Modelling solid tumour growth using the theory of mixtures.

In this paper the theory of mixtures is used to develop a two-phase model of an avascular tumour, which comprises a solid, cellular, phase and a liquid phase. Mass and momentum balances which are used to derive the governing equations are supplemented by constitutive laws that distinguish the two phases and enable the stresses within the tumour to be calculated. Novel features of the model include the dependence of the cell proliferation rate on the cellular stress and the incorporation of mass exchange between the two phases. A combination of numerical and analytical techniques is used to investigate the sensitivity of equilibrium tumour configurations to changes in the model parameters. Variation of parameters such as the maximum cell proliferation rate and the rate of natural cell death yield results which are consistent with analyses performed on simpler tumour growth models and indicate that the two-phase formulation is a natural extension of the earlier models. New predictions relate to the impact of mechanical effects on the tumour's equilibrium size which decreases under increasing stress and/or external loading. In particular, as a parameter which measures the reduction in cell proliferation due to cell stress is increased a critical value is reached, above which the tumour is eliminated.     

Phototoxic damage to sebaceous glands and hair follicles of mice after systemic administration of 5-aminolevulinic acid correlates with localized protoporphyrin IX fluorescence.

The skin of albino mice given 5-aminolevulinic acid (ALA) by intraperitoneal injection rapidly developed the characteristic red fluorescence of protoporphyrin IX. Fluorescence microscopy of frozen tissue sections revealed intense red fluorescence within the sebaceous glands and a much weaker fluorescence within the epidermis and hair follicles. Little or no fluorescence was detected in the dermis, blood vessels, or cartilage of the ear. Light microscopy of skin taken at intervals after whole-body exposure of ALA-injected mice to photoactivating light revealed destruction of sebaceous cells, focal epidermal necrosis with a transient acute inflammation, and diffuse reactive changes in the keratinocytes. The dermis showed transient secondary edema and inflammation. The location and severity of the phototoxic damage correlated well with the location and intensity of the red fluorescence. The light-exposed skin appeared to recover completely except for a persistent reduction in the number of hair follicles.     

Pretreatment of plantar warts with azone enhances the effect of 5-aminolevulinic acid photodynamic therapy.

5-Aminolevulinic acid (5-ALA) is a well characterized precursor in the synthesis of various endogenous porphyrins used in photodynamic therapy (PDT). It is most often administered topically into a tumor which is then irradiated with visible light at established wavelength to sensitize porphyrins accumulated therein. Our main aim in the present study was to increase the penetration of 5-ALA through the altered skin by application of 3% azone (1-dodecyl-azepan-2-one) before the application of 20% 5-ALA in patients with plantar warts: mosaic warts (MW) and myrmecia (MY). We also used 20% 5-ALA only to treat warts in other patients. We compared the therapeutic and cosmetic effects of the two treatment modalities. The lesions treated with modification of 5-ALA-PDT by pretreatment with azone responded with better effectiveness. In 18 patients subjected to 5-ALA-PDT plus 3% azone, we observed 66.7% complete response of MW and 100% of MY following PDT repeated two or three times; whereas in other 18 patients treated with 5-ALA-PDT alone, we observed only 37.5% complete response of MW and 70% of MY. These results provide evidence that the pretreatment with azone should be considered as the step that enhances 5-ALA penetration in tissues and thus increases the effectiveness of applied PDT.     

Spectroscopic measurements of photoinduced processes in human skin after topical application of the hexyl ester of 5-aminolevulinic acid.

Although 5-aminolevulinic acid, ALA, and its derivatives, have been widely studied and applied in clinical photodynamic therapy (PDT), there is still a lack of reliable and non-invasive methods and technologies to evaluate physiological parameters of relevance for the therapy, such as erythema, melanogenesis, and oxygen level. We have investigated the kinetics of these parameters in human skin in vivo during and after PDT with the hexyl ester of ALA, ALA-Hex. Furthermore, the depth of photosensitizer (protoporphyrin IX, PpIX) production after different application times was investigated. It was found that the depth increased with increasing application time of ALA-Hex. We also investigated the depth of PpIX before and after light exposure causing 50% photobleaching at 407 nm. The PpIX localized in superficial layers of the normal tissue was removed during the bleaching. Thus, after bleaching, the remaining PpIX was localized mainly in the deeper layers of normal tissue. We have applied fluorescence emission spectroscopy, fluorescence excitation spectroscopy, and reflectance spectroscopy in the study of the above-mentioned parameters. In conclusion, fluorescence excitation spectroscopy and reflectance spectroscopy are simple, useful, reliable, and noninvasive techniques in the evaluation of the processes taking place in human skin in vivo during and after PDT. Using these methods we were able to quantify melanogenesis, O2 level, erythema, vasoconstriction, and vasodilatation.     

Accumulation of porphyrins in thyroid tissue and cells induced by σ-aminolevulinic acid

σ-Aminolevulinic acid and phenanthroline induced accumulation of metal-free porphyrins in homogenates of thyroid tissue and cells obtained after thyroidectomy. The rate of pigment synthesis considerably increased in specimens isolated from pathologically changed tissue, and the pigments were primarily located in cells. The results indicate that endogenous porphyrins can be used in the diagnosis and phototherapy of thyroid tumors. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 128, No. 8, pp. 222–225, August, 1999     

New derivatives of 5-aminolevulinic acid for photodynamic therapy: chemical synthesis and porphyrin production in in vitro and in vivo biological systems.

Photodynamic therapy (PDT) has become a new treatment for several oncological and nononcological disorders. This procedure involves systemic or topical administration of a lesion-localizing photosensitizer or prodrug, followed by irradiation with visible light to cause singlet oxygen-induced damage to the target tissue. 5-aminolevulinic acid (ALA) is an endogenous precursor for several photosensitizing porphyrins formed by heme biosynthesis, and has been studied for PDT with promising results for some superficial diseases of the skin and hollow internal organs. Hydrophilic ALA has a limited ability to penetrate certain biological barriers and has a relatively low selectivity for lesions. In addition, its ability to induce intracellular porphyrins has been shown to be low compared to most esters of ALA. This stimulated a search for lipophilic derivatives of ALA to overcome the shortcomings of ALA. Thirty-two new esters of ALA were prepared and their ability to induce porphyrin formation was assessed in the WiDr human carcinoma cell line in vitro and in the normal skin of Balb/c nude mice in vivo. Branched-chain alkyl esters and substituted benzyl esters were found to be the most efficient porphyrin precursors of the compounds studied.     

Low-level laser therapy using the minimally invasive laser needle system on osteoporotic bone in ovariectomized mice

This study tested the effectiveness of low-level laser therapy (LLLT) in preventing and/or treating osteoporotic trabecular bone. Mice were ovariectomized (OVX) to induce osteoporotic bone loss. The tibiae of eight OVX mice were treated for 5 days each week for 2 weeks by LLLT (660 nm, 3 J) using a minimally invasive laser needle system (MILNS) which is designed to minimize loss of laser energy before reaching bone (LASER group). Another eight mice received a sham treatment (SHAM group). Structural parameters of trabecular bone were measured with in vivo micro-computed tomography images before and after laser treatment. After LLLT for 2 weeks, the percentage reduction (%R) was significantly lower in BV/TV (bone volume fraction) and Tb.N (trabecular number, p < 0.05 and p < 0.05) and significant higher in Tb.Sp (trabecular separation) and SMI (structure model index, p < 0.05 and p < 0.05) than in the SHAM group. The %R in BV/TV at sites directly treated by LLLT was significantly lower in the LASER group than the SHAM group (p < 0.05, p < 0.05). These results indicated that LLLT using MILNS may be effective for preventing and/or treating trabecular bone loss and the effect may be site-dependent in the same bone.     

Plasma cell tumour progression in iMycEmu gene-insertion mice

The authors have recently reported that gene-targeted iMyc(Emu) mice that carry a His(6)-tagged mouse Myc cDNA, Myc(His), just 5' of the immunoglobulin heavy-chain enhancer, Emu, are prone to 'spontaneous' neoplasms of the B-lymphocyte lineage. The present study has used histological, immunohistochemical, and molecular genetic methods to investigate a subset of these neoplasms referred to as extraosseous plasmacytomas (PCTs). It is shown that 20.8% (20/96) of tumour-bearing iMyc(Emu) mice on a mixed genetic background of segregating C57BL/6 and 129/SvJ alleles develop PCT by 500 days. The Myc(His)-induced PCTs produced monoclonal immunoglobulin and developed in the gut-associated lymphoid tissue (GALT), particularly the mesenteric node and Peyer's patches. The PCTs overexpressed Myc(His), at the expense of normal Myc, and exhibited gene expression changes on cDNA macroarrays that were consistent with Myc(His)-driven neoplasia. Surprisingly, in one of three PCT-derived cell lines, Myc(His) was 'replaced' by a naturally occurring T(12;15) translocation, which changed the mode of Myc deregulation from gene insertion (Myc(His) transgene) to chromosomal translocation (juxtaposition of normal Myc to the immunoglobulin heavy-chain locus Igh). These findings provide evidence that recreation of the mouse PCT-associated T(12;15)(Igh(Emu)-Myc) translocation by gene insertion in mice results in the predictable development of PCTs in approximately one-fifth of the tumour-bearing mice. Myc(His)-driven PCTs recapitulate aspects of human plasma cell neoplasms, for which relatively few models exist in mice. For example, PCT development in the iMyc(Emu) mice may provide a good system to study the mechanism by which human MYC facilitates the progression of plasma cell myeloma (multiple myeloma) in humans.     

Functional roles of immature dendritic cells in impaired immunity of solid tumour and their targeted strategies for provoking tumour immunity

Dendritic cells play a crucial role in initiating tumour immunity as well as in the immune response for invading foreign pathogens such as bacteria and viruses. For bacterial and viral infections, the immature dendritic cells (iDCs) residing in peripheral tissues are efficiently activated and matured by pathogen signals for performing the immune response. In contrast, for self-antigens, the naive T cells are not activated by iDCs but proceed to anergy/deletion, and the generation of regulatory T cells for immune tolerance. The induction of immune response and tolerance is regulated strictly by iDCs as the sensor for homeostasis of immune response in the host. Despite the identification of some tumour antigens, tumour immunity is not provoked successfully. Even though there are some critical obstacles to inhibit effective tumour immunity, tumour cells are able to exploit the functional roles of iDCs for tumour progression, which are induced by tumour-derived soluble factors such as vascular endothelial growth factor (VEGF) and functionally modulated in the microenvironment. The iDCs still remain as the critical target for provoking tumour immunity. In this review, the functional roles of tumour-associated iDCs and the strategy for targeting iDCs in effective tumour immunity for the cancer patient are discussed.     

Photodynamic inhibition of infection caused by herpes simplex virus type 1 in the cultured cells, by using 5-aminolevulinic acid-induced porphyrins

On simulating infection caused by different herpes simplex virus type 1 (HSV-1) variants responsive and unresponsive to the drugs acyclovir and phosphonoacetic acid in the cultured Vero and C6 cells has revealed the higher ability of target cells to accumulate 5-aminolevulenic acid (ALA)-induced endogenous porphyrins, which determines the selectivity of their photo damages. Optimal conditions have been defined for all the studied HSV-1 variants to show a virus-inhibiting effect upon photodynamic exposure of infected and ALA-treated cell cultures.     

Porphyrobilinogen biosynthesis from δ-aminolevulinic acid by the viscera of albino rats

Ability to synthesize porphyrobilinogen (PBG) from -aminolevulinic acid (ALA) was determined in homogenates of tissues of the lungs, heart, liver, kidneys, spleen, pancreas, and small intestine of 77 albino rats. All these organs were found to be able to synthesize PBG. Highest ALA dehydratase activity was found in the liver tissue, followed in descending order by the kidneys, lungs, pancreas, small intestine, heart, and spleen. On the addition of a lead solution to the synthesizing system a significant decrease in enzyme activity was observed in the liver tissue, but in kidney tissue its activity was unchanged. On the addition of lead and D-penicillamine simultaneously no changes were found in the toxic effect of lead.M. F. Vladimirskii Moscow Regional Clinical Research Institute. (Presented by Academician of the Academy of Medical Sciences of the USSR S. S. Debov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 86, No. 12, pp. 687–689, December, 1978.     

Effect of (R)L-sulforaphane on 5-aminolevulinic acid-mediated photodynamic therapy

Topical photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA), or so-called ALA-PDT, is a standard procedure in the clinical practice. For optimal treatment of nonmelanoma skin cancer, actinic keratoses and other dermatoses improvements are required because of adverse side effects, which include pruritus, erythema, edema, and pain. (R)L-sulforaphane (SF) is a compound that protects against erythema, but it can also induce DNA fragmentation that leads to cell death by apoptosis. The aim of our study was to investigate whether SF has any impact on protoporphyrin IX (PpIX) production and on PDT effectiveness. We have investigated some relevant properties of SF: its photostability in dimethyl sulfoxide (DMSO), its effect on ALA-induced production of PpIX in A431 human squamous carcinoma cells and in human skin, its effect on the photoinactivation of PpIX sensitized cells, and its effect on the rate of photobleaching of PpIX. SF had no influence on PpIX photodegradation, neither in solution nor in A431 cells. The synthesis of PpIX was increased by SF in human skin, but not in A431 cells. The average increase in PpIX fluorescence in human skin was 18% +/- 6% and 43% +/- 10% for ALA combined with 80 nmol/L SF and 120 nmol/L SF, respectively. Pretreatment with (R)L-sulforaphane before topical ALA-PDT may improve penetration of ALA through the stratum corneum, and, subsequently, increase PpIX synthesis.     

Brain content of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid and immune response in aggressive C57Bl/6J mice

Catabolism of 5-hydroxytryptamine in the midbrain raphe nuclei of aggressive C57Bl/6J mice increased after 10 and 20 days of confrontations. Both catabolism and concentration of 5-hydroxytryptamine increased in the dopaminergic nuclei A11, A10, A9, and in the amigdala. The level of 5-hydroxyindoleacetic acid in the A9 and raphe nuclei decreased after 20 days of confrontations, which coincided with manifestation of the immune response. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 130, No. 10, pp. 399–401, October, 2000     

The histological response to a xenogeneic tumour in mice

We have examined, by conventional histological methods, the immune response of normal and ALS-treated mice to a tumour xenograft. In normal mice the histology of the tumour site and lymphoid organs is in agreement with the hypothesis that rejection of tumour is by a cell-mediated response. In ALS-treated mice, lymphoid organs severely depleted of small lymphocytes, show many blast cells which may be responsible for in vitro cytotoxicity. After cessation of ALS there is still a striking lack of infiltrate at the tumour site suggestive of some form of `blocking' mechanism.