In addition, such incredibly worthless projects totally dismiss the biological compensatory molecular events of body [ 18 , 22 , 33 — 38 ]. For example, clinical trials using combination of two inhibitors of EGFR for treating colon cancer did not improve the efficacy compared with single agent, and they are not remarkably different from treating with conventional LMW drugs shown above. Therefore, it is reasonable to conclude that molecular targeted drugs based on identification of one or few mutated genes or their expression products in the chaotic molecular landscape of cancers cancer molecular tsunami would produce very little to benefit the patients.
Analyses of similar data on cancer targeted therapies that apply combination drugs such as dasatinib, gemcitabine or debrafenive debrafenib, or Tafinlar alone vs. These are examples of marginal effects that are economically very costly with tremendous patients suffering [ 12 , 14 , 16 , 18 , 21 , 22 — 25 , 70 ]. The inherent and diverse compensatory mechanisms of immune and non-immune systems e. Preliminary observations in experimental model of mouse tumors demonstrated that blocking VEGF by antibody caused suppression of tumor growth.
However, as treatment with antibody discontinued, tumor growth resumed at similar rate Maeda et al. The latter has a very limited number of mutations and thus respond with higher degrees toward drugs such as Gleevec imatinib , an inhibitor of protein tyrosine kinase for treating chronic myelogenous leukemia. However, even Gleevec-treated patients suffer from drug-resistant as the consequence of DNA mutations in the treated host at later stages. Recently many drugs developed for Gleevec-resistant patients have considerable success. Although it is an endless game but worth to pursue for better therapeutic for ultimate cure.
While these efforts to control the drug-resistance to Gleevec may be encouraging, major motives behind such efforts, seem economical [ 5 ]. Currently, the effectiveness of mogamulizumab that is used in combination with conventional anti-leukemic agents makes interpretations of its true efficacy difficult [ 80 ]. It is anticipated that if the number of chemical modifications on genome were to be excessive than normal under such conditions as exposures to infective agents, chronic inflammation, environmental, chemical or biological hazards, as well as pathogen-specific vaccines or drug-induced toxicity, particularly during aging, accumulation of defective cells and proteins e.
As detailed elsewhere, sustained oxidative stress and loss of balance in Yin and Yang of effective immunity could promotes accumulation of molecular errors in tissues and increased damages to genomic stability [ 22 , 44 , 45 , 52 — 66 ]. In summary, the designs of effective cancer clinical immunotherapeutic studies await acceptance of decision makers in cancer community that the inherent immune cancer surveillance that was recently defined as the balance between dual properties of Yin tumoricidal and Yang tumorigenic arms of effective immunity [ 18 , 22 , 44 , 45 , 62 — 65 ].
When immune surveillance loses its ability to arrest the growth of oncogenic defective cells, cancerous cells progressively and continuously mutate throughout multistep developmental phases of tumorigenesis, carcinogenesis and angiogenesis in susceptible tissues. The results would be progressive expression and co-expression of mismatched and unresolved growth-arresting Yin, or tumoricidal and growth-promoting Yang, or tumorigenic factors in the immune-responsive tissues e. Over the last few decades, cancer immunotherapy, including stem cell transplantation have emerged as the choice for curing cancer on the assumption that cancer cells possessing one or more new antigenic epitopes that could provoke immunological responses, similar to those of immune surveillance in normal host [ 5 , 16 , 22 , 33 , 34 , 36 , 65 , 73 , 74 ].
However, there is no dispute that cancer patients are immune compromised, to varying degrees [ 5 , 16 , 22 , 33 , 34 , 52 , 62 — 66 , 83 , 85 — 87 ]. Such approach is therefore unrealistic for treatment of cancer patients. Although this treatment has not been approved by Japanese National Health Insurance, it is still performed in Japan and perhaps other cancer treatment centers around the world.
In cancer immunotherapy, adaptive and innate immune cells such as cytotoxic T cells CTCs , natural killer cells NKs and dendritic cells DCs are applied to target T- or B-cell surface receptor molecules with the goal to treat site-specific cancers [ 22 , 64 , 66 — 71 ]. However, actual success in such approaches requires fundamental understanding of their use and identification and resolution of the current biological gaps that hinder effectiveness of treatment.
One should keep in mind that the outcomes of treatment methodologies using antibody-like molecules that mimic T-cell receptors TCRs on host T cell surface proteins that would suppress or arrest the growth; or applying lymphocyte-activated killer cells LAK may be different in different site-specific tissues.
For example, lung airways, gut-associated lymphoid tissues GALTs or conjunctival-associated lymphoid tissues CALTs have immunological features that are different from those in liver, stomach, pancreas or non-muscle bladder tissues that potentially contribute to unsuccessful treatment or drug delivery technologies [ 18 , 22 , 37 — 39 , 65 , 66 , 89 , 93 ].
As such, the tremendous knowledge gaps on cellular compositions of target tissues and interactions, or synergies between host tissue and treatment options are likely to limit the effectiveness of such approaches [ 18 , 22 , 37 — 44 , 62 — 65 ]. Furthermore, jury is still out on the outcomes and effectiveness of stem cell therapy and bone marrow transplant that are used for treating myelocytic leukemia on patients pre-treated with whole body radiation to destroy majority of mutated blood cells. It should be noted that clinical effectiveness of using the overall immune activation by application of bacterial cell components i.
However, even BCG has its adverse biological effects [ 22 , 28 , 39 , 42 — 45 , 97 , 98 ]. Nanoparticle tumor targeting or delivery is based on the enhanced permeability and retention EPR effect [ 94 — ]. EPR effect is a hallmark for targeted drug delivery of biocompatible nanomedicine or macromolecular drugs in tumor tissue [ 53 , 96 , 99 , — ].
The effect can be observed in both primary and metastatic tumors. The EPR effect can be visualized in vivo tumor models or human tumors [ 99 , ]. The EPR effect reflects pathophysiology of solid tumor including defective vascular architecture, upregulated neoangiogenesis and excessive production of various vascular mediators.
It is noteworthy that these factors are common immune disruptors and contribute to the immune dysfunction. Evaluation of some drug encapsulated liposomes and micellar nanoparticles reveal another example of failed attempts in cancer chemotherapy. Nanotechnology-based nanomedicine has been the focus of great attention in the past couple of decades. Initially, liposome particles presented the poorest outcomes in the pharmacokinetics because of little considerations of the rapid clearance and removal of nanoparticles by phagocytic cells. However, current methods of attaching biocompatible polymers such as polyethylene glycol PEG to the surface of particles potentially protect them against this problem.
However, in the in vivo setting, it is important that drug-encapsulated liposomes or nanoparticles remain stable and intact enough to reach to the target tissues without disruption of particles or micelles on its way to reach cancer clumps. Otherwise, the active component of LMW drug would often leak out from such particles during circulation and subject to rapid clearance by urinary tract or lymphatic channels, as well as potential decomposition by the liver and the bile.
Issues and progress with protein kinase inhibitors for cancer treatment
The possibility that particles would burst before reaching the target make such drugs to lose effectiveness while producing adverse effects similar to the parental LMW drug given iv as shown in Fig. As demonstrated in Fig. In contrast, covalently linked nanodrugs or micellar drugs have better plasma stabilities in vivo. Schematic representation of plasma concentration of different molecular size drugs [ 33 , 34 ]: a low-MW free drugs e.
The drug concentration in plasma after i. Representative polymer conjugates, micelles, and the liposomal drug DOX complex remain in the plasma at higher levels b—e. However b shows a micellar drug of non-covalently encapsulated low MW drug which burst rapidly.
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This stable liposome complex is a pegylated stealth liposome. However, it is too stable and thus little drug release even after reaching to the target tumor, and thus only a limited therapeutic effect. Nano-size drugs c—e of high biocompatibility, having long plasma half-lifer, are advantageous for tumor selective targeting because they can utilize the EPR effect [ 33 , 34 ]. The use of micellar drug e. The same logics apply for another biocompatible polymer DOX-conjugates, i.
Another example of confusing outcome is a drug designed for macromolecular size, based on the EPR effect for tumor-selective accumulation.
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In this approach, the miceller agent, fluorescein isothiocyanate FITC is covalently linked to a polymer-carrier, while the micelle also contained non-covalently encapsulated candidate-drug tritiated paclitaxel [PAX] [ 99 , , ]. The in vivo results showed accumulation of PAX at tumor site was close to null. However, had paclitaxel covalently linked to the polymer it would have selectively accumulated in the tumor site, as seen in FITC conjugated polymer-chain as the proof of the EPR effect [ , ].
Therefore, designing effective macromolecular drug complexes requires considerations to include that the selected drugs are stable enough and possesses sufficient biocompatible property, with effective tumor accumulation by EPR effect of the targeted tumors.
After delivery in tumor tissue, appropriate drug release need to be incorporated in such drug-complexed nanoparticles [ 33 , 34 , 53 , ]. In summary, despite decades of enthusiasm for nanomedicine including liposomal, micellar and polymeric drug complex, there are several problems that need to be addressed.
To be effective, such molecular complexes should possess special features, including:. Retain at high levels in plasma for adequate duration several hours to a few days having suitable biocompatibility to be utilized for EPR effect;. Complexes would be capable of clearance by lymphatic system in normal tissues, in contrast to cancerous tissue; and. Furthermore, there are great differences on cellular uptake rates of different low MW drugs. For example, free pirarubicin THP exhibits over to folds higher cellular uptake into tumor cells pancreatic SUIT-2 compared with free DOX, although both belong to the anthracycline family in which a specific transporter system e.
Details of the problematic issues in cancer drug discovery and screening methods using experimental mice or rats models of site-specific tumors have been recently reported [ 22 , 44 , — ]. The major concerns on drug screening are safety and therapeutic efficacies, as well as ethical and financial considerations of decision makers who apply the results that are produced in small animal models in clinical trials to test various anticancer agents in patients which repeatedly failed.
The principal concerns with the use of anticancer drugs in clinical trials are briefly discussed below:. Traditionally, drug development for chronic diseases e. These primates are genetically, behaviorally and biologically the closest animal species to humans. However, in the last few decades, nearly all experimental models of cancer drug screening, safety and efficacy evaluation are performed in lower animals such as rats and mice. The drug screening, efficacy and toxicity of candidate drugs, e.
Consequently, as expected the pharmacokinetic parameters or compatibilities of the drugs tested in lower animals are vastly different from those in cancer patients with regard to time scale and immunobiological response profiles and tolerance [ 22 — 24 , 44 , — , ]. For example, drug screenings are routinely tested in mouse peritoneal leukemia L and P models. In such studies, tumors are implanted intraperitoneally ip , and the drugs also administered via the same route. In such cases, a given drug is likely to be readily accessible to tumor cells in the peritoneal cavity.
Under these conditions, pharmacological properties of drugs such as plasma level, tissue distribution, inactivation or clearance from the liver and kidney, and access to vasculature do not pose any serious problem. These traditional approaches, although better than screening in vitro tumor-cell-panels, totally ignore and downplay the complexity of human solid tumors with complex cellular, stromal or matrix and vascular architectural features of the tumor microenvironment including the neoangiogenesis and vascular permeability, hypoxia, low pH, induction of altered immune and non-immune response dynamics, various proteases that cancer cells excrete, coagulation and cellular clumps of disorganized adhesion properties of cancer cells.
The anatomical sites used for implanted tumors in mice and the role that vasculature plays will pose differences in efficacies. Implanted tumors are frequently located in the skin or muscle at early stage of development, and not in the orthotopic sites for the primary cancer sites.
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As a result, one may reasonably question such tests since the drug access to vasculature in experimentally selected sites e. It is worth emphasizing that even renal cancer cells or hepatoma cells implanted in the muscle tissue of mice do not possess the same features of vascular network, comparable to the kidney or the liver, respectively.
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