Gene Therapy of Solid Cancers: Methods and Protocols

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Evaluate the feasibility of identifying mutant MGMT-GA-transduced and O6-benzylguanine BG - and temzolomide-resistant hematopoietic and stromal progenitors from the bone marrow of these patients. Evaluate the feasibility of in vivo enrichment of the transduced hematopoietic progenitors in patients treated with BG and temzolomide.

Evaluate the toxicity of this regimen in these patients. Determine the antitumor effect of this regimen in these patients.

Gene Therapy of Solid Cancers - Methods and Protocols | Wolfgang Walther | Springer

FDA Resources. Arms and Interventions. Patients receive carmustine IV over 1 hour every 6 weeks for 5 courses. Four weeks after the completion of BG and carmustine, patients receive temozolomide IV over 1 hour every 4 weeks for up to 5 courses, in the absence of hematologic toxicity. Outcome Measures.

Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

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Please refer to this study by its ClinicalTrials. Layout table for investigator information Study Chair: Stanton L. More Information. Layout table for additonal information Responsible Party: Stanton L. National Library of Medicine U. National Institutes of Health U. Includes cutting-edge methods and protocols Provides step-by-step detail essential for reproducible results Contains key notes and implementation advice from the experts see more benefits.

Buy eBook. Buy Hardcover. Buy Softcover. FAQ Policy. About this book This volume provides insight into recent developments on experimental and clinical strategies for cancer gene therapy. Show all. However, using iniparib in crossover trials is not effective for patients with triple-negative breast cancer [ 3 ].

One should keep in mind that in general, PARP inhibitors iniparib lack intrinsic value for solid tumor. For example, reports for trials that use combination of gemcitabine plus carboplatin, showed outcomes of progression-free survival of only 3. Furthermore, analyses of data on the outcomes of crossover trials using iniparib, for its effect on sensitization of temozolomide bevacizumab in glioblastoma xenograft or clinical targeted therapies of advanced glioma are inconclusive [ 3 , 14 — 16 , — ]. Photodynamic therapy PDT for treating diseases is known for more than a century.

Indeed, N. Finsen received the Nobel Prize in Medicine and Physiology in for his novel phototherapy of dermal tuberculosis. The key component required in PDT is excitation of photosensitizers by appropriate wavelength in the tumor tissue. Most of currently used photosensitizers are derivatives of tetrapyrrolic compounds [ — ].

It should also be mentioned that not all tissues, particularly cancer tissues, are similarly loaded with heme components, like in the normal liver, spleen and blood. When the tissue surface of, for instance, breast cancer is observed visually, or colon cancer by endoscope, the solid tumors exhibit no reddish appearance. Thus upon iv infusion, they are distributed nearly indiscriminately throughout the body [ 93 , 94 , 96 , ] providing no EPR effect and little tumor selectivity.

Using low MW photosensitizer, while producing no remarkable antitumor effect, the patients are advised to avoid exposure to ambient daylight as it is expected to damage the skin with hypersensitivity reactions of the exposed areas. Fluorescence shows as visible only in tumors a and b T marks. Polymer-ZnPP alone or light irradiation alone respectively has no therapeutic effect [ 99 , ]. Figures were adapted from Refs.

While majority of such drugs produced no reasonable benefit to meaningfully extend survival of cancer patients, particularly those with solid tumors, they are tremendously costly for the patients, their families and the public [ 2 — 8 , 13 , 18 , 20 — 22 , 24 , 32 , 37 , 39 , 44 , 65 — 67 , 98 , — , , ]. In the Japanese National Health Insurance System, all patients are eligible to receive government-approved medications and treatments.

Thus, patients who use any additional unapproved medications lose all privileges of receiving the insurance benefits, even though the particular procedure could potentially provide the needed therapy with proven benefit. For instance, concomitant use of nitroglycerin together with low MW chemotherapeutic agents, significantly benefits the patients with marginal cost [ — ]. The government is faced with decision, either to cut this heavy burden for paying the ineffective therapeutic modalities, or alternatively raise the public income-taxes.

In the United States, nearly half of the reported personal filings for bankruptcy are due to high cost of medical care resulted from astronomical cost of drugs, hospitalization, medical procedures and patient care [ 22 , 44 , — ]. Concerned voices of independent and competent professionals, oncologists and scientists that are raised for seeking the truth in cancer science, on behalf of the cancer-stricken public for changing the directions in cancer research or therapy or safety and unethical motives behind development of pathogen-specific vaccines e.

To lessen the heavy burden of costs, for Japanese complex insurance policies, we recommend that the unapproved but potentially effective and safe drugs should become available to cancer patients. The public insurance system should remain continuing coverage of the cost of those drugs that are already approved and marketed for different indications, while those who are willing to undergo treatment with additional experimental drugs, pay out-of-pocket for the cost of drugs that are yet to be approved.

It is anticipated that such methods of payment reduce the cost of care for patients who need additional drugs, while the Japan National Health Insurance System can avoid increased debt. Lack of systematic approaches to cancer biology is perhaps the principal reason for the extremely slow progress in understanding cancer science, evidenced by high failure rates in cancer therapy and associated loss of millions of lives and tremendous economic burden to the society.

Recent paper by Prasad and colleagues [ ] supports our scientific concerns that despite reported reduction in disease-specific mortality, the overall mortality was unchanged or increased. Many cancer drugs would initiate or accelerate other causes of death such as disseminated intravascular coagulation DIC and multiple organ failures MOFs as the consequences of complications such as extreme fatigue or infections, interstitial pneumonia, acute cardiac arrest or cachexia, often resulting in loss of patients lives.

Nearly all other claimed molecular targeted therapies that are heavily publicized and funded, focus on identification of infinite genetic mutations in site-specific solid cancers, produced little, if any, success to benefit cancer patients. Majority of such drugs that often accompany total or partial body radiation therapy produce biological poisons to the already immune-compromised patients. The drugs, not only produce life-threatening side effects, but they are extremely costly for patients and insurance companies.

Below we outline that future systematic approaches to study the amazing complex role of immune disruptors-induced initial immune dysfunction toward multistep carcinogenesis that are intimately associated with angiogenesis hallmark of tissue growth, hypoxia and altered bioenergetics offer tremendous opportunities for research and therapeutic considerations [ 22 , 36 — 39 , 56 , 65 — 67 , , — ]. Modalities that utilize nanotechnologies for tumor-selective drug delivery, based on the EPR effect with full consideration of tumor environments.

Gene Therapy of Solid Cancers: Methods and Protocols

Utilization of tumor environments for tumor-selective drug accumulation include the lower pH of tumor tissue 1—1. In addition, the unique features of upregulated glucose transporter in tumor provide good targets using glycosyl-containing moiety for drug development.

Furthermore, hypoxia that is the result of embolized blood flow in solid tumor vessels may be restored by nitro agents or alike, to improve the blood flow and drug delivery. Acidic environment of tumor are suggested suitable site for EPR and cleavage by hydrolytic enzymes e. Systematic studies to understand immune disruptors- oxidative stress induced initial pathways in developmental phases of immune dysfunction in the direction of multistep tumorigenesis and angiogenesis.

Effective immunity was defined as the balance between two highly regulated and biologically opposing arms, Yin tumoricidal and Yang tumorigenic properties of acute inflammation, an amazingly precise signal communications between immune and non-immune systems. The Yin and Yang events were hypothesized requiring differential bioenergetics at different stages of life, from fetus growth, after birth toward adulthood and aging process or chronic diseases.

Detailed understanding of the loss of balance in tumoricidal Yin and tumorigenic Yang properties of effective immunity that guards health should be the focus of future studies. Details of pathogen-host interactions and immune response profiles in susceptible tissues. We recently proposed that chronic inflammation causes release of histamine at local and distant tissues altering numerous other immune responses and the acid-base behaviors in tissues including vasculature.

Cell and Gene Therapies for Cancer: Future Promises and Challenges

The above logical approaches to therapy and basic research on complex biology of effective immunity are expected to result in the design of cost-effective projects for understanding not only the cancer biology or how to prevent or control treat it, but also effective approaches for development of universal vaccines and overall promotion of health. Furthermore, systematic approaches in understanding effective immunity are expected to lay a foundation for minimizing or delaying the onset of nearly all other chronic and preventable diseases for the aging populations around the world [ 22 , 36 — 39 , 43 — 45 , 65 , 66 ].

The focus of this perspective was to assess the limitations of current therapeutic approaches to cancer. In the last six decades, only limited success was achieved with drugs such as Gleevec or few other modalities that used for treating patients with hematopoietic cancers and soft tissue or seminoma. These tremendously costly projects totally disregard the suffering and life-altering experiences of patients and their families or caregivers [ 18 , 22 , 28 , 32 , 37 , 39 , 44 , 65 , 66 , — , ].

This horrendous view for making profit out of misery of patients can no longer be sustained or tolerated. Another serious concern in process of drug development, however wrong, is the long processes and delays in obtaining patents, proprietary and approval for new drugs. In most countries, exclusivity of proprietary for marketing a specific drug often guaranteed for up to a decades.

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We propose abolishing the currently imposed regulations of drug patent system with the goal to accelerate generic drug development and improved access of drugs to patients. Often the industry manages to extend blocking the patented drugs for unlimited time, for maintaining the marketed drug prices at sky high and for high profits. HM and MK co-designed and wrote the manuscript, they both revised the manuscript.

Both authors read and approved the final manuscript. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. October 10, Kennedy, Jr. Hiroshi Maeda and Mahin Khatami contributed equally to this work. Mahin Khatami, Email: moc.

National Center for Biotechnology Information , U. Journal List Clin Transl Med v.

Gene Therapy of Solid Cancers

Clin Transl Med. Published online Mar 1. Hiroshi Maeda 1, 2, 3 and Mahin Khatami 4. Author information Article notes Copyright and License information Disclaimer. Corresponding author. Received Jan 16; Accepted Jan This article has been cited by other articles in PMC.

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Background Review of over six decades of cancer chemotherapy and tremendous investment for understanding cancer biology and cure reveal minimal or partial success for only the treatment of leukemia and non-solid or soft tissue tumors [ 1 — 7 ]. Scientific bases for repeatedly failed therapeutic approaches. Chemotherapeutic approaches using low molecular weight LMW agents: indiscriminate drug-distribution to normal and cancerous tissues The standard or classic cancer chemotherapy, using low molecular weight LMW drugs such as mitomycin C, doxorubicin, methotrexate alone, or even in combination with other drugs for treating solid tumor have not been successful.

Targeting genetic mutations in site-specific solid cancers that produced repeatedly failed outcomes while generated huge corporate profits Molecular target drugs created great business motives for drug industry to focus on them in the last six decades.