• The Korean Journal of Physiology and Pharmacology
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• 제5권4호
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• pp.359-366
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• 2001

We have synthesized a novel platinum(II) coordination complex containing cis-1,2-diaminocyclohexane (DACH) as a carrier ligand and 1,3-dichloropropane (DCP) as a leaving group. A new series of [Pt(cis- DACH)(DCP)](PC) was evaluated for its cytotoxic activity on MKN-45 human gastric adenocarcinoma cells and normal primary cultured kidney cells. The new platinum complex has demonstrated high efficacy in the cytotoxicity against MKN-45/P, MKN-45/ADM and MKN-45/CDDP cell-lines. The cytotoxicity of PC against rabbit proximal renal tubular cells, human renal cortical cells and human renal cortical tissues, determined by MTT assay, the $[^3H]-thymidine$ uptake and glucose consumption tests, was found to be quite less than those of cisplatin. Based on these results, this novel platinum(II) coordination complex appears to be better for improving antitumor activities with low nephrotoxicity and is a valuable lead in the development of new, clinically available anticancer chemotherapeutic agents.

• The Korean Journal of Physiology and Pharmacology
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• 제4권2호
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• pp.159-167
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• 2000

We have synthesized a novel platinum(II) coordination complex containing cis-1,2-diaminocyclohexane (DACH) as a carrier ligand and 1,2-dichloroethane (DCE) as a leaving group. In addition, nitrate was added to improve the water-solubility. A new series of [Pt(cis-DACH)(DCE)] $2NO_3(PC)$ was evaluated for its cytotoxic activity on T-24 and J-82 human bladder carcinoma cells and normal primary cultured kidney cells. PC has demonstrated high levels of cytotoxicity against T-24 and J-82 cells. The cytotoxicity of PC against rabbit proximal renal tubular cells, human renal cortical cells and human renal cortical tissues, determined using the MTT assaying technique, the $[^3H]-thymidine$ uptake and glucose consumption tests, was found to be quite less than those of cisplatin. Based on these results, this novel platinum(II) coordination complex appears to be better for improving antitumor activities with low nephrotoxicity and is a valuable lead in the development of new clinically available anticancer chemotherapeutic agents.

• 약학회지
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• 제43권3호
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• pp.369-377
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• 1999

A new series of highly water soluble platinum(II) complexes {Pt(II)[1,3-bis(phenylthio) propane](trans- -1,2-diaminocyclohexane) (PC-1) and Pt(II)[1,3-bis-(phenythio)propane] cis-1,2-diaminocyclohexane(PC-2)} were synthesized, and characterized by their elemental analysis and by various spectroscopic techniques[infrared(IR), 13C-nuclear magnetic resonance (NMR)]. In vitro antitumor activity of new Pt(II) complexes was tested against P-388 and L-1210 mouse lymphocytic leukemia cell lines, PC-14 / P, PC-14/ADM and PC-14 / CDDP human pulmonary adenocarcinima, DU-145 human prostate carcinoma, HT-1376 human bladder carcinoma, ZR-75-1 human breast carcinoma, MKN-45/P and MKN-45/CDDP human gastric adenocarcinoma cell lines using colorimetric MTT[3-(4,5-dimethyl thiazol-2-yl)-2.5-diphenyltetrazoliumbromide] assay for cell survival and proliferation. PC-1 showed active against L-1210, P-388 leukemia, human lung, stomach, prostate, bladder and breast cancer cell lines, and the antitumor activity of these compounds were comparable or superior to those of PC-2 and displatin. The nephrotoxicities of PC-1 and PC-2 were found quite less than that of cisplatin using MTT and [3H] thymidine uptake in rabbit proximal tubule cells and human kidney cortical cells. Based on these results, this novel platinum (II) complex compound (PC-1) represents a valuable lead in the development of a new anticancer chemotherapeutic agent capable of improving antitumor activity and low nephrotoxicity.

• Biomolecules & Therapeutics
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• 제8권3호
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• pp.228-234
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• 2000

We have synthesized a novel platinum(II) coordination complex containing trans-ι-1,2-diaminocy-clohexane (DACH) as a carrier ligand and 1,2-dichloroethane (DCE) as a leaving group. A new series of [Pt(trans-ι-DACH)(DCE)](PC) was evaluated for its cytotoxic activity on MKN-45 human gastric adenocar-cinoma cells and normal primary cultured kidney cells. The new platinum complex has demonstrated high efficacy in the cytotoxicity against MKN-45/P, MKN-45/ADM and MKN-45/CDDP cell-lines. The cytotoxicity of PC against rabbit proximal renal tubular cells, human renal cortical cells and human renal cortical tissues, determined by MTT assay, the [$^3H$]-thymidine uptake arid glucose consumption tests, was found to be quite less than those of cisplatin. Based on these results, this novel platinum(II) coordination complex appears to be better for improving antitumor activities with low nephrotoxicity and is a valuable lead in the development of new, clinically available anticancer chemotherapeutic agents.

• 약학회지
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• 제44권5호
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• pp.399-405
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• 2000

We have synthesized a novel platinum (II) coordination complex containing trans-ι-1,2-diaminocyclohexane (DACH) as a carrier ligand and 1,2-bis (diphenylphosphino)ethane (DPPE) as a leaving group. In addition, nitrate was added to improve the water-solubility. A new series of [Pt (trans-ι-DACH) (DPPE)].2NO$_3$(PC) was evaluated for its cytotoxic activity on MKN-45 human gastric adenocarcinoma cells and normal primary cultured kidney cells. PC has demonstrated high levels of cytotoxicity against MKN-45/S, MKN-45/ADR and MKN-45/CDDP cells. The cytotoxicity of PC against rabbit proximal renal tubular cells, human renal cortical cells, and human renal cortical tissues, determined using the MTT assaying technique, the ($^3$H)-thymidine uptake and the glucose consumption tests, was found to be quite less than those of cisplatin. Based on these results, this novel platinum (II) coordination complex appears to be better for improving antitumor activities with low nephrotoxicity and is a valuable lead in the development of new clinically available anticancer chemotherapeutic agents.

• Asian Pacific Journal of Cancer Prevention
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• 제14권11호
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• pp.6883-6888
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• 2013

Background: Platinum based concurrent chemo-radiation is the de-facto standard of care in the non-surgical management of locally-advanced head and neck cancer of squamous origin. Three-weekly single agent cisplatin at 100 $mg/m^2$ concurrent with radical radiotherapy has demonstrated consistent improvement in loco-regional control and survival. This improvement is however at the cost of considerable hematologic toxicity and poor overall compliance. The routine use of this regime is improbable in developing countries with limited resources. We therefore aimed to determine the safety and efficacy of an alternative regime of weekly cisplatin and concurrent radiotherapy in such patients. Materials and Methods: January-05 and April-12, 188 patients of locally-advanced head and neck cancer of squamous origin were treated with concurrent weekly-cisplatin at $35mg/m^2$ and conventional radiotherapy 60-66Gy/30-33 fractions/5days per week. Results: Overall, 95% patients received planned doses of RT while 74% completed within the stipulated overall treatment time of <50 days. Eighty-two percent received at-least 5 weekly cycles. Grade-III/IV mucositis was seen in 58%/9% respectively, which resulted in mean weight loss of 9.2% from a pre-treatment mean of 54.5 kg. Grade-III hematologic toxicity-0.5%; grade II nephrotoxicity-2.5% and grade III emesis-3% were also seen. Grade-III/IV subcutaneous toxicity-10%/1% and grade-III/IV xerostomia-10%/0% were observed. Complete responses at the primary site, regional nodes and overall disease were seen in 86%, 89% and 83% patients respectively. The median and 5-years disease-free survival were 26 months and 39.4% respectively, while the median and overall survival were 27 months and 41.8% respectively. Conclusions: Weekly-cisplatin at 35 $mg/m^2$ when delivered concurrently with conventional radical RT (at-least 66y/33 fractions) in locally-advanced head and neck cancer is well tolerated with minimal hematologic and neprologic toxicity and can be routinely delivered on an out-patient basis. It is an effective alternative to the standard 3-weekly cisplatin especially in the context of developing countries.

• Radiation Oncology Journal
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• 제19권3호
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• pp.205-210
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• 2001

목적 : 국소진행된 두경부종양 환자에서 방사선감작제로서 cisplatin을 방사선치료와 동시병용하였을때, 반응율과 독성을 알아보고 국소재발율 및 단기생존율을 분석해 보고자 하였다. 대상 및 방법 : 1995년 1월부터 1998 8월까지 AJCC 병기 II-IV의 국소진행된 두경부종양으로 근치적방사선치료중 cisplatin 동시화학요법을 받은 환자 29명을 대상으로 하였다. 비인강암이 16예였고 구인두암이 5예, 하인두암과 후두암이 각각 4예씩이었다. 대상환자의 연령분포는 22세에서 74세로 중앙값은 56세였고 남녀비는 22:7이었다. 방사선치료는 6 MV와 15 MV X선 및 $9\~14\;MeV$ 전자선을 사용하여 원발병소와 전이된 임파절에 총 $7,000\~7,560\;cGy$ (중앙값 7,020 cGy)까지 조사하였다. Cisplatin은 $100\;mg/m^2$을 방사선치료와 동시에 매 3주 간격으로 3회까지 투여하는 것을 원칙으로 하였다. 결과 : 치료에 대한 반응율은 완전관해가 21예$(72.4\%)$, 부분관해가 5예$(17.2\%)$, 경미한 반응이 3예$(10.4\%)$로 나타났다. 치료 후 잔여임파절병변에 대한 경부곽청술이 2예에서 시행되었다. 추적관찰기간($5\~55$개월, 평균 37개월)중 8례에서 원발병소 혹은 임파절에서 재발하여 국소재발율은 $27.6\%$였고, 원격전이가 4예$(13.8\%)$에서 관찰되었다. 3년무병생존율은 $60\%$였으며 원발병소가 비인강암인 경우나 치료에 완전반응을 보였던 경우가 무병생존율이 유의하게 높은 것으로 나타났다. 치료에 다른 급성독성으로 10예$(34.5\%)$에서 grade 3의 점막염, 5예$(17.2\%)$에서 grade 3의 백혈구감소증이 관찰되었다. 전체 환자 중 21예$(72.4\%)$가 3회의 Cisplatin 화학요법을 완료하였다. 3예에서는 grade 3의 백혈구 감소증, 2예는 전신상태불량으로 cisplatin이 2회만 투여되었고, 다른 3예는 신기능이상 및 신경독성으로 인해 치료중간에 5-FU로 대치되었으며, 전체치료기간이 2주 이상 지연되는 major deviation은 3예$(10.3\%)$에서 관찰되었다. 결론 : 국소진행된 두경부 종양환자에서 Cisplatin을 근치적방사선치료와 동시에 병용하는 치료전략은 비교적 높은 치료반응율, 국소제어율 및 생존율을 나타내었다. 급성치료독성의 빈도가 높았으나 치료에 대한 순응도는 비교적 양호하였다. 향후 좀더 많은 증례의 수집 및 장기추적관찰과 함께 원발병소에 따른 독립적인 연구가 필요할 것으로 사료되었다.

• BMB Reports
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• 제39권6호
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• pp.656-661
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• 2006

Cisplatin (CDDP) is a widely used anticancer drug, but at high dose, it can produce undesirable side effects such as hepatotoxicity. Because silymrin has been used to treat liver disorders, the protective effect of silymarin on CDDP -induced hepatotoxicity was evaluated in rats. Hepatotoxicity was determined by changes in serum alanine aminotransferase [ALT] and aspartate aminotransferase [AST], nitric oxide [NO] levels, albumin and calcium levels, and superoxide dismutase [SOD], glutathione peroxidase [GSHPx] activities, glutathione content, malondialdehyde [MDA] and nitric oxide [NO] levels in liver tissue of rats. Male albino rats were divided into four groups, 10 rats in each. In the control group, rats were injected i.p. with 0.2 ml of propylene glycol in saline 75/25 (v/v) for 5 consecutive days [Silymarin was dissolved in 0.2 ml of propylene glycol in saline 75/25 v/v]. The second group were injected with CDDP (7.5 mg /kg, I.P.), whereas animals in the third group were i.p. injected with silymarin at a dose of 100 mg/kg/day for 5 consecutive days. The Fourth group received a daily i.p. injection of silymarin (100 mg/kg/day for 5 days) 1 hr before a single i.p. injection of CDDP (7.5 mg/kg). CDDP hepatotoxicity was manifested biochemically by an increase in serum ALT and AST, elevation of MDA and NO in liver tissues as well as a decrease in GSH and the activities of antioxidant enzymes, including SOD, GSHPx in liver tissues. In addition, marked decrease in serum NO, albumin and calcium levels were observed. Serum ALT, AST, liver NO level, MDA was found to decreased in the combination group in comparison with the CDDP group. The activities of SOD, GSHPx, GSH and serum NO were lower in CDDP group than both the control and CDDP pretreated with silymarin groups. The results obtained suggested that silymarin significantly attenuated the hepatotoxicity as an indirect target of CDDP in an animal model of CDDP-induced nephrotoxicity.

• 대한약학회:학술대회논문집
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• 대한약학회 2002년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2
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• pp.276.1-276.1
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• 2002

It is well known that cisplatin. one of chemotherapeutic agents. induces DNA damage and kill cancer cells mainly by apoptosis. We recently synthesized a novel Pt(IV)-based anticancer agent. trans.cis-Pt(acetato)2C12(1.4-butanediamine) (K101) with octahedral structure. To evaluate antitumor activity about human cancer of K101, we have performed histoculture drug response assay in 35 cases of colorectal cancer patients. (omitted)

• 대한약리학회지
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• 제29권2호
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• pp.283-295
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• 1993

일부 malignant tumor에 Pt-complex의 임상 응용 과정에서 신장독성등의 심한 부작용이 문제점으로 지적되고 있다. 이 연구에서는 기존의 cisplatin보다 항암효과는 우수하면서, 부작용을 감소시킨 새로운 Pt-complex의 개발에 역점을 두었다. 본 연구에서는 합성한 Pt (II) complex는 carrier ligand로서 1, 2-diaminocyclohexane (dach)을 사용하였고, leaving group으로는 diphosphine류인 1, 3-bis (diphenylphosphine)의 propane (DPPP) 및 ethane (DPPE)을 도입하였으며, 물에 대한 용해도를 높이기 위해 dinitrate로 만들었다. 새로이 합성한 [Pt (II)-(trans-1-dach)(DPPP)] $(NO_3)_2$ 과 [Pt (II)(trans-1-dach)(DPPE)] $(NO_3)_2$ 는 원소 분석, IR 및 $^{13}C-NMR$ 분석 data에 의하여 위의 물질임이 확인되었다. KHPC-001과 KHPC-002는 MTT assay method에 의한 항암활성 연구를 통하여 P-388, L-1210 lymphocytic leukemia cell에서 항암효과가 인정되었으며, 이 항암효과는 대조 약물로 사용된 cisplatin에 비하여 우수하였다. KHPC-001과 KHPC-002는 토끼의 신세뇨관 세포와 인체의 신피질 세포를 이용한 cytotoxity 및 thymidine 섭취율과 인체 신피질 조직 배양을 이용한 glucose consumption 실험을 통하여 모두 cisplatin보다 신장독성이 현저히 감소되었다. 이상의 결과로 보아 Pt (II) complex는 carrier ligand와 leaving group의 선택에 따라 항암활성의 증가와 신독성의 감소를 일으키는 요인으로 보여지며, 이 연구에서 만들어진 두 Pt (II) complex는 앞으로 다각적인 검토를 거쳐 새로운 anticancer chemotherapeutic agent로 개발될 가능성이 있을 것으로 생각된다.