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S V Kozin

Publications and source records attributed to S V Kozin.

At least 19 recordsLinked to original sources
PubMed2001

Topotecan selectively enhances the radioresponse of human small-cell lung carcinoma and glioblastoma multiforme xenografts in nude mice.

PURPOSE: To evaluate the therapeutic efficacy of different combinations of the DNA topoisomerase I-targeting drug, topotecan (TPT), with radiation for treatment of two human tumor xenografts. METHODS AND MATERIALS: The small cell lung carcinoma 54A and glioblastoma multiforme U87 were transplanted into nude mice. Equal i.p. injections of TPT and/or equal fractions of tumor irradiation were administered daily, for 5 consecutive days. When combined, TPT was injected at different constant time intervals prior to or after each radiation fraction. The tumor growth delay and changes in skin radiation reaction by TPT were evaluated. Tumor oxygenation was measured using the Eppendorf pO(2) histography. RESULTS: The tumor growth delay induced by such chemoradiotherapy was independent of interval and sequencing of the agents for either tumor model. The efficacy of TPT alone or in combination with radiation was always dose-dependent, although of different magnitude in the two xenografts. In 54A xenografts, TPT alone induced longer growth delay, but its combined effect with radiation was not more than additive. In contrast, U87 responded less to TPT alone, however the drug and radiation interacted synergisticly in this tumor model. Using both a radiobiological approach (tumor irradiation under normoxia vs. clamp hypoxia conditions) and the polarographic electrode measurements, it was shown that TPT did not modify tumor oxygenation and, thus, unlikely modulated oxygen-related tumor radiosensitivity. In contrast to tumors, TPT virtually unchanged skin radiation reaction. CONCLUSIONS: Our data suggest that TPT, when combined with radiation treatment of tumors, provides a therapeutic gain without substantial local and systemic adverse effects.

Animals↗
PubMed2001

The cell transmembrane pH gradient in tumors enhances cytotoxicity of specific weak acid chemotherapeutics.

The extracellular pH is lower in tumor than in normal tissue, whereas their intracellular pH is similar. In this study, we show that the tumor-specific pH gradient may be exploited for the treatment of cancer by weak acid chemotherapeutics. i.v.-injected glucose substantially decreased the electrode estimated extracellular pH in a xenografted human tumor while its intracellular pH, evaluated by (31)P magnetic resonance spectroscopy, remained virtually unchanged. The resulting increase in the average cell pH gradient caused a parallel increase in tumor growth delay by the weak acid chlorambucil (CHL). Regardless of glucose administration, the effect of CHL was significantly greater in tumors preirradiated with a large dose of ionizing radiation. This suggests that CHL was especially pronounced in radioresistant hypoxic cells possessing a larger transmembrane pH gradient. These results indicate that the naturally occurring cell pH gradient difference between tumor and normal tissue is a major and exploitable determinant of the uptake of weak acids in the complex tumor microenvironment. The use of such drugs may be especially effective in combination with radiation.

Animals↗
PubMed2001

Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts.

Antiangiogenic therapy can enhance radiation-induced tumor growth inhibition. However, the effects of combined antiangiogenic and radiation therapy on long-term tumor control and normal tissue response have not been reported. We treated mice bearing two different human tumor xenografts with anti-vascular endothelial growth factor receptor-2 antibody (DC101) and five dose fractions of local radiation and followed them for at least 6 months. DC101 significantly decreased the dose of radiation necessary to control 50% of tumors locally. The decrease was 1.7- and 1.3-fold for the moderately radiosensitive small cell lung carcinoma 54A and the highly radioresistant glioblastoma multiforme U87, respectively. In contrast to tumors, no increase in skin radiation reaction by the antibody was detected. Surprisingly, 44% of mice bearing 54A tumor developed clear ascites after DC101 treatment at its highest dose; this was fatal to 20% of mice. This adverse effect was seen only in mice that received whole-body irradiation 1 day before tumor implantation. The encouraging results on two human tumor xenografts suggest that vascular endothelial growth factor receptor-2 blockade merits further investigation to assess its potential as an enhancer of radiation therapy in the clinic.

Angiogenesis Inhibitors↗
PubMed1999

Relative biological effectiveness of proton beams in clinical therapy.

PURPOSE: In clinical proton beam radiation therapy, an RBE of 1.1 relative to megavoltage X-rays is currently being employed at most treatment centers. This RBE pertains to radiation in the spread out Bragg-peak (SOBP) for all tissue systems, all dose levels per fraction and all proton beam energies. As the number of centers and treatment sites for which proton beam therapy continues to increase and additional experimental data is accrued, a re-assessment of the justification for a generic RBE is warranted. In this paper we address: (1) the constancy of the RBE along the central axis from the plateau entrance to the distal SOBP (upstream of the distal edge); (2) RBE as a function of dose (or cell survival level); and (3) the target cell or tissue (alpha/beta) dependency of the RBE. This analysis pertains to modulated proton beams of initial energies of approximately 70-200 MeV and SOBPs of approximately 2-10 cm, respectively. RESULTS AND CONCLUSIONS: With exceptions, the available experimental data indicate that the RBE of SOBP protons increases with decreasing dose or dose per fraction and increasing depth in the SOBP, with the magnitude of both effects likely being dependent on the alpha/beta ratios of the target cells or tissues. The use of a generic RBE of 1. for all tissues, especially those exhibiting low alpha/beta values such as CNS, may be too low, especially at dose levels of < or = 2 Gy/fraction. Systematic determination of the RBE values dependent upon the three interdependent variables identified in this manuscript (beam depth, dose size and target tissue) will provide an enhanced data base for detailed treatment planning and institutional trial comparisons, thereby maximizing the therapeutic benefit of proton beams.

Animals↗
PubMed1999

The pH partition theory predicts the accumulation and toxicity of doxorubicin in normal and low-pH-adapted cells.

The accumulation and toxicity of the weak base doxorubicin has been investigated as a function of extracellular pH, intracellular pH and the cellular pH gradient in cells previously cultured under normal (pH 7.4) and low-pH (6.8) conditions. Low-pH-adapted cells exhibit transmembrane pH gradients which substantially differ from normal cells at the same extracellular pH. No relationship was obtained between intracellular pH and the uptake or toxicity of doxorubicin in the two cell types. In contrast, doxorubicin accumulation and toxicity increased with increasing extracellular pH in both normal and low-pH-adapted cells. However, at the same extracellular pH, drug cytotoxicity was more pronounced in normal than in low-pH-adapted cells. The difference in doxorubicin accumulation and cytotoxicity at the same extracellular pH was found to be dependent on the difference in the transmembrane pH gradient of the two cell types. As the cellular pH gradient differs between tumour and normal tissue, this observation suggests a basis for enhancing cellular drug uptake in either tissue type.

Animals↗
PubMed1999

Thermoradiotherapy with hydralazine: the effect of preirradiation of the tumor bed on blood flow and growth delay of Ehrlich carcinoma.

Ehrlich carcinoma transplanted into preirradiated calf muscle of mice was used as a model for tumor recurrence after unsuccessful radiotherapy. Due to the tumor bed effect (TBE), these grafts grew more slowly than control tumors implanted in the unirradiated tissue. When these tumors achieved the same volume (0.3-0.4 cm3), in 10-11 days for tumors implanted in irradiated tissue and 7-8 days for control tumors, they were treated with radiation, the tumor blood flow inhibitor hydralazine, and hyperthermia, alone or in different combinations. In the case of the trimodality treatment, single irradiation of tumors at a dose of 12.5 Gy was followed 2.5-3 h later by administration of hydralazine (2.5 mg/kg) and local hyperthermia (water bath, 43 degrees C for 30 min). The growth delay induced in the different tumor types by irradiation, hydralazine and hyperthermia, alone or in different combinations, was related to the blood flow measured in the tumors by the 133Xe clearance technique 24-48 h after treatment. It was shown that the reduction of blood flow after treatment with hyperthermia or hydralazine was approximately equal in both types of tumors. However, the combined inhibiting effect of these agents differed in the tumors: It was synergistic in control tumors and close to additive in tumors implanted in irradiated tissue. In terms of the specific tumor growth delay, the latter tumors were slightly more sensitive to hyperthermia, but were more resistant to radiation and thermoradiotherapy compared to control tumors. Hydralazine potentiated the tumoricidal effects of heat alone and heat combined with radiation. The enhancement was more substantial in control tumors compared to tumors implanted in irradiated tissue. A general correlation between the hydralazine-induced enhancement of the effects of heat on tumor blood flow and growth delay was observed. In tumors implanted in irradiated tissue, the inhibition of perfusion after treatment with hydralazine plus hyperthermia was smaller, and presumably a less marked treatment response to these agents (with or without radiation) was therefore achieved as a result in these tumors compared to the control tumors.

Animals↗
PubMed1998

Cytotoxicity of weak electrolytes after the adaptation of cells to low pH: role of the transmembrane pH gradient.

Theory suggests that the transmembrane pH gradient may be a major determinant of the distribution of lipophilic weak electrolytes across the cell membrane. The present study evaluates the extent to which this factor contributes to pH-dependent changes in the cytotoxicity of two such chemotherapeutic drugs: chlorambucil and mitoxantrone. Experiments were performed with two cell types of the same origin but exhibiting different pH gradients at the same extracellular pH (pHe): CHO cells cultured under normal physiological conditions (pH 7.4) and acid-adapted cells obtained by culturing under low pH conditions (6.8). Over the pHe range examined (6.0-7.6), the difference between intracellular pH (pHi) and pHe increased with decreasing pHe. Acid-adapted cells were more resistant to acute changes in pHi than normal cells, resulting in substantially larger gradients in these cells. Drug cell survival curves were performed at pHe values of 6.4, 6.8 and 7.4. The cytotoxicity of chlorambucil, a weak acid, increased with decreasing pHe, and low pH-adapted cells were more sensitive than normal cells at the same pHe. In contrast, for the weak base, mitoxantrone, cytotoxicity increased with pHe and was more pronounced in normal cells. As predicted by the theory, the cytotoxicity of both drugs changed exponentially as a function of the pH gradient, regardless of cell type. For mitoxantrone, the rate of such change in cytotoxicity with the gradient was approximately two times greater than for chlorambucil. This difference is probably due to the presence of two equally ionizable crucial groups on mitoxantrone vs one group on chlorambucil. It is concluded that the cellular pH gradient plays a major role in the pH-dependent modulation of cytotoxicity in these weak electrolytes. The data obtained also suggest that a pronounced differential cytotoxicity may be expected in vivo in tumour vs normal tissue. In comparison with normal cells at a pHe of 7.4 (a model of cells in normal tissues), acid-adapted cells at a pHe of 6.8 (a model of cells distal from supplying blood vessels in tumours) were more sensitive to chlorambucil, with a dose-modifying factor of approximately 6, and were more resistant to mitoxantrone by a factor of 14.

Adaptation, Physiological↗
PubMed1994

Hydralazine at thermoradiotherapy: tumor size and blood flow effects.

PURPOSE: This study was aimed to assess the dependence on tumor size and blood flow of the efficacy of a vasoactive drug hydralazine with thermoradiotherapy. METHODS AND MATERIALS: Experiments were performed on mice bearing SCC-VII tumors with volumes of about 85 and 340 mm3 (7-8 or 11-12 days after transplantation, respectively). Local hyperthermia (water bath, 43 degrees C, 0.5 h) was started 3 h after irradiation of tumors. Hydralazine (2.5 mg/kg, IP) was given 0.5 h before heating. Tumor blood flow was evaluated by laser Doppler flowmetry before, during and up to 2 days after the treatments. RESULTS: It was shown that hydralazine and hyperthermia, even in combination with each other, had very weak anti-tumor effect, especially for 85 mm tumors. The agents also insignificantly enhanced the efficacy of radiotherapy excluding the case of polyradiomodification for 340 mm3 tumors when a dose modifying factor of about 2.0 was achieved. Thermometry showed only a small improvement by HDZ in heating patterns of tumors of both sizes. Meanwhile, the therapeutic efficacy of hydralazine and heat was correlated with the changes in tumor blood flow, first of all with the delayed effects. The radiomodifiers induced only minor and transient suppression of perfusion in the smaller tumors, and more markedly and for longer time decreased blood flow in the larger tumors. In the latter case, the inhibiting effect of the drug plus hyperthermia remained for at least 48 h after the treatment. CONCLUSION: (a) The combined use of hydralazine and heat seems to be advisable only at radiotherapy of rather large advanced tumors; (b) the efficacy of such radiomodification is correlated with prolonged inhibition of tumor blood flow by these agents; and (c) hydralazine and hyperthermia are likely to kill selectively both acutely and chronically hypoxic radioresistant cancer cells.

Animals↗
PubMed1991

[Quantitative assessment of morphologic changes in tumors during combined use of irradiation, induced hyperglycemia and local hyperthermia].

The paper is concerned with morphometric evaluation of changes in Ehrlich mouse solid carcinoma after a separate, dual and combined use of x-ray irradiation, induced hyperglycemia (IH) and local hyperthermia (HT), using two-staged quantitative analysis of tumor tissue injuries. A portion of viable tissue was determined at the first stage, and the density of location of undestroyed tumor cells was evaluated at the second stage. The general result was characterized by the product of these indices. Disorders in the tumor tissue structure were noted in 24 h, the main damage being done by IH and HT in the center of a tumor. In 48 h the total effect was on the increase only in groups with irradiation as a result of cell death in the peripheral zone. In the double use of the agents their combined effect was less than the additive one, and the combined use of all three methods resulted in obvious synergism, and the number of viable tumor cells (by morphological criteria) was decreased by more than two orders.

Animals↗
PubMed1990

[Hyperglycemia as a means of increasing the efficacy of hyperthermia in radiotherapy of tumors].

In experiments on mice with Ehrlich carcinoma transplanted into the thigh the authors determined a gain in tumor heating from the use of induced hyperglycemia (IH) during thermoradiotherapy. Tumors were irradiated at a dose of 20 Gy followed in 3 h by local hyperthermia (HT) by emerging a tumor into water at 40-45 degrees C for 30 min. IH followed irradiation (i.e. 3 h before HT) in the form of 5-time ip administration of glucose at a total dose of 10.4 g/kg for 2 h. Isoeffective tumor damage was achieved in irradiation combined with HT (45 degrees C) only and in irradiation with subsequent IH and HT (40 degrees C), i.e. a gain in the temperature of heated water as a result of glucose use was 5 degrees C. In the independent use (without irradiation) of HT this value was equal approximately 2.5 degrees C. Thermometric investigations have shown that these effects are partially accounted for by better heating (by 0.2-0.4 degrees C) of tumor tissue in IH. However glucose action was mainly connected with resultant physiological changes in tumors like a noticeable decrease in pH and stable disorder of the blood flow.

Animals↗
PubMed1990

[Polyradiomodification. The efficacy of the postradiation use of hyperglycemia and hyperthermia in treating tumors of different sizes].

The paper is concerned with comparative assessment of the effectiveness of the separate and combined postradiation use of induced hyperglycemia (IH) and local hyperthermia (HT) with respect to tumor size in experiments on mice with transplantable Ehrlich carcinoma. The antitumor effect of these modalities was estimated by the criteria of the duration of tumor growth inhibition and cure of animals. The combined use of IH and HT significantly enhanced antitumor action of prior irradiation and resulted in improved therapeutic results for medium- and large-size tumors as compared to small ones. The authors discussed probable causes of enhancing the effectiveness of IH and HT with tumor growth, as a result of changes in pH, blood supply and other tumor characteristics.

Animals↗
PubMed1990

[Ultrasonic hyperthermia during radiotherapy of experimental tumors].

The paper is devoted to the development of an experimental device and methods for controlled ultrasound hyperthermia of animal tumors and to the estimation of a radiomodifying effect of ultrasound hyperthermia in radiation therapy of neoplasms as compared to the effect achieved in a water bath. Experiments were staged on mice with transplantable Ehrlich's carcinoma. Marked and approximately equal in value enhancement of radiation action on malignant tumors with the DMF of ionizing radiation of 1.3-1.4 was obtained with both methods of tumor heating (ultrasound and in a water bath). The results obtained indicate the advisability of a practical use of ultrasound heating in radiation therapy of tumors.

Animals↗
PubMed1989

[Possibility of lowering the dose of metronidazole during the irradiation of tumors using subsequent artificial hyperglycemia].

The therapeutic efficacy of a scheme of poly-radiomodification with metronidazole (MZ) administration was investigated in experiments on mice with Ehrlich carcinoma before local irradiation of tumors and with subsequent induced hyperglycemia (IH) depending on a MZ dose. For equally effective potentiation of the effect of radiation on a tumor during a combined use of MZ and postradiation IH a 4-fold lower dose of the drug was required as combined to MZ used alone. The combined effect of the modifiers was superadditive. The use of IH in this scheme not only potentiated skin radiation reactions on a tumor growth zone but also slightly weakened their expression.

Animals↗
PubMed1989

[Polyradiomodification. Optimization of the combined use of hyperglycemia and local hyperthermia in tumor irradiation].

Therapeutic potentialities of various types of polyradiomodification were compared in experiments on mice with solid Ehrlich carcinoma by using separate and combined use of short-term hyperglycemia (SH) and local hyperthermia (HT). In the combination of modifiers SH was always created 3 h after the beginning of glucose administration. Irradiation of tumors was performed in either of 5 moments: 4 h or immediately before SH, in-between SH and HT, 30 min. or 2.5 h after SH. Two control schemes, in which irradiation was combined with one of the modifiers only, corresponded to each polyradiomodification regimen. The combined use of SH and HT produced a more noticeable effect than their separate action. A maximum effect on a tumor was observed in the combined use of both modalities shortly after irradiation, and it was not accompanied by enhanced skin radiation injury in a tumor growth zone. Irradiation after or in-between SH and TH resulted in enhanced skin radiation reactions. Thus, the highest therapeutic effect was noted in those schemes of polyradiomodification in which SH and HT followed radiation treatment. SH and HT induced suppression of the blood supply in tumors played an important role in the optimization of the combined use of SH and HT with irradiation.

Animals↗
PubMed1988

[The role of a decrease in pH in enhancing the antitumor action of ionizing radiation with the aid of hyperglycemia].

The role of a pH decrease in glucose-enhanced antitumor action of prior irradiation was investigated in experiments on mice with Ehrlich solid carcinoma. For this purpose changes in pH and the blood flow as well as the modification of a tumor radiation effect caused by glucose and weakly metabolizing galactose injected in similar regimens, were compared in parallel groups. It was shown that in both regimens glucose and galactose injections resulted in approximately the same reduction of a blood flow rate in tumors, however a pH decrease after the use of glucose was much greater, and glucose-enhanced antitumor radiation action was more noticeable. A conclusion has been made that a pH decrease in tumors is a major factor determining the efficacy of glucose as a radiomodifier.

Animals↗