Treatment Of Human Cancer Patients Research Articles

Zinc Nanoparticles as a Cancer Therapeutic

In this essay, Zinc specific method of use as Nano particles will be examined for its role as an anti-cancerous agent. In a long list of referenced studies, presented one by one by the authors' own words, in a seeming endless line, this essay will show that Zinc Nanoparticles are efficient against Cancer in a way that reaches maximum inhibition capacity. Unfortunately, per the researches available on this study, that only some would be summarized here for not to overload, but these studies are often in vitro, sometimes in vivo and mostly haven't been tested almost at all on humans. Since Zinc in all its forms is anti-cancerous, more studying regarding Zinc Nano particles and plain Zinc in the treatment of human cancer patients, is urgently needed.

A novel mechanism for A-to-I RNA-edited AZIN1 in promoting tumor angiogenesis in colorectal cancer

Adenosine (A) to inosine (I) RNA editing catalyzed by adenosine deaminases acting on RNA (ADAR) enzymes is a post-transcriptional modification that emerged as a key player in tumorigenesis and cancer progression. Antizyme inhibitor 1 (AZIN1) is one of the most frequent A-to-I RNA alterations in many human cancers. RNA-edited AZIN1 is known to confer a gain-of-function phenotype associated with aggressive tumors. However, the functional impact of RNA-edited AZIN1 in cancer angiogenesis remains unexplored. We showed here that RNA-edited AZIN1 promoted tumor angiogenesis through the upregulation of IL-8 via in vitro and in vivo experiments. And we subsequently demonstrated that delaying c-Myc degradation by OAZ2-mediated ubiquitin-independent proteasome pathway contributed to increase mRNA level and the secretion of angiogenic factor IL-8. Our study suggests an important contribution of RNA-edited AZIN1 to the tumor vascular microenvironment and highlights its translational potential. Thus, we revealed a potential approach to explore small-molecule antagonists such as reparixin attenuating IL-8 signaling for treatment of human cancer patients detected with hyper-editing.

Abstract A09: Improving the immunogenicity of dendritic cell-derived exosome vaccines for the immunotherapy of melanoma

Abstract Dendritic cell (DC)-derived exosomes (Dexo) are promising vaccine candidates since they carry key molecules, normally found in DCs, that are essential for the activation of adaptive immune responses. Moreover, Dexo have a longer in vivo half-life than DCs, are not subject to the effects of immunomodulators, and are devoid of the risks of cell-based vaccines. As such, clinical trials were conducted to test the feasibility, safety and efficacy of vaccines composed of Dexo carrying tumor antigens for the immunotherapy of melanoma and small-cell lung carcinoma patients. Even though these trials proved the feasibility and safety of Dexo vaccination for the treatment of human cancer patients, the clinical benefits associated with the treatment were limited. We reasoned that the limited efficacy of Dexo vaccines could be ascribed to the low immunogenicity of the Dexo formulations tested in the clinical trials. Indeed, such formulations were produced from DCs loaded with tumor antigens in the absence of any pro-inflammatory stimuli that could provide the danger signals necessary to elicit a proper anti-tumor immune response in vivo. The objective of our work was thus to identify a Dexo formulation with stronger immune stimulatory properties as compared to the Dexo formulations previously tested in pre-clinical and clinical settings. As adaptive immune responses are elicited by antigen-presenting cells activated in the presence of antigens and pro-inflammatory signals, we produced Dexo from DCs loaded with specific antigens (either Ovalbumin, OVA, or tumor-derived antigens) and matured with the Toll-like receptor (TLR)-3 ligand poly(I:C) as danger signal. As a preliminary assessment, we tested Dexo produced from DCs loaded with OVA and stimulated with poly(I:C) (Dexo(OVA+pIC) in in vivo models of vaccination, proving that Dexo(OVA+pIC) could induce efficient activation of transferred or endogenous OVA-specific CD4+ and CD8+ T cells, leading to pro-inflammatory Th1 immune responses. We then moved to a model of therapeutic vaccination in melanoma tumor-bearing mice, taking advantage of the B16F10 melanoma model. To this purpose, we produced Dexo from DCs matured with poly(I:C) and cultured in the presence of oxidized B16F10 cell lysates (Dexo(B16+pIC)), in order to provide additional pro-inflammatory stimuli as well as all the B16F10 antigens to the exosome-producing DCs. Mice bearing subcutaneous B16F10 tumors were vaccinated intradermally in order to target tumor-draining lymph nodes (tdLN). This protocol of vaccination resulted in reduced tumor growth and limited metastasis burden and, most importantly, in prolonged survival of the mice vaccinated with Dexo(B16+pIC). Such benefits were associated with increased frequencies of effector CD8+ T cells in the tdLNs, spleen and tumor masses, reduced frequencies of tumor-infiltrating exhausted PD-1+ CD8+ T cells and increased frequencies of tumor-infiltrating NK and NK-T cells obtained upon vaccination with Dexo(B16+pIC) as compared to vaccination with Dexo(B16). Our results demonstrate that poly(I:C) is a promising candidate for the production of Dexo vaccines with improved immune stimulatory properties suitable for the immunotherapy of cancer. Citation Format: Martina Damo, David Scott Wilson, Jeffrey Alan Hubbell. Improving the immunogenicity of dendritic cell-derived exosome vaccines for the immunotherapy of melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A09.

Species differences in tumour responses to cancer chemotherapy.

Despite advances in chemotherapy, radiotherapy and targeted drug development, cancer remains a disease of high morbidity and mortality. The treatment of human cancer patients with chemotherapy has become commonplace and accepted over the past 100 years. In recent years, and with a similar incidence of cancer to people, the use of cancer chemotherapy drugs in veterinary patients such as the dog has also become accepted clinical practice. The poor predictability of tumour responses to cancer chemotherapy drugs in rodent models means that the standard drug development pathway is costly, both in terms of money and time, leading to many drugs failing in Phase I and II clinical trials. This has led to the suggestion that naturally occurring cancers in pet dogs may offer an alternative model system to inform rational drug development in human oncology. In this review, we will explore the species variation in tumour responses to conventional chemotherapy and highlight our understanding of the differences in pharmacodynamics, pharmacokinetics and pharmacogenomics between humans and dogs. Finally, we explore the potential hurdles that need to be overcome to gain the greatest value from comparative oncology studies.

Abstract LB-331: Effective chemoimmunotherapy with anti-TGFβ antibody and cyclophosphamide on a mouse model of breast cancer.

Abstract Elimination of CD4+FoxP3+ regulatory T cells (Tregs) has become an important strategy of cancer immunotherapy. It was reported that TGFβ is responsible for accumulation of Tregs in tumor. Thus, we treated mouse 4T1 mammary carcinoma model with 1D11 (0.1 mg/mouse), a neutralizing antibody of TGFβ(1,2,3). The treatment delayed growth of primary tumor, however, unexpectedly increased the proportion of FoxP3+ Tregs present in the intratumoral CD4 cells. In order to enhance the anti-tumor effect, 1D11 was administered with a single dose of cyclophosphamide (4 mg/mouse), a chemotherapeutic agent which was previously shown to selectively eliminate intratumoral TNFR2+ Tregs. This combination, but not the therapeutics by themselves, resulted in tumor-free long term survival of up to 80% of mice, and those tumor free mice were more resistant to re-challenge with 4T1 tumor. In order to examine the phenotype of tumor infiltrating immune cells, 4T1 tumor bearing mice were treated with 1D11 and a lower dose of cyclophosphamide (2 mg/mouse). This treatment markedly inhibited tumor growth, accompanied by a massive infiltration by IFNγ-producing T cells. Furthermore, this combination markedly decreased the number of splenic MDSCs, and increased their expression levels of MHC II and CD80. Taken together, our data show that anti-TGFβ Ab and cyclophosphamide represents a novel chemoimmunotherapeutic combination which may prove useful in the treatment of human cancer patients.(Funded by NCI Contract HHSN261200800001E) Citation Format: Xin Chen, Yuan Yang, Qiong Zhou, O.M.Zack Howard, John McPherson, Lalage Wakefield, Joost J. Oppenheim. Effective chemoimmunotherapy with anti-TGFβ antibody and cyclophosphamide on a mouse model of breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-331. doi:10.1158/1538-7445.AM2013-LB-331 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Antineoplastic Agents. 445. Synthesis and Evaluation of Structural Modifications of (Z)- and (E)-Combretastatin A-4

A series of cis- and trans-stilbenes related to combretastatin A-4 (1a), with a variety of substituents at the 3'-position of the aryl B-ring, were synthesized and evaluated for inhibitory activity employing six human cancer cell lines (NCI-H460 lung carcinoma, BXPC-3 pancreas, SK-N-SH neuroblastoma, SW1736 thyroid, DU-145 prostate, and FADU pharynx-squamous sarcoma) as well as the P-388 murine lymphocyte leukemia cell line. Several of the cis-stilbene derivatives were significantly inhibitory against all cell lines used, with potencies comparable to that of the parent 1a. All were potent inhibitors of tubulin polymerization. The corresponding trans-stilbenes had little or no activity as tubulin polymerization inhibitors and were relatively inactive against the seven cancer cell lines. In terms of inhibition of both cancer cell growth and tubulin polymerization, the dimethylamino and bromo cis-stilbenes were the most potent of the new derivatives, the latter having biological activity approaching that of 1a. As part of the present study, the X-ray crystal structure of the 3'-O-phosphate of combretastatin A-4 (1b) was successfully elucidated. Compound 1b has been termed the "combretastatin A-4 prodrug", and it is currently undergoing clinical trials for the treatment of human cancer patients.

Generation of effective cancer vaccines genetically engineered to secrete cytokines using adenovirus-enhanced transferrinfection (AVET)

Cancer vaccines are based on the concept that tumors express novel antigens and thus differ from their normal tissue counterparts. Such putative tumor-specific antigens should be recognizable by the immune system. However, malignant cells are of self origin and only poorly immunogenic, which limits their capability to induce an anticancer immune response. To overcome this problem, tumor cells have been isolated, genetically engineered to secrete cytokine gene products and administered as cancer vaccines. We used adenovirus-enhanced transferrinfection (AVET), which allows high-level transient transgene expression, to introduce cytokine gene expression vectors into murine melanoma cells. The efficiency of AVET makes laborious selection and cloning procedures obsolete. We administered such modified tumor cells as cancer vaccines to syngeneic animals and investigated their impact on the induction of anticancer immunity. We found that IL-2 or GM-CSF gene-transfected murine melanoma cells are highly effective vaccines. Both of these cytokine-secreting vaccines cured 80% of animals which bore a subcutaneous micrometastasis prior to treatment, and induced potent antitumor immunity. The generation of antitumor immunity by these cytokine-secreting vaccines requires three different steps: (1) tumor antigen uptake and processing by antigen-presenting cells (APCs) at the site of vaccination; (2) migration of these APCs into the regional lymph nodes where T-cell priming occurs; (3) recirculation of specific, activated T-cells that recognize distinct tumor load and initiate its elimination. Extending our previously reported studies, we have now comprehensively analysed the requirements for effective antitumor vaccination in animals. This may also become the basis for treatment of human cancer patients.

INDUCTION OF ENDOGENOUS TNF PRODUCTION BY BIOLOGICAL RESPONSE MODIFIERS AND BACTERIAL PREPARATIONS

This review summarizes experiments on the endogenous induction of tumor necrosis factor (TNF) in mice by various biological response modifiers and bacterial preparations, such as heat-killed Streptococcus pyogenes (OK-432) or Lactobacillus casei (LC). Intravenous administration of OK-432 or LC transiently elicited endogenous TNF in mice. The endogenous TNF production was significantly enhanced by priming (pretreatment) with high molecular-weight lignins or polysaccharides, but not by phenylpropenoid precursors or partially hydrolyzed products of glucans. When stimulated with lignins and OK-432, tumor-bearing and aged mice produced much lower amounts of TNF than normal and young mice. Endogenously produced TNF was concentrated more in serum, liver and lungs, than in other organs. On the other hand, a much lower concentration of IL-1alpha was induced in the serum fraction, whereas significant amounts of this cytokine were detected in liver and lungs. Histochemical examination revealed significant increase in the number and swelling of Kupffer cells and sinusoidal endothelium in the liver of the treated mice. The results suggest the possible efficacy of applying endogenous TNF production for the treatment of human cancer patients.

The Influence of Certain Limited Diets Upon Tumor Susceptibility and Growth in Albino Rats and Mice

It is only within comparatively recent years that the influence of diet upon the growth of tumors in experimental animals has been systematically studied (1–16). Some of these experiments have indicated the existence of a subtle relation between certain dietary deficiencies and neoplastic growth. Some attempts have been made to utilize this method of dietetic treatment in human subjects suffering from malignant diseases, but with essentially negative results. Thus we have tested a diet containing bananas, cooked oatmeal and sugar (a diet deficient in water-soluble Vitamin B) (15) in persons affected with cancer, but found that the treatment was not successful because of the impossibility of starving the tumor without starving the host, which is the usual outcome of experiments along this line. A study made by Wyard (17) showed that the growth of human malignant neoplasms and their subsequent ulceration and the occurrence of cachexia were not affected by feeding patients with Solac, a diet free from fat-soluble Vitamin A. The data were compiled from 64 patients who underwent dietetic treatment for periods from less than a month to 12 months. Copeman (18) and Bulkley (19) have claimed favorable results in the dietetic treatment of human cancer patients. Gibson (20) and Kellogg (21) have discussed the relation of diet to cancer. There is current an idea that the ingestion of an excess quantity of foods very rich in animal protein favors the development of cancerous growths. Although many papers have been written on this subject and there has been much discussion, no definite experimental evidence has been presented (22–38) in this connection. For this reason, investigations upon the influence of natural foods very rich in protein or very poor in protein, and of a diet entirely devoid of protein but containing a large amount of carbohydrate and fat, have been carried out and are reported in the present paper.