NANOMEDICINE: will it offer possibilities to overcome multiple drug resistance in cancer?

This review is written with the purpose to review the current nanomedicine literature and provide an outlook on the developments in utilizing nanoscale drug constructs in treatment of solid cancers as well as in the potential treatment of multi-drug resistant cancers. No specific design principles for this review have been utilized apart from our active choice to avoid results only based on in vitro studies. Few drugs based on nanotechnology have progressed to clinical trials, since most are based only on in vitro experiments which do not give the necessary data for the research to progress towards pre-clinical studies. The area of nanomedicine has indeed spark much attention and holds promise for improved future therapeutics in the treatment of solid cancers. However, despite much investment few targeted therapeutics have successfully progressed to early clinical trials, indicating yet again that the human body is complicated and that much more understanding of the fundamentals of receptor interactions, physics of nanomedical constructs and their circulation in the body is indeed needed. We believe that nanomedical therapeutics can allow for more efficient treatments of resistant cancers, and may well be a cornerstone for RNA based therapeutics in the future given their general need for shielding from the harsh environment in the blood stream.

Cancer Metastases: Early Dissemination and Late Recurrences.

BACKGROUND: Metastatic cells from a primary tumor can occur before the primary cancer is detected. Metastatic cells can also remain in the patient for many years after removal of the primary tumor without proliferating. These dormant malignant cells can awaken and cause recurrent disease decades after the primary treatment. The purpose of this article is to review the clinical evidence for early dissemination and late recurrences in human malignant tumors. We used the following definitions: dormancy of cells may be defined as a nonproliferating state or an arrest in the cell cycle that results in a prolonged G0 phase. If one accepts the term "late metastases" to indicate a period exceeding 10 years from the removal of the primary tumor, then the two malignancies in which this occurs most frequently are cutaneous malignant melanoma (CMM) and renal cell carcinoma (RCC). METHODS: PubMed, Web of Science, and Scopus were searched with the keywords "metastases," "early dissemination," "late recurrences," "inadvertently transmitted cancer," "tumor growth rate," "dormancy," "circulating tumor cells," and "transplantation of cancer." RESULTS: Several case reports of early dissemination and late recurrences of various types of malignancies were found. Analyses of the growth rates of several malignant tumors in the original host indicated that the majority of cancers had metastasized years before they were detected. CMM, RCC, and malignant glioblastoma were the three most common malignancies resulting from an organ transplantation. CMM and RCC were also the two most common malignancies that showed dormancy. In several cases of transplanted CMM and RCC, the donor did not have any known malignancy or had had the malignancy removed so long ago that the donor was regarded as cured. CONCLUSION: (1) Metastases can frequently exist prior to the detection of the primary tumor. (2) Metastatic cells may reside in organs in the original host that are not usually the site of detectable secondary tumors, for example, the kidneys and heart. (3) Metastatic cells remain dormant for decades after the primary tumor has been removed. (4) Dormancy might be reversible and lead to late recurrences.

Nanotechnology in the war against cancer: new arms against an old enemy - a clinical view.

Clinical oncology is facing a paradigm shift. A new treatment philosophy is emerging and new targets are appearing that require new active agents. The medical use of nanotechnology - nanomedicine - holds several promising possibilities in the war against cancer. Some of these include: new formats for old drugs, that is, increasing efficacy while diminishing side effects; and new administration routes - that is, dermal, oral and pulmonary. In this overview, we describe some nanoparticles and their medical uses as well as highlight advantages of nanoparticles compared with conventional pharmaceuticals. We also point to some of the many technical challenges and potential risks with using nanotechnology for oncological applications.

Hypofractionation in radiotherapy. An investigation of injured Swedish women, treated for cancer of the breast.

BACKGROUND: The Swedish Insurance Company for Patient Injuries asked the two authors of this report to identify the Swedish women with cancer of the breast who had been injured by radiotherapy with a hypofractionated schedule. The purpose was to provide a basis on which the Company could decide if indemnification could be given. MATERIAL AND METHODS: We define hypo-fractionation as any fraction dose exceeding 2.0 gray (Gy) per day. We set the lower limit for the "late effect" at 53.0 Gy with 2 Gy/fraction. All departments of radiotherapy in Sweden were asked to identify women who had developed brachial plexus neuropathy (BPN). Their medical records were obtained. The clinical picture of their injuries was recorded, and the absorbed dose was calculated or reconstructed. All doses, no matter in what way they were expressed, were recalculated to "late effect", presented in EQD(2 Gy) (Equalized Total Dose in 2 Gy/fraction). The latency period from therapy to onset of symptoms was also noted. RESULTS: A variety of treatment techniques was used, fractions ranging in size from 2.5 to 6.0 Gy. Absorbed doses up to a Biologically Equivalent Dose (BED) 146 EQD(2 Gy) in late effects were recorded (6 Gy x 13). More than 95% of the injured women had a combination of stiff shoulder, paralysis, pain, oedema and atrophy of the muscles to the arm and/or hand. Latency from end of radiotherapy to onset of symptoms could be as long as 30 years. Discussion. Hypofractionated radiotherapy has injured severely numerous patients. The lesions have become a medico-legal issue in some countries. The life of many of these women has been ruined: physically, mentally, socially and economically. CONCLUSION: Hypofractionated radiotherapy can cause injuries if the target volume is not exact, or the total dose is not adjusted to a tolerable level as compared to conventional treatments employing 2 Gy/day fractions.

Comparison between effects of intravenous and nebulized histamine in guinea pigs: correlation between changes in respiratory mechanics and exhaled nitric oxide.

Nitric oxide (NO) is a marker of airway inflammation in humans, despite not having effects on basal bronchial tone. Inhibition of NO synthesis can lead to enhanced airway reactivity in humans and it is therefore of importance to understand how bronchial provocation can affect endogenous NO. Presently, we have studied the role of exhaled nitric oxide in airway reactivity by measuring changes in pulmonary mechanics in response to histamine in anaesthetized guinea pigs. Two groups were challenged i.v. and four groups were challenged by aerosol at different doses. One of the i.v. and one of the aerosol groups received an inhibitor of NO synthesis, N(omega)-nitro-L-arginine methyl ester (L-NAME), to reduce endogenous production of NO before histamine challenge. All animals with intact NO production showed a decrease in exhaled nitric oxide after challenge. There were positive correlations between the peak in exhaled nitric oxide and pulmonary resistance, and between the decrease in exhaled nitric oxide and lung compliance. L-NAME pretreatment increased the reactivity to aerosolized histamine but not to i.v. histamine. We conclude that the different ways of administration elicit different response patterns of exhaled nitric oxide, resistance, and compliance, even when compared at similar insufflation pressure changes. The effects of L-NAME suggest that, although different mechanisms might be responsible for the changes in pulmonary mechanics, inhibition of endogenous NO enhances decrements in pulmonary function when histamine is administered in an aerosol. The close relationship between changes in exhaled nitric oxide and changes in lung compliance and pulmonary resistance merits further studies on the relationship between NO and airway reactivity.