Combinations of Cytotoxic Agents that have less than Expected Toxicity on Normal Tissues in Mice

Metformin Sensitizes Osteosarcoma Cells to Chemotherapy Through IGF-1R/miR-610/FEN1 Pathway

10.21203/rs.3.rs-147084/v1 ◽

2021 ◽

Author(s):

Suwei Dong ◽

Yanbin Xiao ◽

Ziqiang Zhu ◽

Xiang Ma ◽

Zhuohui Peng ◽

...

Keyword(s):

Underlying Mechanism ◽

Cytotoxic Agents ◽

Luciferase Reporter ◽

Osteosarcoma Cell ◽

Metformin Treatment ◽

Normal Tissues ◽

Qrt Pcr ◽

In Vivo Experiments

Abstract Background: Due to constitutive or acquired non-sensitive to cytotoxic agents, the prognosis of osteosarcoma remains unfavorable. It’s has been proved that metformin could enhance the chemosensitivity of cancer cells to anticancer drugs. A novel finding states that IGF-1R involves in cancer chemoresistance, However, whether IGF-1R play a role in metformin-induced osteosarcoma chemosensitivity is incompletely understood. Hence, the current study aimed to elucidate the role of metformin in OS cell chemosensitivity modulation to identify the underlying mechanism of metformin regulating the IGF-1R/miR-610/FEN1 signaling.Methods: Immunohistochemistry and qRT-PCR were used to evaluate the expression pattern of IGF-1R, miR-610 and FEN1 in osteosarcoma and paired normal tissues. Western blot and qRT-PCR were performed to determine changes in expression of key molecules in the IGF-1R/miR-610/FEN1 signaling pathway after various treatments. The direct modulation between miR-610 and FEN1 was monitored by luciferase reporter assay. Osteosarcoma cell sensitivity to chemotherapy was detected by MTS assay. In vivo experiments were conducted to further verify the role of the metformin in the chemosensitivity modulation of OS cells to ADM.Results: We found that IGF-1R, miR-610 and FEN1 were abberently expressed in osteosarcoma, and participated in apoptosis modulation (p < 0.05). We found that this effect was abated by metformin treatment. Luciferase reporter assays confirmed that FEN1 is a direct target of miR-610. Moreover, we observed that metformin treatment decreased IGF-1R and FEN1, but elevated miR-610 expression. Metformin sensitized OS cells to cytotoxic agents, while overexpression of FEN1 compromised the sensitizing effects of metformin partly. Furthermore, metformin was observed to enforce the ADM treatment effect in nude mice xenograft models.Conclusions: Overall, metformin enhanced the sensitivity of OS cells to cytotoxic agents via the IGF-1R/miR-610/FEN1 signaling axis, highlighting the capacity of metformin as an adjunct to the chemotherapy of OS.

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Molecular Radiobiology: The State of the Art

Journal of Clinical Oncology ◽

10.1200/jco.2014.57.2776 ◽

2014 ◽

Vol 32 (26) ◽

pp. 2871-2878 ◽

Cited By ~ 26

Author(s):

Amato J. Giaccia

Keyword(s):

Cancer Therapy ◽

Normal Tissue ◽

Tissue Injury ◽

Tumor Biology ◽

Cytotoxic Agents ◽

Tumor Control ◽

Normal Tissues ◽

Dividing Cells ◽

Technical Advances ◽

Targeted Agent

Traditional cytotoxic agents used in cancer therapy were initially discovered based on their ability to kill rapidly dividing cells. The targets of these early-generation agents were typically one or more aspects of DNA synthesis or mitosis. Thus, dose-limiting toxicities commonly associated with these agents include GI dysfunction, immunosuppression, and other consequences of injury to normal tissues in which cells are replicating under normal physiologic conditions. Although many of these agents still play an important role in cancer therapy when given concurrently with radiation therapy, the major thrust of radiobiology research in the last two decades has focused on discovering tumor-specific traits that might be exploited for more selective targeting that would enhance the efficacy of radiotherapy with less normal tissue toxicity. These newer generation molecular targeted therapies interfere with the growth of tumor cells by inhibiting genes and their protein products that are needed specifically by the tumor for survival and expansion. These agents can be complementary to radiotherapy, a spatially targeted agent. Although there have been extraordinary technical advances in radiotherapy in recent years, we are reaching the limits of improvements that radiotherapy delivery technology can bring and need different approaches. This review will highlight promising new tumor biology–based targets and other novel strategies to reduce normal tissue injury, increase tumor control, and expand the use of radiotherapy to treat widespread metastatic disease.

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The rabbit as an experimental model for regional chemotherapy 2. Isolated perfusion of hindlimbs

Laboratory Animals ◽

10.1258/002367786780808848 ◽

1986 ◽

Vol 20 (4) ◽

pp. 347-350 ◽

Cited By ~ 3

Author(s):

T. Davidson ◽

J. Wallace

Keyword(s):

Primary Tumour ◽

Regional Chemotherapy ◽

Drug Uptake ◽

Cytotoxic Agents ◽

Plant Toxin ◽

Arterial Infusion ◽

Normal Tissues ◽

Vx2 Carcinoma ◽

Isolated Perfusion ◽

Node Metastases

Regional chemotherapy to a tumour is most commonly delivered by intra-arterial infusion. An alternative method of regional drug delivery, isolated perfusion, may be used where anatomical considerations permit. The technique of isolated perfusion in the rabbit hindlimb is described. The use of this model with the implantable rabbit VX2 carcinoma allows estimation of drug uptake by normal tissues, primary tumour and popliteal lymph node metastases. Correlation of such data with blood now measurements enables targeting of new cytotoxic agents to be evaluated. The effect of perfusate composition on tissue uptake of such an agent, the plant toxin ricin, has been determined.

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Chemotherapy and Dietary Phytochemical Agents

Chemotherapy Research and Practice ◽

10.1155/2012/282570 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 76

Author(s):

Katrin Sak

Keyword(s):

Side Effects ◽

Cancer Therapy ◽

Anticancer Agents ◽

Multiple Organ ◽

The Body ◽

Cytotoxic Agents ◽

Adverse Side Effects ◽

Chemotherapy Drugs ◽

Normal Tissues ◽

Organ Systems

Chemotherapy has been used for cancer treatment already for almost 70 years by targeting the proliferation potential and metastasising ability of tumour cells. Despite the progress made in the development of potent chemotherapy drugs, their toxicity to normal tissues and adverse side effects in multiple organ systems as well as drug resistance have remained the major obstacles for the successful clinical use. Cytotoxic agents decrease considerably the quality of life of cancer patients manifesting as acute complaints and impacting the life of survivors also for years after the treatment. Toxicity often limits the usefulness of anticancer agents being also the reason why many patients discontinue the treatment. The nutritional approach may be the means of helping to raise cancer therapy to a new level of success as supplementing or supporting the body with natural phytochemicals cannot only reduce adverse side effects but improve also the effectiveness of chemotherapeutics. Various plant-derived compounds improve the efficiency of cytotoxic agents, decrease their resistance, lower and alleviate toxic side effects, reduce the risk of tumour lysis syndrome, and detoxify the body of chemotherapeutics. The personalised approach using various phytochemicals provides thus a new dimension to the standard cancer therapy for improving its outcome in a complex and complementary way.

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Mitochondrial Apoptotic Priming Measured by BH3 Profiling Regulates Clinical Response to Chemotherapy in Myeloma and Acute Lymphoblastic Leukemia and Explains Therapeutic Index

Blood ◽

10.1182/blood.v118.21.1442.1442 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1442-1442

Author(s):

Triona Ni Chonghaile ◽

Kristopher Sarosiek ◽

Jeremy Ryan ◽

Vicki Del Gaizo Moore ◽

Yu-Tzu Tai ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Response ◽

Board Of Directors ◽

Cytotoxic Agents ◽

P Value ◽

Advisory Committees ◽

Normal Tissues ◽

Response To Chemotherapy ◽

Protein Reduction

Abstract Abstract 1442 Cytotoxic chemotherapy, still a mainstay of current cancer treatment, targets ubiquitous elements such as DNA and microtubules. Despite decades of clinical use of chemotherapy, determinants of response to such treatments are poorly understood. Here, we showed that clinical response to cytotoxic agents is largely regulated by the initial proximity of tumors' mitochondria to the apoptotic threshold. Cells that are close to the apoptotic threshold we refer to as “primed” for death. Priming is assessed by a functional assay we call BH3 profiling that measures mitochondrial response to standardized death signals in the form of peptides from the pro-apoptotic BH3-only proteins. We assessed priming across a total of 51 patient samples, 25 of which had clinical follow-up. Priming correlated to % M-protein reduction, a marker of reduced disease burden in multiple myeloma following treatment (spearman r = 0.8039, P= 0.00005 Fig 1A). Patient's with highly primed mitochondria also demonstrated a better clinical response in both multiple myeloma (P= 0.001) and in acute lymphoblastic leukemia (P= 0.0119). Pediatric ALL responds better to therapy and has a much higher long term survival rate than adult ALL (80–90% vs. 40%) (Pui et. al N Engl J Med, 2006). We found that pediatric ALL samples were more primed than adult (P = 0.007). To demonstrate the relationship between priming and chemosensitivity we perturbed priming by co-culture with stroma or by pretreatment with ABT-737 and demonstrated that altering priming changed chemosensitivity predictably. By far the most important dichotomy in sensitivity to chemotherapy is between normal tissues and cancer cells. Differences in proliferation rate, the classic explanation for this dichotomy offers only modest explanatory power with many exceptions. We therefore tested whether differential mitochondrial apoptotic priming was an important determinant of the therapeutic index from cytotoxic chemotherapy. We directly tested the mitochondrial priming of a series of normal tissues from both human (8 tissues) and mouse (8 tissues). Significantly, we found that most normal tissues along with chemoresistant (Serous borderline ovarian, Renal and Endometrial) cancers had relatively low priming (Fig 1B). Conversely chemosensitive cancers and normal hematopoietic tissues were highly primed. Differential mitochondrial priming may provide a novel explanation for the otherwise puzzling existence of a therapeutic window for cytotoxic agents. This newly appreciated determinant of response to chemotherapy could be exploited to rationally improve efficacy of cytotoxic agents or to devise better combinations of drugs.Fig 1:Mitochondrial priming regulates clinical response to chemotherapy in multiple myeloma and acute lyphoblastic leukemia (A) Loss of δΨm caused by the BMF peptide in myeloma patient samples correlates to %M-protein reduction. (B) Comparison of priming among all primary human cancers and normal tissues. The cancers with clinical follow up were classified as known chemosensitive or known chemoresistant. Cancers classified as typically chemoresistant (Serous borderline n=3, Endometrial n=3 and Renal n=3) or typically chemosensitive (childhood ALL n=17) lacked individual response data. Data shown are mean ± s.d. across all specimens tested. ANOVA was used to demonstrate statistical significance between the different categories with a Tukey's multiple comparison post test. ns - p value > 0.05 and *** p-value <0.001.Fig 1:. Mitochondrial priming regulates clinical response to chemotherapy in multiple myeloma and acute lyphoblastic leukemia (A) Loss of δΨm caused by the BMF peptide in myeloma patient samples correlates to %M-protein reduction. (B) Comparison of priming among all primary human cancers and normal tissues. The cancers with clinical follow up were classified as known chemosensitive or known chemoresistant. Cancers classified as typically chemoresistant (Serous borderline n=3, Endometrial n=3 and Renal n=3) or typically chemosensitive (childhood ALL n=17) lacked individual response data. Data shown are mean ± s.d. across all specimens tested. ANOVA was used to demonstrate statistical significance between the different categories with a Tukey's multiple comparison post test. ns - p value > 0.05 and *** p-value <0.001. Disclosures: Richardson: Millennium:; Celgene:; Johnson & Johnson:; Novartis:; Bristol Myers Squibb:. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Acetylon: Membership on an entity's Board of Directors or advisory committees. Mitsiades:Millennium: Consultancy, Honoraria. Sallan:Enzon Pharmaceuticals: Honoraria. Letai:Eutropics Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Surface Ultrastructure of Human Ectocervix in Certain Pathological Conditions

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100119636 ◽

1985 ◽

Vol 43 ◽

pp. 570-571

Author(s):

S. Mukherjee ◽

T. Guha ◽

B. Chakrabarti ◽

P. Chakrabarti

Keyword(s):

Epithelial Cells ◽

Marked Reduction ◽

Squamous Epithelium ◽

Malignant Tumour ◽

Surface Ultrastructure ◽

Normal Tissues ◽

Pathological Conditions ◽

Hexagonal Shape ◽

Columnar Cells ◽

Scanning Electron

The cervix is an important organ in reproduction. Its malfunction is frequently a factor for infertility. Ectocervix region does not appear to have received much attention although many studies have been reported on the endocervix. We report here our SEM observations on ectocervix in certain pathological conditions compared to normal ectocervix.Ectocervix specimens from human females with specific pathological disorders were processed for Scanning Electron Microscopy by conventional method and they were examined in a Philips SEM.The normal ectocervix is lined by flat layer of squamous epithelial cells with microridges (Fig. 1). These cells are known to be formed from columnar cells through metaplastic transformation. The cells of carcinoma-bearing ectocervix show a disorganised appearance (Fig. 2). In non-malignant tumour surface some cuboidal and few columnar cells were seen (Fig. 3). A cyst appears like an overgrowth on the surface of the squamous epithelium (Fig. 4). In ulcerated ectocervix a marked reduction of epithelial cells are observed (Fig. 5); the cells are devoid of microridges and, the large polygonal cells, as observed in normal tissues, have somehow acquired comparatively small hexagonal shape

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Glucose metabolism in cancer cells: immunogold localization of hexokinase to the outer mitochondrial membrane

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100141597 ◽

1995 ◽

Vol 53 ◽

pp. 1044-1045

Author(s):

Krishan K. Arora ◽

Glenn L. Decker ◽

Peter L. Pedersen

Keyword(s):

Tumor Cells ◽

Mitochondrial Membrane ◽

Present Report ◽

Large Fraction ◽

Mitochondrial Fraction ◽

Immunogold Labeling ◽

Outer Mitochondrial Membrane ◽

Immunogold Localization ◽

Hexokinase Activity ◽

Normal Tissues

Hexokinase (ATP: D-hexose 6-phophotransferase EC 2.7.1.1) is the first enzyme of the glycolytic pathway which commits glucose to catabolism by catalyzing the phosphorylation of glucose with ATP. Previous studies have shown diat hexokinase activity is markedly elevated in rapidly growing tumor cells exhibiting high glucose catabolic rates. A large fraction (50-80%) of this enzyme activity is bound to the mitochondrial fraction (1,2) where it has preferred access to ATP (3). In contrast,the hexokinase activity of normal tissues is quite low, with one exception being brain which is a glucose-utilizing tissue (4). Biochemical evidence involving rigorous subfractionation studies have revealed striking differences between the subcellular distribution of hexokinase in normal and tumor cells [See review by Arora et al (4)].In the present report, we have utilized immunogold labeling techniques to evaluate die subcellular localization of hexokinase in highly glycolytic AS-30D hepatoma cells and in the tissue of its origin, i.e., rat liver.

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