Antitumor Activity Of Carboplatin Research Articles

Erratum to: Antitumor activity of carboplatin in the composition of a copolymer of lactic and glycolic acids

To the article “Antitumor activity of carboplatin in the composition of a copolymer of lactic and glycolic acids,” by E. D. Nikolskaya, O. A. Zhunina, N. G. Yabbarov, V. A. Zenin, O. G. Tereshchenko, M. V. Fomicheva, M. B. Sokol, A. V. Lobanov, and E. S. Severin, Vol. 66, No. 10, pp. 1867–1872, October, 2017. In the original international version of the article, seventh author’s name was omitted. In should be M. R. Faustova.

Antitumor activity of carboplatin in the composition of a copolymer of lactic and glycolic acids

Polymer particles containing carboplatin (CPt) were developed by the inclusion of this antitumor agent in a copolymer of lactic and glycolic acids (PLGA-COOH 50/50). The polymer particles were found to have a spherical form with an average diameter not exceeding 200 nm, the ζ-potential is equal to–32.2±1 mV. The CPt-loaded polymer particles possess a cytotoxic activity against human small cell and non-small cell lung carcinoma (lines H69 and A549), as well as against mouse mammary adenocarcinoma (line Ca755). The results of the in vivo studies carried out on female mice of line C57Bl/6 with inoculated mouse melanoma of line B16 showed increasing of lifespan of the animals and inhibition of tumor growth for groups treated with the polymer particles, as compared to the animals treated with the drug substance CPt.

Abstract C169: ER maleate is a novel anticancer agent in oral cancer cells: Implications for cancer therapy

Abstract ER maleate was investigated as a novel anticancer agent for oral squamous cell carcinoma (OSCC), the most common head and neck squamous cell carcinoma (HNSCC). We identified its putative molecular targets, demonstrated their clinical relevance, and showed its chemosensitization potential for platinum drugs to aid in HNSCC management. Biologic effects of ER maleate were determined on cell proliferation, spheroid/colony formation, caspase activity, cell migration and invasion in vitro and using oral tumor xenografts in vivo. mRNA profiling, real time PCR and western blot suggested ER maleate modulated the expression of polo-like kinase 1 (PLK1) and spleen tyrosine kinase (Syk). Their clinical significance was determined in oral SCC patients by immunohistochemistry and correlated with prognosis by Kaplan-Meier survival analysis. ER maleate induced cell apoptosis, inhibited proliferation, colony formation, migration and invasion in oral cancer cells. Imagestream analysis revealed cell cycle arrest in G2/M phase and increased polyploidy, unravelling deregulation of cell division and cell death. Mechanistically, ER maleate decreased expression of PLK1 and Syk, induced cleavage of PARP, caspase 9 and caspase 3 and increased chemosensitivity to carboplatin; significantly suppressed tumor growth and increased antitumor activity of carboplatin in tumor xenografts. ER maleate treated tumor xenografts showed reduced PLK1 and Syk expression; clinical investigations revealed overexpression of PLK1 and Syk in oral SCC patients that correlated with disease prognosis. In conclusion, our in vitro and in vivo findings provide a strong rationale for pre-clinical efficacy of ER maleate as a novel anti-cancer agent and chemosensitizer of platinum drugs for OSCC. Citation Format: Guodong Fu, Sr.. ER maleate is a novel anticancer agent in oral cancer cells: Implications for cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C169.

Abstract 670: Aurora kinase inhibitor VE 465 synergistically enhances cytotoxicity of carboplatin in ovarian cancer cells through induction of apoptosis and downregulation of histone 3

Abstract Aurora kinases are essential for the regulation of chromosome segregation and cytokinesis during mitosis and play a role in tumorigenesis and progression in human tumors, including ovarian cancer. Aurora A and Aurora B are frequently overexpressed in high-grade and low-grade ovarian cancers. Targeting aurora kinases has great potential for improving the efficacy of treatment of ovarian cancer. In this study, we investigated whether the Aurora kinase inhibitor VE 465 will enhance the antitumor activity of carboplatin in human ovarian cancer cells. Cell viability was tested using the MTT assay in seven established human epithelial ovarian cancer cell lines with varying p53 status. We found that VE 465 and carboplatin had a synergistic effect (defined by the combination index) in both platinum-sensitive and -resistant ovarian cancers and that the growth-inhibitory effect was accompanied by reduction in expression of histone 3 and an increase in apoptosis. Aurora kinase inhibition in combination with carboplatin chemotherapy is an attractive combination for further development. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 670.

Abstract 5374: LY-GSK-3i, a novel glycogen synthase kinase-3 inhibitor, potentiates the apoptotic activity of cytotoxic agents in combination chemotherapy protocols in in vitro and in vivo tumor models

Abstract Combination chemotherapy regimens for the treatment of cancer arise from the need to either enhance single agent activity, circumvent drug resistance or reduce toxicity by allowing lower dosing of cytotoxic agents. Glycogen synthase kinase 3 (GSK-3) is a constitutively active protein kinase with two highly homologous isoforms, GSK-3α and GSK-3β. Elevated GSK-3 activity has been described in a variety of tumors types and pharmacological or genetic inhibition of this kinase has been shown to reduce the survival of these tumors. In order to explore the potential for GSK-3 inhibitors in cancer therapy we developed LY-GSK-3i, which potently inhibits the enzymatic activity of GSK-3α and GSK-3β with IC50s of 1.5 nM and 0.9nM respectively and reduces the phosphorylation (Ser-396) of its substrate protein, Tau, with an EC50 of 1.4 nM. Here we report the novel and potent chemo-potentiating activity of LY-GSK-3i in a broad range of tumor models in combination with cytotoxic agents having different mechanisms of action. In in vitro caspase 3 activation assays, LY-GSK-3i enhances the apoptotic activity of pemetrexed, a multi-targeted anti-folate, in the NCI-H460 NSCLC cell line. The LY-GSK-3i/ pemetrexed combination enhances apoptotic activity 4-fold over the additive effect of each individual chemotherapeutic agent. DNA damaging agents such as platinum containing cytotoxics are also subject to chemopotentiation by LY-GSK-3i. In the NCI-H460 model, LY-GSK-3i potentiates the action of carboplatin 2 fold. Similarly, in the FaDu and SiHa squamous carcinoma cell lines, a 2-3 fold increase in apoptotic activity is observed with the combination treatment of LY-GSK-3i and cisplatin relative to treatment with either agent alone. Camptothecin is a DNA topoisomerase I inhibitor with modest apoptotic activity in the A2780, ovarian tumor cell line. The combination of camptothecin with LY-GSK-3i resulted in significant elevation in caspase 3 activation. Interestingly, commercially available GSK3/CDK inhibitors, such as SB216763, LiCl, alsterpaullone and purvalanol A have modest chemo-potentiating effect on Camptothecin toxicity compared to LY-GSK-3i. In vivo xenograft growth studies indicated that administration of LY-GSK-3i significantly improved the antitumor efficacy of cisplatin against Colo-205 colorectal tumors. Furthermore, LY-GSK-3i also potentiated in vivo the antitumor activity of carboplatin, or a combination of carboplatin/pemetrexed in NCI-H460 xenografts. Taken together, these data provide evidence for the potential therapeutic utility of LY-GSK-3i, in combination with cytotoxic agents, for the treatment of cancer. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5374.

Combretastatin A-1 phosphate potentiates the antitumor activity of carboplatin and paclitaxel in a severe combined immunodeficiency disease (SCID) mouse model of human ovarian carcinoma

In search for new therapeutic modalities to target epithelial ovarian carcinomas, we investigated the effect of the antiangiogenic drug combretastatin A-1 phosphate (CA1P) as a single treatment or in combination with established therapy, ie, carboplatin and paclitaxel. Five different human epithelial ovarian carcinoma cell lines were inoculated subcutaneously into FOX CHASE CB-77 severe combined immunodeficiency disease (SCID) mice. When tumors reached a volume of approximately 100 mm(3), the treatment was initiated. All drugs were given intraperitoneally at weekly doses. CA1P was more effective as an antitumor agent than combretastatin A-4 phosphate as a single-drug treatment or in combination with carboplatin and paclitaxel. CA1P had a strong tumor outgrowth inhibiting effect on four out of five tumors included in this study. Comparing animals receiving CA1P with animals receiving a combination of carboplatin and paclitaxel, CA1P was more effective on two out of three tested tumors, whereas carboplatin and paclitaxel were more effective on one out of three of the tumors. We show that treatment of human ovarian carcinomas with CA1P in the SCID mouse model results in a strong antitumor effect both as a single-drug treatment and as an enhancement of the therapeutic effect in a combination treatment protocol with carboplatin and paclitaxel.

頭頚部癌患者に対する動注化学療法および放射線療法による術前治療 カルボプラチンとシスプラチンの組織学的所見からみた効果の比較

From the histological viewpoint, antitumor activity of carboplatin (CBDCA) was compared with that of cisplatin (CDDP), which had been studied previously, in the course of preoperative treatment combined with intraarterial chemotherapy and radiotherapy for head and neck cancers.The CBDCA group consisted of 13 previously untreated patients who received both the intraarterial chemotherapy with CBDCA (80mg/m2, on day 1 and 8) and peplomycin (PEP, 5mg/body/day, from day 1 to 5 and day 8 to 12) and 60Co-radiotherapy (2 Gy/day, total to 20 Gy) before surgery. The CDDP group consisted of 14 analogous patients who had received the same therapy except for intraarterial infusion of CDDP (20mg/m2, on days 1 and 8) in spite of CBDCA. The tumors in both groups were resected 7 to 10 days after the preoperative treatments and examined histologically in several portions.Therapeutic effects were judged according to Oboshi's histological classification in the resected materials. The effect of Grade II B or more, which meaned less than 1/4 living tumor cells, was judged as respondent, and that of Grade II A or less was as irrespondent. Nine out of 13 patients (69%) in CBDCA group and 11 out of 14 patients (79%) in CDDP group were judged as respondent. Though the difference of responsibility between the two groups was not statistically significant, it was impressed that CDDP group showed slightly greater response to the chemo-and radio-therapy.It was suggested from the above results that the CBDCA dosage should be increased within a limited dose with no severe adverse effects appearing.