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Protein sensitizer of tumor chemotherapeutics

A chemotherapeutic drug and sensitizer technology, applied in the field of biopharmaceuticals, can solve the problems of non-specific silencing and off-target at the molecular level, no effect, low stability, etc., to promote killing, significantly inhibit growth and promote apoptosis Activity and usage reduction effect

Active Publication Date: 2012-03-07
EAST CHINA UNIV OF SCI & TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The above patents belong to the inhibition of the normal function of survivin at the nucleic acid level, which has low stability in the body and is easily degraded. Non-specific silencing and off-target phenomena may occur at the molecular level. Therefore, we need high transfection rate, easy production, high stability and low risk. Gene recombination drugs with low toxicity and strong therapeutic effect overcome the bottleneck in the current tumor treatment process
[0006] As a preliminary study of the present invention, Chinese patent: 200510026847.8 (authorized announcement number: CN 100424096C) discloses the survivin mutant Survivin and its preparation method and preliminary functions, revealing that the fusion protein TmSm of the Survivin mutant has obvious pro-apoptotic effect on cancer cells effect, but did not address its effect when used in combination with cancer chemotherapy drugs

Method used

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  • Protein sensitizer of tumor chemotherapeutics
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  • Protein sensitizer of tumor chemotherapeutics

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1: Comparison of the cytotoxic effects of doxorubicin (ADM) on three breast cancer cell lines MCF-7, T47-D, and Bcap-37.

[0027] MCF-7, T47-D, and Bcap-37 are preserved by our laboratory. These three cell lines are commonly used cell lines in breast cancer research and can be purchased from the market. Doxorubicin was diluted to an appropriate concentration in high-glucose DMEM medium in equal proportions, and the cytotoxic effect of doxorubicin on MCF-7, T47-D, and Bcap-37 was determined by rapid colorimetry with thiazolium blue (MTT).

[0028] MCF-7, T47-D, and Bcap-37 cells in the logarithmic growth phase were mixed with 1~5*10 4 Add one per well into a 96-well plate, culture overnight until adherent, and then culture with high-sugar DMEM medium containing the corresponding concentration of doxorubicin for 48 hours, and then add a non-cytotoxic dose on the basis of the amount of ADM added in each gradient TmSm cultured for 48h to observe the results. After...

Embodiment 2

[0030] Example 2: Comparison of IC50 of TATm-Survivin (T34A) combined with doxorubicin and doxorubicin alone.

[0031] The cytotoxicity of doxorubicin to breast cancer cell lines MCF-7, T47-D, Bcap-37, and the cytotoxicity of combined drugs were measured by MTT method (refer to Example 1 for specific experimental steps). SPSS18. 0 to determine the half inhibitory concentration (IC50) of the cells, each experiment was repeated more than three times (P Figure 4 .

[0032] from Figure 4 It can be clearly seen that the addition of TATm-Survivin (T34A) reduces the dosage of doxorubicin chemical drugs, which in turn can reduce the tolerance of cancer patients to doxorubicin and other chemical drugs and the corresponding toxic and side effects. Increased sensitivity of breast cancer cells to chemicals such as doxorubicin.

Embodiment 3

[0033] Example 3: The sensitization of breast cancer MCF-7 cells to TATm-Survivin (T34A) is time- and dose-dependent.

[0034] MCF-7 cells in the logarithmic growth phase were divided into 1~5*10 4 Each well was inoculated in a 96-well culture plate, and a low dose of doxorubicin was added to each well, and three gradients (0.05-15ug / ml) of TATm-Survivin (T34A) without cell inhibition rate were added, each group Set up five parallel wells, 37°C, 5% CO 2and saturated humidity incubator for 24h, 48h, 72h, after the end of the experiment, add 20ul MTT (5mg / ml), incubate at 37℃, 5% CO2 and saturated humidity incubator for 4h, suck out the medium, add 150ul of DMSO, detected by 490nm microplate reader after 10min.

[0035] from Figure 5 It can be seen that with the increase of the dose of TATm-Survivin (T34A) (limited in the range of non-cytotoxicity of TATm-Survivin (T34A), the sensitization effect is significantly improved, so it can be seen that this effect is not only due t...

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Abstract

The invention discloses a protein sensitizer of tumor chemotherapeutics and an application thereof, the protein sensitizer comprises Survivin mutant protein, the protein sensitizer has 90% of homology with Survivin through gene engineering preparation, the Survivin comprises one point mutation, multipoint mutation, combinatorial mutation and simultaneous mutation of sites of 20 site, 34 site, 84 site and 117 site. The protein sensitizer is combined with tumor chemotherapeutics for usage, the tumor chemotherapeutics refers to one or more of doxorubicin, epirubicin, daunorubicin or paclitaxel. According to the effect of Survivin protein in cell signal pathway and the influence of Survivin protein on multi-drug resistance reversing, the chemotherapeutics is combined with TmSm, the TmSm is capable of effectively promoting the killing effect of the chemical medicines, effectively reducing the application amount of the chemical medicines and increasing the killing effect of the chemical medicines on cells, and is the effective protein sensitizer of tumor chemotherapeutics.

Description

technical field [0001] The invention relates to the field of biopharmaceuticals, more specifically, the invention relates to a novel synergistic substance for tumor chemotherapy. Background technique [0002] After years of unremitting efforts in the study of tumors, people found that the drug resistance of tumor cells is the main stumbling block in the treatment of tumors. Statistics show that more than 90% of the annual cancer mortality rate is related to drug resistance. While chemical drugs kill tumor cells, they also have cytotoxicity, damage normal tissues and organs, reduce the immune function of the body and other toxic and side effects, affect the effect of chemotherapy, and even be forced to give up chemotherapy. [0003] At present, in order to improve the effect of chemotherapy and radiotherapy, researches are mainly focused on reversing drugs or sensitizing drugs. It is hoped that through the mechanism of drug resistance, we can look for reversing drugs that ma...

Claims

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Application Information

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IPC IPC(8): A61K38/17A61K47/48A61P35/00A61K31/337A61K31/704
Inventor 马兴元许玉馨郑文云朱玲
Owner EAST CHINA UNIV OF SCI & TECH
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