of cellperiod. Wide type p53 gene combines with taxol, cisplatin,adriamycin and other drugs to more effectively inhibit thegrowth of tumor cells [11, 12].

Factors for Drug Resistance to Chemotherapy: There aremany factors resulting in drug resistance of chemotherapyof gynecologic malignant tumors. Possibly related withthe following aspects: (1) the dosage of chemotherapydrugs and therapeutic course are not enough, resulting intumor cells not being completely eliminated buttemporarily latent, which will bring out future drugresistance and recurrence. (2) the choice of chemotherapyscheme is not reasonable, without considering individualcase to choose sensitive chemotherapy drugs, tumor cellscannot be specifically and effectively controlled, inducingdrug resistance. (3) doctors’ prescription forchemotherapy is not normative, delaying thechemotherapy opportunity due to not receiving timelychemotherapy as soon as possible after the operation; interms of patients’ cooperation, many patients stop thetherapy without authorization due to physique, economicproblems and other reasons; many patients would not liketo suffer from the side effect resulting from chemotherapyand the side effect cannot be corrected effectively, so thepatients do not receive the chemotherapy on time anymore or intermission is not regular, finally drug resistancewill occur. (4) clinical doctors are not thoroughly familiarwith the functional mechanism and features of allchemotherapy drugs, so they do not make an individualtherapy scheme from the perspective of evidence-basedmedicine and cannot find and solve the specificproblems in time during chemotherapy process.Thousands of patients, the same prescription results indrug resistance [13].

CONCLUSION

Application of the below mentioned treatments mayprevent drug resistance to chemotherapy.

Selection of Reasonable Chemotherapy Scheme: As faras malignant tumors of ovary are concerned, thechemotherapy schemes often adopted are PC, PVB, CAP,CBP, TP, TTP, VBP and so on, in order to lower

with physicochemical properties of chemotherapeuticdrugs, characteristics of vivo metabolism and anti-tumormechanism is required, so that chemotherapeutic drugscan be rationally applied. On the basis of acquiringpathological diagnosis of gynecologic malignant tumors,surgical-pathologic staging or clinical staging ofgynecologic malignant tumors will be confirmed, byreferring to tumor markers and imaging data, puttingforward specific chemotherapeutic indication andpurpose, pertinently and correctly choosechemotherapeutic schemes. If the diagnosis is doubtful,any experimental chemotherapy should be carried out onpatients, resulting in delaying disease and tumors’ drugresistance for chemotherapy and finally influencingchemotherapeutic effect. A timely assessment on patientsshould be done as soon as when chemotherapy has beenfinished, including efficacy, toxic side effects and so on.Finding, treating and preventing serious toxic side effectsin time is the basic guarantee for completing the wholechemotherapy scheme. Based on the assessment, adjustchemotherapy dosage and scheme in time in order to treatcancer at its best and lower influence on patients from itstoxic side effects [14-16].

Receive Sufficient and Timely Normative Chemotherapyas Early as Possible: According to patients’ specific stateafter operation, chemotherapy should be carried out asearly as possible. After researches Buller and otherexperts put forward that three years’ survival rate ofpatients will be influenced if there is more than threeweeks’ interval between chemotherapy and operation.Taxol, topetican and other drugs should be administratedonce every three weeks, other drugs once every three orfour weeks, generally three to six courses of treatment arebest. Course of treatment should be determined on thebasis of the length of increment cycle of tumor cells.Generally it is advocated one course of treatment extendscontinuous administration for more than two incrementcycles of tumor cells or more than two tumormultiplication time. Thus, if some tumor cells are not killedin the first cycle, they can be killed in the second and thirdcycles. The length of intervals between courses oftreatment is the best when drugs’ toxicity function almostdisappears, normal function of organism almost recovers,killed tumor cells have not been repaired yet. Whileconsolidating every course of chemotherapy, tumormarkers (CA125, CA199, AFP, HCG and so on) andimaging (ultrasonic, CT, MRI and so on) should be usedto assess efficacy, avoiding blind use[17].

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Multi-Drug Chemotherapy: Different tumor cells have gynecologic malignant tumors. Although the research ondifferent drug resistance mechanism to the same drug and drug resistance mechanism has developed greatly till now,the same cell produces multi-drug resistance mechanism certain mechanism is not yet clear. A further explorationto the same drug. Hence, multi-drug combination is still needed for research on drug resistance and itschemotherapy can avoid drug resistance from single drug therapy. Therefore, from the perspective of evidence-as much as possible. Nevertheless, when combining based medicine, there is a great significance for extendingdifferent drugs, the following aspects should be patients’ survival time and raising their quality of life byconsidered: toxic side effects from different drugs, order offering them with reasonable and suitable therapeuticof medication, way of medication, dosage, length of schemes.course of treatment, interval and so on. It should be paidmore attention that it is not more different drugs used, REFERENCESbetter efficacy can achieve, or it is not accumulation ofmany kinds of drugs, either. Interaction among different 1. Jian, S. and L. Jinghe, 2002. Problems and Challengesdrugs should be noticed and avoid abuse by all means. At on Gynecologic Tumors (M). Renmin Healthpresent, in China clinically generally adopt the first line Publishing House, Beijing, pp: 120-129.chemotherapeutic scheme for ovarian cancer, mainly 2. Obata, H., T. Yahata, J. Quan, M. Sekine andincluding carboplatin plus cyclophosphamide, carboplatin K. Tanaka, 2006. Association Between Singleplus cyclophosphamide plus adriamycin and taxol or Nucleotide Polymorphisms of Drug Resistance-carboplatin and so on; chemotherapeutic scheme for associated Genes and Response to Chemotherapynourishing cell tumor includes EMA/EP or EMA/co and in Advanced Ovarian Cancer. Anticancer Res.,so on; chemotherapy for cervical cancer generally adopts 26: 2227-2232.cisplatin combined with 5-FU; chemotherapy for 3. Chan, W.M., T.Y.Y. Lai, A.L. Wong, J.P. Tong,endometrial carcinoma generally adopts PA and PAC D.T.L. Liu and D.S.C. Lam, 2006. Combinedschemes [18]. photodynamic therapy and intravitreal triamcinolone

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