Therapeutic Effect Of Chemotherapy Research Articles

New immune therapy targets tumor-associated environment: from bone marrow to tumor site

New immune therapy targets tumor-associated environment: from bone marrow to tumor site

Interaction of a traditional Chinese Medicine (PHY906) and CPT-11 on the inflammatory process in the tumor microenvironment

Background -Traditional Chinese Medicine (TCM) has been used for thousands of years to treat or prevent diseases, including cancer. Good manufacturing practices (GMP) and sophisticated product analysis (PhytomicsQC) to ensure consistency are now available allowing the assessment of its utility. Polychemical Medicines, like TCM, include chemicals with distinct tissue-dependent pharmacodynamic properties that result in tissue-specific bioactivity. Determining the mode of action of these mixtures was previously unsatisfactory; however, information rich RNA microarray technologies now allow for thorough mechanistic studies of the effects complex mixtures. PHY906 is a long used four herb TCM formula employed as an adjuvant to relieve the side effects associated with chemotherapy. Animal studies documented a decrease in global toxicity and an increase in therapeutic effectiveness of chemotherapy when combined with PHY906.Methods -Using a systems biology approach, we studied tumor tissue to identify reasons for the enhancement of the antitumor effect of CPT-11 (CPT-11) by PHY906 in a well-characterized pre-clinical model; the administration of PHY906 and CPT-11 to female BDF-1 mice bearing subcutaneous Colon 38 tumors.Results -We observed that 1) individually PHY906 and CPT-11 induce distinct alterations in tumor, liver and spleen; 2) PHY906 alone predominantly induces repression of transcription and immune-suppression in tumors; 3) these effects are reverted in the presence of CPT-11, with prevalent induction of pro-apoptotic and pro-inflammatory pathways that may favor tumor rejection.Conclusions -PHY906 together with CPT-11 triggers unique changes not activated by each one alone suggesting that the combination creates a unique tissue-specific response.

Clinical Study on the Treatment of Adriamycin-induced Cardiotoxicity with the Method of Nourishing Yin

Objective To investigate the preventive effect of treating cardiotoxicity induced by adriamycin (ADM) with the method of nourishing yin. Methods 90 cancer patients underwent adriamycin therapy were randomly recruited intoa treatment group (45 cases) and a control group (45 cases). The treatment group was treated with Wushen decoction, while the control group was treated with antioxidant drugs. The changes of ECG, blood SOD, GSH-Px, MDA content etc were observed after one course of four weeks' treatment. Results The incidence of cardiactoxicity was 15.56% in the treatment group and 40.00% in the control group, showing significant difference ( U=2.02, P<0.05 ) ; the incidence of ECG abnormalities was 13.33% in the treatment group and 37.78%, in the control group, showing significant difference (U= 2.18, P< 0.05 ) : the effective rate was 82.22% in the treatment group and 62.22% in the control group, showing significant difference ( U=2.18, P <0.05) ; and SOD, GSH-Px, MDA content at the 1, 7, 14, and 28days between the two groups also demonstrated significant differences (P<0.05) . Conclusion The method of nourishing yin has excellent attenuation to adriamycin-induced cardiotoxicity, besides it enhances therapeutic effects of chemotherapy. Key words: Wushen decoction; Adriamycin; Clinical study

Correlation of chemosensitivity tested using histoculture drug response assay to expression of multidrug resistance genes and proteins in colorectal cancer tissues

The therapeutic effects of chemotherapy for malignant neoplasms are still unsatisfactory. This study was to evaluate the chemosensitivity of colorectal cancer tissues to therapeutic agents using histoculture drug response assay (HDRA), and explore the correlation of chemosensitivity to the expression levels of multidrug resistance (MDR) genes and proteins. Twenty-two specimens of colorectal cancer were collected. The inhibition rates of single agents, including epirubicin, cisplatin (DDP), oxaliplatin, 5-FU, taxetere, irinotecan, and combinations of these agents, including 5-FU+epirubicin+DDP, 5-FU+irinotecan, 5-FU+oxaliplatin, 5-FU+taxetere+ DDP on colorectal cancer tissues were evaluated by HDRA. The agent whose inhibition rate was greater than 30% was considered sensitive, and the sensitivity was calculated. mRNA and protein levels of MDR genes and proteins in colorectal cancer tissues were measured by RT-PCR and immunohistochemistry. Among the single agents, the inhibition rate of oxaliplatin (17.5%) and sensitivity of cancer tissues to 5-FU (36.4%) were the highest. In the combination groups of agents, the inhibition rate of 5-FU+ oxaliplatin (54.1%), and sensitivity of cancer tissues to 5-FU+epirubicin+DDP (71.4%) and to 5-FU+taxetere+DDP (71.4%) were the highest. The inhibition rates of and sensitivity of cancer tissues to combined agents were higher than those of single agents (P<0.05). Expressions of MDR1, multidrug resistance protein-1 (MRP1), ABC-binding cassette transporter superfamily-G-2 (ABCG2) mRNA were detected in 88.9%, 55.6% and 55.6% of specimens respectively; while those of MDR1, MRP1 and ABCG2 proteins were detected in 55.6%, 33.3%, and 50.0% of specimens respectively. Expressions of mRNA and proteins had no correlation in MDR1, MRP1 and ABCG2 (P>0.05). High expression of ABCG2 protein was correlated to the resistance of colorectal cancer cells to epirubicin (P<0.05). Expressions of MDR proteins are correlated to chemosensitivity of colorectal cancer to some extents. By combining HDRA with measurement of MDR genes and proteins, chemosensitivity of individual tumors may be predicted to guide selection of effective chemotherapeutic agents.

A pilot study of weekly docetaxel chemotherapy combined with regional hyperthermia for pretreated stage III non-small cell lung cancer

Objective To evaluate the feasibility and therapeutic effect of chemotherapy combined with regional radio frequency hyperthermia for pretreated locally advanced non-small cell lung cancer.

Effect of the all-trans retinoic acid on neural growth factor serum levels (NGF) and chemotherapy induced neuropathy in patients with advanced lung cancer

Background Peripheral neuropathy is a common adverse event in patients treated with chemotherapy. The development of peripheral neuropathy observed in chemotherapy is similar to the diabetic patients where there is reduction of the expression and transport of Neural Growth Factor (NGF). Retinoic acid (RA) regulates genes related to cellular proliferation and the expression of NGF. Phase 1 and in vitro studies suggested that retinoic acid may synergize the therapeutic effect of chemotherapy, in particular paclitaxel and cisplatin. We conducted a phase II randomized double blind clinical trial to determine the effect of all-trans retinoic acid on the development of chemotherapy induced neuropathy based on the combination of paclitaxel and cisplatin in patients with advanced lung cancer; in addition we analyzed the therapeutic effect of retinoic with chemotherapy.

Overexpression of heat shock protein 27 is associated with good prognosis in the patient with oral squamous cell carcinoma

We investigated the expression and biological significance of heat shock protein (HSP)-27 in patients with oral squamous cell carcinoma (SCC). The expression of HSP-27 was quantified immunohistochemically in specimens from 37 patients with oral SCC. Findings were correlated with lymph node metastases, effect of chemotherapy, and survival. The presence of HSP-27 was identified in 31 of the 37 specimens (84%). Expression was low in 4 patients (11%), intermediate in 13 (35%), and high in 14 (38%). There were significant differences in the therapeutic effect of chemotherapy (Oboshi–Shimosato's grade) and prognosis in relation to expression of HSP-27. We found no correlation between the extent of expression of HSP-27 and stage or differentiation of the tumour.

Targeting Bcl-2 with oblimersen for patients with hormone refractory prostate cancer

Patients with metastatic hormone refractory prostate cancer (HRPC) have limited treatment options and new therapies are needed. Advances in the understanding of the molecular mechanisms implicated in prostate cancer progression have identified many potential therapeutic gene targets including Bcl-2, an important pro-survival regulator of apoptotic cell death. Bcl-2 is overexpressed in a variety of human malignancies including prostate cancer where it has also been associated with androgen independent progression and treatment resistance. Oblimersen is a phosphorothioate antisense oligonucleotide complimentary to the Bcl-2 mRNA and a potent inhibitor of Bcl-2 expression which in pre-clinical testing can significantly enhance the therapeutic effect of chemotherapy, hormone and radiation therapy. Clinical trials evaluating oblimersen in combination with chemotherapy in a variety of cancers have shown good tolerability and promising response rates. Randomized trials are required to determine if oblimersen can enhance the effectiveness of docetaxel in patients with HRPC.

In vitro testing of platinum-based drugs on a panel of human ovarian tumour cell lines

Much improvement in the treatment of ovarian cancer has been achieved since the introduction of platinum compounds in the 1980s, with the result that single-agent platinum-based therapy following primary surgery is now the standard treatment for advanced ovarian cancer. The main therapeutic effect of chemotherapy is based on the sensitivity of the patient’s tumour to the drug. However, testing a new chemical compound on humans requires much care, time and resources, whereas prior testing of drugs on cancer cell lines may indicate those drugs particularly suited to treatment of a specific disease. This study investigates the actions of two established platinum-based chemotherapeutic agents (cisplatin and carboplatin) on a panel of 10 human ovarian cancer cell lines. Each cell line was plated onto 96-well tissue culture plates, incubated for 72 hours with the drug, formalin-fixed and then assessed using the methylene blue colorimetric microassay to detect viable cells. The IC50 values for each cell line were calculated in order to assess the toxicity of each drug, and a wide range of responses were observed across the 10 cell lines investigated. This suggests that the panel reflected the heterogeneous nature of ovarian cancer, a malignancy in which a huge range of drug sensitivities can be seen even among tumours of the same histological type. The results indicate that the panel could be of use either as a primary screen to test new drugs against ovarian cancer or to investigate the drug resistance that is so common in this disease.

Clinical pharmacology of encapsulated sustained-release cytarabine.

The therapeutic effectiveness of chemotherapy is often limited by the inability to sustain cytotoxic concentrations at the tumor site. Cytarabine liposome injection (DepoCyt), a sterile, injectable suspension of the antimetabolite cytarabine, encapsulated into multivesicular, lipid-based particles, has been developed to improve the treatment of neoplastic meningitis (NM) through sustained release of cytarabine. To review the pharmacokinetics, efficacy, and safety of intrathecal DepoCyt for the treatment of NM secondary to lymphoma or solid tumors. In preclinical and clinical studies, DepoCyt markedly extended the duration of tumor exposure to cytotoxic concentrations of cytarabine compared with administration of unbound cytarabine. Data from recent clinical studies demonstrate that DepoCyt improves complete response rates among patients with NM secondary to lymphoma. Trends in time to neurologic progression and median survival also favored DepoCyt over unbound cytarabine in these studies. Data have also been presented that suggest that patients with NM secondary to solid tumors benefit more from DepoCyt than from conventional treatment approaches. Chemical arachnoiditis (i.e., headache, fever, nausea, vomiting) was common in patients receiving DepoCyt, however, symptoms were manageable with oral dexamethasone. Encapsulation of cytarabine into liposomes for sustained release prolongs tumor exposure to cytotoxic concentrations of cytarabine, which may improve therapeutic efficacy in patients with NM secondary to lymphoma or solid tumors.

Human IgM monoclonal antibody to ganglioside GM2 and complement suppress virus propagation in ex vivo cultures of lymphocytes from HIV-1 infected patients.

HIV-1 infection induces aberrant ganglioside GM2 expression on infected cell lines, and human IgM anti-GM2 monoclonal antibody (L55 Ab) together with normal fresh human serum (FHS) as a source of complement causes complement mediated cytolysis of HIV-1 infected cells as well as HIV-1 particles. We report here that high expression of GM2 was also detected on HIV-1 infected lymphocytes from HIV-1 seropositive patients. L55 Ab effectively suppressed the generation of HIV in the presence of FHS in primarily cultured lymphocytes from HIV-1 infected patients in ex vivo experiments, and the suppression was enhanced additively by AZT. These data suggest that L55 Ab may increase the therapeutic effect of chemotherapy.

Prognostic value of histopathological therapeutic effects and mitotic index in locally advanced breast cancers after neoadjuvant chemotherapy.

A study was conducted to examine whether or not the histopathological therapeutic effects of preoperative chemotherapy could be useful for determining prognosis in women with locally advanced breast cancer. The patients were 37 women with locally advanced breast cancer who received preoperative chemotherapy between 1977 and 1987. The histological grade of malignancy (HGM) and histopathological therapeutic effects of chemotherapy (TEf) were examined in resected specimens. Patients with HGM 3 showed a poorer 10-year overall survival (38%) than those with HGM 1 or 2 (62%). Patients showing a better histopathological response (TEf 1b plus 2) had a poorer 10-year overall survival (20%) than those with a poorer response (TEf 0 plus 1a) (60%). Therapeutic effects were significantly related to histological grade, nuclear atypia and mitotic index (p = 0.03, 0.005 and 0.002, respectively). Histopathological therapeutic effects were not directly correlated with patient prognosis. Cox proportional hazard regression analysis revealed that mitotic index was the most significant prognostic factor related to 10-year overall survival.

FUNCTIONAL-CHARACTERIZATION OF DEVELOPING TUMOR VASCULAR SYSTEM AND DRUG DELIVERY (REVIEW)

This review summarizes our recent experiments on the process of tumor vascularization and character of tumor vessels. By vitalscopic observation with transparent chambers in rats, we found that the sites where tumor vessels originated were usually terminal portions of terminal arterioles and that an intricate tumor vascular network was constructed from incorporated preexisting vessels and newly formed vessels by three different modes, i.e., sprouting, cross-connecting and splitting. Observation and hydrogen clearance studies showed that tumor blood flow changed remarkably during the development of the tumor vascular network. At an early stage of tumor growth, there were some regions of high flow in the tumor. At an advanced stage, however, there was a rapid increase in low-flow or no-flow areas which were resistant to access of anticancer drugs and oxygen. Angiotensin II-induced hypertension produced a several-fold increase in tumor blood flow without increasing tissue blood flow of normal tissues. These good conditions for drug delivery to tumor tissue are able to enhance therapeutic effects of chemotherapy, irradiation, antibody and photodynamic therapy.

MECHANISM OF ACTION OF ADJUVANT CHEMOTHERAPY IN EARLY BREAST CANCER

The relation between tumour oestrogen and progesterone receptor status, menstrual status, relapse-free survival, and overall survival was analysed in 411 patients with early breast cancer randomised to receive either postoperative adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) or no additional treatment (control). Prolongation of time to recurrence and survival was seen predominantly in premenopausal patients; these effects were seen only with tumours positive for steroid receptors, particularly progesterone. Chemotherapy led to permanent amenorrhoea in 61% of premenopausal patients. The therapeutic effects of chemotherapy were seen only when CMF induced permanent amenorrhoea in premenopausal patients. These findings support the hypothesis that the effect of adjuvant chemotherapy in early breast cancer may be mediated by ovarian suppression.