• Tuberculosis and Respiratory Diseases
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• 제65권2호
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• pp.142-146
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• 2008

소세포폐암은 비교적 초기 항암치료에 대한 반응이 우수하지만 빠르게 진행하는 것으로 알려져 있다. Topotecan은 topoisomerase I inhibitor로 소세포폐암에서 이차치료제로 사용된다. Topotecan의 흔한 부작용으로는 빈혈, 혈소판감소증, 호중구감소증과 같은 혈액학적 부작용이 있으나, topotecan에 의한 폐독성은 잘 알려져 있지 않다. 저자들은 일차치료에 불응하여 이차치료제로 topotecan을 투여 받던 소세포폐암 환자에서 3주기 topotecan 투약중에 발생한 급성호흡곤란증후군을 경험하여 보고한다. 환자는 호흡곤란을 호소하면서 호흡부전에 빠졌으며, 흉부전산화단층촬영에서 약제에 의한 폐손상을 시사하는 미만성 간유리음영을 보였다. 환자는 급성호흡곤란증후군으로 사망하였다.

• Asian Pacific Journal of Cancer Prevention
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• 제17권2호
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• pp.799-805
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• 2016

Background: There is no standard treatment for patients with platinum-resistant or refractory epithelial ovarian cancer. Single agent chemotherapies have evidence of more efficacy and less toxicity than combination therapy. Most are very expensive, with appreciable toxicity and minimal survival. Since it is difficult to make comparison between outcomes, economic analysis of single-agent chemotherapy regimens and best supportive care may help to make decisions about an appropriate management for the affected patients. Objective: To evaluate the cost effectiveness of second-line chemotherapy compared with best supportive care for patients with platinum-resistant or refractory epithelial ovarian cancer. Materials and Methods: A Markov model was used to estimate the effectiveness and total costs associated with treatments. The hypothetical patient population comprised women aged 55 with platinum-resistant or refractory epithelial ovarian cancer. Four types of alternative treatment options were evaluated: 1) gemcitabine followed by BSC; 2) pegylated liposomal doxorubicin (PLD) followed by BSC; 3) gemcitabine followed by topotecan; and 4) PLD followed by topotecan. Baseline comparator of alternative treatments was BSC. Time horizon of the analysis was 2 years. Health care provider perspective and 3% discount rate were used to determine the costs of medical treatment in this study. Quality-adjusted life-years (QALY) were used to measure the treatment effectiveness. Treatment effectiveness data were derived from the literature. Costs were calculated from unit cost treatment of epithelial ovarian cancer patients at various stages of disease in King Chulalongkorn Memorial Hospital (KCMH) in the year 2011. Parameter uncertainty was tested in probabilistic sensitivity analysis by using Monte Carlo simulation. One-way sensitivity analysis was used to explore each variable's impact on the uncertainty of the results. Results: Approximated life expectancy of best supportive care was 0.182 years and its total cost was 26,862 Baht. All four alternative treatments increased life expectancy. Life expectancy of gemcitabine followed by BSC, PLD followed by BSC, gemcitabine followed by topotecan and PLD followed by topotecan was 0.510, 0.513, 0.566, and 0.570 years, respectively. The total cost of gemcitabine followed by BSC, PLD followed by BSC, gemcitabine followed by topotecan and PLD followed by topotecan was 113,000, 124,302, 139,788 and 151,135 Baht, respectively. PLD followed by topotecan had the highest expected quality-adjusted life-years but was the most expensive of all the above strategies. The incremental cost-effectiveness ratios (ICER) of gemcitabine followed by BSC, PLD followed by BSC, gemcitabine followed by topotecan and PLD followed by topotecan was 344,643, 385,322, 385,856, and 420,299 Baht, respectively. Conclusions: All of the second-line chemotherapy strategies showed certain benefits due to an increased life-year gained compared with best supportive care. Moreover, gemcitabine as second-line chemotherapy followed by best supportive care in progressive disease case was likely to be more effective strategy with less cost from health care provider perspective. Gemcitabine was the most cost-effective treatment among all four alternative treatments. ICER is only an economic factor. Treatment decisions should be based on the patient benefit.

• Journal of Pharmaceutical Investigation
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• 제39권5호
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• pp.367-372
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• 2009

A rapid liquid chromatography/tandem mass spectrometry (LC/MS/MS) assay method was developed for the determination of topotecan levels in rat serum. The assay utilized a single liquid-liquid extraction with a mixture of ethy l acetate and acetonitrile (6:1 v/v) and isocratic elution. The multiple reaction monitoring was based on the transition of m/z 422.0$\rightarrow$376.5 for topotecan and 315.1$\rightarrow$226.6 for clomipramine (internal standard). The developed assay was validated to demonstrate the specificity, recovery, lower limit of quantification (LLOQ), accuracy and precision. The assay was linear over a concentration range from 0.5-100 ng/mL, with LLOQ being 0.5 ng/mL using a small volume of rat serum (0.1 mL). The mean intra- and inter-day assay accuracy was 87.7-111.0% and 97.8-108.3, respectively, and the mean intra- and interday precision was between 1.6-4.3% and 3.8-10.3, respectively. The developed assay was applied to a pharmacokinetic study after a bolus i.v. injection of topotecan in rats.

• Tuberculosis and Respiratory Diseases
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• 제52권3호
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• pp.230-240
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• 2002

연구배경 : 소세포폐암은 1차 화학요법에 반응율은 높으나 대부분이 1차 화학요법 1년이내에 진행하고 재발하여, 2차 화학요법에 대한 반응율 및 생존율은 매우 불량하다. 최근 들어 camptothecin 유도체로서 topoiso-merase I 억제제인 topotecan이 소세포폐암의 확장 기에서 1차요법으로서 단독사용시에 39%의 반응율과 10개월의 중앙생존기간이 보고되고 있어, 소세포 폐암의 1차화학요법후 진행, 재발시에 2차요법으로 사용하여 반응율, 생존율 및 부작용등을 검토하였다. 대상 및 방법 : 소세포폐암으로 진단받은 후 1차 화학요법 3주기 시 행후 반응이 없었던 9예와 1차 화학요법 6 주기 완료 후 재발한 10 예, 총 19예를 대상으로 topotecan (hycamtin$^{(R)}$, Glaxo-Smith-Kline, USA) 1.5mg/$m^2$을 매 3주 간격으로 첫 1일부터 5일까지 5일간 30분간에 걸쳐 정맥 투여를 총 6주기 실시하여, 3주기와 6주기후에 반응을 측정하였고, 생존율은 Kaplan-Meier법으로 구하였고, 비교군끼리의 생존율 비교는 Log-rank 검정하였다. 결 과 : 전 대상군에서의 반응율은 26.3% (5/19, CR 2, PR 3, SD 3, PD 11) 이었고, 중앙생존기간은 24주였으며, 1차화학요법의 무반응군 (9예)과 반응군(10예)의 반응율은 각각 22.2%(2/9, PR 2, SD 3, PD 4), 30%(3/10, CR 2, PR 1, PD 7)이었고, 중앙생존기간은 각각 17주, 24주였으며, 1차 화학요법 완료 3개월 이내와 3개월 이후에 재발한 refractory군(6 예)과 sensitive군 (4예)의 반응율은 각각 16.6%(1/6, CR 1, PD 5),50%(2/4, CR 1, PR 1, PD 2)이었고, 중앙생존기간은 각각 14주, 39주였고, 제한기(9예)와 확장기 (10예)의 반응율은 각각 44.4% (4/9, CR 2, PR 2, SD 1, PD 4),10.0%(1/10, PR 1, SD 2, PD 7)이었고 중앙생존기간은 각각 36 주로서 대사예가 적어 통계적 유의성에 이르지는 못하였으나 1차요법 반응군, 1차요법후 늦게 재발한 sensitive군, 제한기의 반응율 및 생존율이 비교적 양호하였다. Topotecan의 유의할 만한 독성 부작용은 전 90주기의 화학요법중 빈혈 grade III 1예, 백혈구 감소증 grade III 6 예, IV 4 예, 혈소판 감소증 grade III 1 예, IV 1예 였으며 구토는 grade III 1예였다. 결 론 : 소세포폐암의 2차 화학요법으로서 topotecan 단독요법은 반응율 26.3%, 중앙생존기간은 24주였으며, 1차 화학요법에 반응을 보인군, 1차 화학요법 완료후 늦게 재발한 군, 제한기의 반응율 및 생존율이 양호하였으며, 더 나아가 다른 2차 화학요법과의 임상대조 시험이 있어야겠다.

• Asian Pacific Journal of Cancer Prevention
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• 제13권6호
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• pp.2909-2912
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• 2012

Aim: To evaluate efficacy and tolerability of topotecan treatment for recurrent small cell lung carcinoma. Patients and Methods: A total of 62 patients were evaluated retrospectively. Statistical analysis was performed using GraphPad Instat (version 3.05). Results: DFifty five of patients (89%) were male and 7 (11%) were female. Median age was $56.7{\pm}9.3$ (34-75). Forty eight of patients (80%) were extensive stage (ES) at the time of diagnosis. Fifty of the patients (80.6 Medical Oncology Clinic) were given median 5.36 cycles of cisplatin-etoposide (2-8 cycles). Time to recurrence was $15.6{\pm}6.13$ weeks in patients with limited stage (LS) and $6.3{\pm}3.82$ weeks in extensive stage (ES) (p<0.0001). Overall survival was $14.0{\pm}6.08$ months in ES and $17.9{\pm}6.88$ months in LS. The difference between two groups was statistically meaningful (p=0.0447). The overall survival of the patients was $14.8{\pm}6.43$ months (4.5-40 months). In terms of survival, there was no difference between males and females (p=0.1171). In 17 (27%) patients who were refractory to topotecan or in whom progression occurred other chemotherapies were used. Conclusion: Small cell lung cancer is chemosensitive, but recurrences occur in short time. Other chemotherapy regimens are used in progression. Topotecan is one of them. Patients who were young and in whom recurrences occur late had given better response to topotecan. Because of the retrospective nature of the study, we couldn't reach the records exactly and consequently, rate and duration of response couldn't be calculated. In recurrent SCLC topotecan is one of the treatment choices. But both hematological and non hematological side effects should be taken into consideration.

• Tuberculosis and Respiratory Diseases
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• 제54권4호
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• pp.415-428
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• 2003

연구배경 : 소세포폐암에 대한 항암화학치료에 etoposide와 cisplatin(EP) 또는 etoposide와 carboplatin(EC)이 가장 흔히 사용되는 병합요법인데, 전반적인 관해율은 75-85%(제한기 65-90%), 완전관해율은 20-30%(제한기 45-75%)로 보고되고 있다. 치료후 재발되는 소세포폐암환자에 대하여 구제(salvage)화학요법제로 topotecan을 사용하였을 때 90일 이내에 재발되는 불응성 재발(refractory relapse, RR)인 경우 관해율이 6.4%인 반면에, 90일 이후에 재발되는 감수성 재발(sensitive relapse, SR)에서는 37.8%의 관해율이 보고되고 있다. 저자는 EC요법과 2차 구제화학요법으로 topotecan요법의 치료효과와 부작용을 조사하여 기존의 성적들과 비교하고자 하였다. 대상 및 방법 : 1996년부터 2002년 6월까지 전남대병원 내과에서 소세포 폐암으로 치료를 받았던 환자들 중에서 EC요법과 재발되어 topotecan구제 화학요법을 받은 환자를 대상으로 임상경과를 후향적으로 조사하였다. 일차치료로서 etoposide 100 $mg/m^2$ (day 1-3), carboplatin 300 $mg/m^2$(day 1)을 3주 이상의 간격을 두고 투여하여, 3주기 이상 화학요법을 받은 경우들을 대상으로 하였고, 이차치료로 topotecan을 투여한 경우에는 1.5 $mg/m^2$을 제 1일에서 제 5일까지 3주 간격으로 2주기 이상 받은 환자들을 대상으로 하였다. 치료에 대한 반응의 평가는 완전관해(complete remission, CR), 부분관해(partial remission, PR), 불변(stable disease, SD), 진행(progressive disease, PD)으로 구분하였고 생존기간은 치료시작일로부터 중앙생존기간(median survival time, MST)으로 표기하였다. 결 과 : 총 101예에서 1차 선택 약제로 EC요법 후 관해율은 57.4%(58예)로 CR은 15.8%(16예), PR은 41.6%(42예)이었다. 제한기(69명)에서의 관해율은 69.6%(48예)로 CR은 23.2%(16예), PR은 46.4%(32예)였으며, 확장기(32명)에서의 관해율은 31.3%(10예)로 모두 PR반응을 보였다. 수행 능력(performance status score, PS)과 동통, 호흡곤란, 기침 등 임상 증상의 변화를 평가하였는데 58예(57.4%)에서 전신상태와 증상의 호전을 보였다. 전체 관해군의 관해 유지기간(중앙값)은 10.3개월(5.8개월~57.7개월)이었고 치료에 따른 호중구 감소증(G4)은 24예(23.8%), 혈소판감소증(Grade 4)은 2예(2%)에서 관찰되었다. 1차 화학치료에 불응하여 바로 다른 약제로 바꾸어 치료한 9예와 1차 치료 후 2차구제화학요법을 받지 않았던 71예를 제외한, 21예의 환자들은 EC요법으로 SD이상 반응을 보였으나 재발하여 topotecan을 투여 받은 군이었다. 총 21예 중 관해율은 SR군(8예)의 경우 PR 25%(2예), SD 25%(2예), PD 50%(4예)를 보였고, RR군(13예)에서는 PR 15.4%(2예), SD 15.4%(2예), PD 69.2%(9예)를 나타냈으나 유의한 차이는 아니었다. 생존 기간의 비교에서도 SR군은 MST 8개월로 RR군의 MST 7개월과 비교하여 유의한 차이는 없었다. 치료에 따른 독성으로 호중구감소증(Grade 4)은 6예 (28.3%), 혈소판감소증(Grade 4)은 3예(14.3%)에서 관찰되었다. 결 론 : EC와 topotecan 치료 모두 기존의 보고들과 비슷한 관해율을 보였으며 수용 가능한 정도의 부작용이 관찰되었다.

• Archives of Pharmacal Research
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• 제21권5호
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• pp.581-590
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• 1998

We developed a novel water-soluble camptothecin analobue, CKD602, and evaluated the inhibition of topoisomerase I and the antitumor activities against mammalian tumor cells and human tumor xenografts. CKD602 was a nanomolar inhibitor of the topoisomerase I enzyme in the cleavable complex assay. CKD602 was found to be 3 times and slightly more potent than topotecan and camptothecin as inhibitors of topoisomerase, respecitively. In tumor cell cytotoxicity, CKD602 was more potent than topotecan in 14 out of 26 human cancer cell lines tested, while it was comparable to camptothecin. CKD602 was tested for the in vivo antitumor activity against the human tumor xenograft models. CKD602 was able to imduce regression of established HT-29, WIDR and CX-1 colon tumors, LX-1 lung tumor, MX-1 breast tumor and SKOV-3 ovarian tumor as much as 80, 94, 76, 67, 87% and 88%, respectively, with comparable body weight changes to those of topotecan. Also the therapeutic margin (R/Emax: maximum tolerance dose/$ED-{58}$) of CKD602 was significantly higher than that of topotecan by 4 times. Efficacy was determined at the maximal tolerated dose levels using schedule dependent i.p. administration in mice bearing L1210 leukemia. On a Q4dx4 (every 4 day for 4 doses) schedule, the maximum tolerated dose (MTD) was 25 mg/kg per administration, which caused great weight loss and lethality in <5% tumor bearing mouse. this schedule brought significant increase in life span (ILS), 212%, with 33% of long-term survivals. The ex vivo antitumor activity of CKD602 was compared with that of topotecan and the mean antitumor index (ATI) values recorded for CKD602 were significantly higher than that noted for topotecan. From these results, CKD602 warrants further clinical investigations as a potent inhibitor of topoisomerase I.

• Archives of Pharmacal Research
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• 제28권5호
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• pp.626-635
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• 2005

Liposome as a carrier of topotecan (TPT), a promising anticancer drug, has been reported in attempt to improve the stability and antitumor activity of TPT. However, the biodistr ibution pattern of TPT liposome in vivo and PEG-modified liposome containing TPT have not been studied systemically. In this paper, the in vitro stability and in vivo biodistribution behavior of several liposomes containing TPT with different lipid compositions and PEG-modification were studied. Compared with the 'fluid' liposome (S-Lip) composed of soybean phosphatidylcholine (SPC), the 'solid' liposome (H-Lip) composed of hydrogenated soybean phosphatidylcholine HSPC decreased the leaking efficiency of TPT from liposome and enhanced the stability of liposome in fetal bovine serum (FBS) or human blood plasma (HBP). The results of biodistribution studies in S$_{180}$ tumor-bearing mice showed that liposomal encapsulation increased the concentrations of total TPT and the ratio of lactone form in plasma. Compared with free TPT, S-Lip and H-Lip resulted in 5- and 19- fold increase in the area under the curve (AUC$_{0\rightarrow\propto}$), respectively. PEG- modified H-Lip (H-PEG) showed 3.7-fold increase in AUC$_{0\rightarrow\propto}$ compared with H-Lip, but there was no significant increase in t$_{1/2}$ and AUC$_{0\rightarrow\propto}$ for PEG-modified S-Lip (S-PEG) compared with S-Lip. Moreover, the liposomal encapsulation changed the biodistribution behavior, and H-Lip and H-PEG dramatically increased the accumulation of TPT in tumor, and the relative tumor uptake ratios were 3.4 and 4.3 compared with free drug, respectively. There was also a marked increase in the distribution of TPT in lung when the drug was encapsulated into H-Lip and H-PEG. Moreover, H-PEG decreased the accumulation of TPT in bore marrow compared with unmodified H-Lip. All these results indicated that the membrane fluidity of liposome has an important effect on in vitro stability and in vivo biodistribution pattern of liposomes containing TPT, and PEG-modified 'solid' liposome may be an efficient carrier of TPT.

• 약학회지
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• 제49권5호
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• pp.428-436
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• 2005

DNA topoisomerase I(TOP1) helps the control of DNA replication, transcription and recombination by assist­ing breaking and rejoining of DNA double strand. Camptothecin (CPT) and its derivative, topotecan, are known to inhibit TOP1 by intercalating into TOP1-DNA complex. Recently various non-CPT intercalators are synthesized for a new class of TOP1 inhibitors. In this study, six compounds isolated from Poria cocos were investigated for their interaction with TOP1­DNA complex using the flexible docking program, FlexiDock. The binding modes were analyzed and compared with the TOP1 inhibition activities. The compounds that showed potent activity were intercalated between the + 1/-1 base pairs of DNA, located near the active site phosphotyrosine723 and formed hydrogen bonds with active site residues. On the other hand, compounds with no activity were not docked at all. The binding modes were well correlated with the inhibition activity, suggesting the possibility that potent inhibitors can be designed from the information presented by the docking study.

• The Korean Journal of Physiology and Pharmacology
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• 제27권1호
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• pp.31-38
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• 2023

Carboplatin, an advanced anticancer drug with excellent efficacy against ovarian cancer, was developed to alleviate the side effects that often occur with cisplatin and other platinum-based compounds. Our study reports the in vitro characteristics, viability, and activity of cells expressing the inducible nitric oxide synthase (iNOS) gene after carboplatin was conjugated with polysuccinimide (PSI) and administered in combination with other widely used anticancer drugs. PSI, which has promising properties as a drug delivery material, could provide a platform for prolonging carboplatin release, regulating its dosage, and improving its side effects. The iNOS gene has been shown to play an important role in both cancer cell survival and inhibition. Herein, we synthesized a PSI-carboplatin conjugate to create a modified anticancer agent and confirmed its successful conjugation. To ensure its solubility in water, we further modified the structure of the PSI-carboplatin conjugate with 2-aminoethanol groups. To validate its biological characteristics, the ovarian cancer cell line SKOV-3 and normal ovarian Chinese hamster ovary cells were treated with the PSI-carboplatin conjugate alone and in combination with paclitaxel and topotecan, both of which are used in conventional chemotherapy. Notably, PSI-carboplatin conjugation can be used to predict changes in the genes involved in cancer growth and inhibition. In conclusion, combination treatment with the newly synthesized polymer-carboplatin conjugate and paclitaxel displayed anticancer activity against ovarian cancer cells but was not toxic to normal ovarian cancer cells, resulting in the development of an effective candidate anticancer drug without severe side effects.