THE USE OF ANTI-HUMAN GLIOMA MONOCLONAL ANTIBODIES FOR TARGETING CHEMOTHERAPY OF BRAIN GLIOMAS(PREPARATION AND CYTOTOXIC PROPERTIES OF ANTIBODY-ADRIAMYCIN IMMUNOCONJUGATES)

Immunoconjugates are antibody-drug hybrid molecules which combine the exquisite selectivity or monoclonal antibodies with the potent toxicity of anticancer agents. A monoclonal antibody SZ39 against human brain gliomas was used as a drug carrier. Adriamycin (ADR) was bound covalently to SZ39 to form a SZ39-ADR conjugate. The cytotoxic activity of the SZ39-ADR conjugate was tested in vitro and demonstrated potent and specific killing of cells derived from a human malignant glioma. 50% inhibitory concentration (IC50) for SZ39-ADR to 'target' cells was 8.14×10-9 M. An index of specificity between 'target' and 'non-target' cells was calculated to be 88-fold. These data suggest that the SZ39-ADR may use as a potent and cell type-specific agent and is a likely candidate for the targeting chemotherapy of malignant gliotnas.

THE USE OF ANTIHUMAN GLIOMA MONOCLONAL ANTIBODIES FOR TARGETING CHEMOTHERAPY OF BRAIN GLIOMAS(POTENT SUPPRESSION OF MALIGNANT GLIOMA GROWTH WITH IMMUNOCONJUGATES IN VIVO)

Athymic nude mice bearing subcutaneous and intracerebral human glioma xenografts were used to assess the therapeutic efficacy of monoclonal anti-body-adriamycin immunoconjugates against malignant gliomas in vivo. Immunoconjugates showed a significantly stronger antitumor effect with a T/C (treated/ control tumor volume) of 30% as compared with free drug (T/C of 84%). The targeting treatment with immunoconjugates significantly prolonged 54% of median survival time of nude mice. Side effects of immunoconjugates on the normal bone marrow and small intestines were much slighter than those of the free drug. The results of this study indicate that the use of monoclonal antibodies as carriers of anti-tumor agents may have many therapeutic advantages and potential for the treatment of brain gliomas.

Neoadjuvant chemotherapy for metastatic colorectal cancer to the liver: from chemotherapy to targeting therapy

Despite the advances in surgical techniques, adjuvant chemotherapy and targeted therapy, approximately 40%-70% of patients with progressive colorectal cancer will develop liver metastases, of whom one-third are found at the time of diagnosis.[1] Surgical resection is now the standard treatment and also the only potentially curative treatment for resectable lesions.

Efficacy and Safety of Chemotherapy with or without Targeted Therapy in Biliary Tract Cancer:A Meta-analysis of 7 Randomized Controlled Trials

The systematic treatment based on gemcitabine plus cisplatin is recommended as the current standard chemotherapy for unresectable or metastatic biliary tract cancers.However,the exact benefits from the recognized regime are still dismal.We thus elicit this study in an attempt to analyze whether targeted therapy coupled with various chemotherapy could produce improvement of survival benefits.The clinical trials were searched electronically from databases till July 2016 published in English and Chinese.Nine hundred and sixty-four patients from 7 trials were identified in our analysis.The overall analysis achieved a significantly higher overall response rate（ORR） among the patients treated with targeted drugs plus chemotherapy than chemotherapy alone（OR=1.87;95% CI：1.37–2.57;P=0.000）,but failed in the overall progression-free survival（PFS） [mean difference（MD）=0.63;95% CI：–0.45–1.72;P=0.26] and overall survival（OS）（MD=–0.67;95% CI：–2.54–1.20;P=0.49）.In the sub analysis,better ORR was obtained with the addition of EGFR（OR=1.75;95% CI：1.20–2.56;P=0.004） and VEGFR（OR=2.5;95% CI：1.28–4.87;P=0.007） targeted therapy.Furthermore,the sub analysis of EGFR target showed an significant improvement on PFS（MD=1.36;95% CI：0.29–2.43;P=0.01）.No significant differences were observed in the incidences of neutropenia（OR=1.37;95% CI：0.89–2.12）,thrombocytopenia（OR=1.40;95% CI：0.83–2.39）,anemia（OR=1.21;95% CI：0.62–2.38）,peripheral neuropathy（OR=1.52;95% CI：0.81–2.88）,increased AST/ALT（OR=1.40;95% CI：0.82–2.39） as well as fatigue（OR=1.65;95% CI：0.96–2.84） in either of the treatment groups.In conclusion,better ORR associated with chemotherapy combined with targeted therapy（both targeting EGFR and VEGF） is found in the present meta-analysis without the cost of increased unacceptable toxicities,but regretfully not for the OS.The sub-analysis of targeting EGFR instead of VEGF obtains a superior PFS.Otherwise,there is no statistically significant difference in the overall PFS between the combination regime and chemotherapy alone.Given the paucity of favorable data,we need further studies to characterize optimal targeted agents to confirm the potential value to biliary tract cancer.

A Modified Method for Preparation of Adriamycin Carried by Magnetic Albumin Microspheres

The targeting of antineoplastic agents to restricted anatomic sites and specific target cells have been challenged clinicians all the time in cancer chemotherapy, which resulted in recent efforts to focus the effects of existing antitumor agents and treatments on tumor cells and spare their effects on normal cells. The drug-carrier complex, adriamycin carried by magnetic albumin microspheres (ADM-MAM) was prepared by using our discovered new and modified method. The physical feature of the prepared drug-carrier microspheres was much better than by the traditional method in comparison. The successful preparation of the drug-carrier complex, ADM-MAM, is one of the key steps for our later further researches in the targeted chemotherapy.

Glioblastoma cell-derived exosomes functionalized with peptides as efficient nanocarriers for synergistic chemotherapy of glioblastoma with improved biosafety

Glioblastoma(GBM)has been regarded as one of the most deadly and challenging cancers to treat with extremely poor prognosis.The limited efficacy of current chemotherapies might be attributed to the presence of glioma stem cells(GSCs)as well as the difficulties in passing through the blood–brain barrier(BBB)and targeting tumor cells.Tumor-derived exosomes are emerging as novel and promising drug delivery systems.However,great concerns regarding the biosafety and BBB penetrability remain to be addressed.Herein,we have developed a simple and feasible strategy to engineer GBM cell-derived exosomes with improved biosafety termed“Exo@TDPs”to deliver the cargos of chemotherapeutic agents temozolomide(TMZ)and doxorubicin(DOX)into GBM tissues.Exo@TDPs decorated with angiopep-2(Ang-2)and CD133-targeted peptides improve the capacity to penetrate the BBB and target tumor cells.Both in vitro and in vivo studies demonstrate that Exo@TDPs can cross the BBB,target GBM cells,penetrate into deep tumor parenchyma,and release the therapeutic cargos effectively.Synergistic delivery of TMZ and DOX by Exo@TDPs exerts therapeutic effects to suppress the tumor growth and prolong the survival time of orthotopic syngeneic mouse GBM models.These findings suggest that our developed Exo@TDPs loaded with chemotherapeutic drugs may bring new possibilities for the application of tumor cell-derived exosomes for brain tumor treatment.

Effects of the number of neoadjuvant therapy cycles on clinical outcomes, safety, and survival in patients with metastatic colorectal cancer undergoing metastasectomy

The controversial outcomes in patients with metastatic colorectal cancer(mCRC)highlight the need for developing effective systemic neoadjuvant treatment strategies to improve clinical results.The optimal treatment cycles in patients with mCRC for metastasectomy remain undefined.This retrospective study compared the efficacy,safety,and survival of cycles of neoadjuvant chemotherapy/targeted therapy for such patients.Sixty-four patients with mCRC who received neoadjuvant chemotherapy/targeted therapy following metastasectomy were enrolled between January 2018 and April 2022.Twenty-eight patients received 6 cycles of chemotherapy/targeted therapy,whereas 36 patients received≥7 cycles(median,13;range,7–20).Clinical outcomes,including response,progression-free survival(PFS),overall survival(OS),and adverse events,were compared between these two groups.Of the 64 patients,47(73.4%)were included in the response group,and 17(26.6%)were included in the nonresponse group.The analysis revealed chemotherapy/targeted therapy cycle and pretreatment serum carcinoembryonic antigen(CEA)level as independent predictors of the response as well as overall survival and chemotherapy/targeted therapy cycle as an independent predictor of progression(all p<0.05).Furthermore,our results revealed shorter operation time,lower estimated operative blood loss,higher response rate,lower progression rate,and higher survival rate in≥7 cycles of chemotherapy/targeted therapy group(all p<0.05),but no statistical differences in adverse events were observed between the two groups(all p>0.05).The median OS and PFS were 48 months(95%CI,40.855–55.145)and 28 months(95%CI,18.952–37.48)in the≥7-cycle group and 24 months(95%CI,22.038–25.962)and 13 months(95%CI,11.674–14.326)in the 6-cycle group,respectively(both p<0.001).The oncological outcomes in the≥7-cycle group were significantly better than those in the 6-cycle group,without significant increases in adverse events.However,prospective randomized trials are mandatory to confirm the potential advantages of cycle numbers of neoadjuvant chemotherapy/targeted therapy.