Regulatory role of T lymphocytes and NK cells in tumor allograft development.

In the present study, the respective roles of T cells and their subpopulations as well as of NK (natural killer) cells in antitumor immune responses were followed using the SaI (H-2a) allograft model. The development of this tumor in B10 (H-2b) mice was evaluated after pretreatment of the recipients with xenogeneic antithymocyte serum (ATS). Anti-Thy 1.2, anti-Lyt 2.2 and anti-L3T4 monoclonal antibodies were used in order to determine T lymphocyte phenotypes and to assess the frequency of TC/S and TH subpopulations at various periods of tumor development. Rabbit polyclonal anti-asialo GM1 antiserum was used for the identification of NK cells. In a previous work it was suggested that the first week following transplantation, the cells predominantly involved in the growth regulation of SaI belong to the TS subclass. Our results based on the use of anti-Lyt 2.2 monoclonal antibodies have further supported this finding. The application of anti-Thy 1.2 on the 3rd and 5th day has hampered a secondary tumor growth while anti-Lyt 2.2 was effective when given on day 5. The depletion of Lyt. 2.2+ cells on day 3 resulted in the inhibition of both primary and secondary tumor development. On the other hand, when anti-Thy 1.2 was applied on day 7 after transplantation, the primary and secondary tumor growth was strikingly enhanced. It appears that Thy 1.2+ lymphocytes display at this period effector functions and contribute, in conjunction with macrophages, to subsequent tumor regression. The depletion of L3T4 cells on days 3 and 5 after tumor inoculation has resulted in primary tumor growth enhancement. This suggests that cells of the L3T4+ phenotype display at this time helper functions contributing to CTL proliferation and maturation. A further indication, supporting the possible suppressor effect of L3T4+ cells, counts from the finding that anti-L3T4 treatment results in an inhibition of secondary tumor growth. The anti-asialo GM1 treatment has not enhanced, at least significantly, primary tumor development but has partially or totally inhibited the growth of secondary tumors. It appears that cells of the GM1+ (NK cells) phenotype do not participate in any substantial way in the early phases of SaI tumor development in ATS treated allogeneic recipients.

Stage dependence of NK cell activity and its modulation by interleukin 2 in patients with breast cancer.

NK cell activity was evaluated in breast cancer patients with different clinical stages of disease prior to surgery. In 58 patients with Stages I-III of breast cancer the peripheral blood NK cell activity was significantly reduced as compared to controls, and NK activity of 11 patients with Stage IV and metastases was significantly reduced as compared to both controls and patients with locoregional disease. In vitro treatment of peripheral blood lymphocytes (PBL) in medium with 10% fetal bovine serum (FBS) alone significantly increased NK cell activity in patients with Stages I-III and Stage IV of disease, although the level of NK cell activity of patients with Stage IV remained below that for less advanced disease. In vitro treatment of PBL of some Stages I-III patients (n = 41) with interleukin 2 (IL 2) gave a significant, dose-dependent enhancement of their NK cell activity so that it was significantly higher than basic NK activity of healthy controls. The results showed decrease of NK cell activity in breast cancer patients especially in advanced disease and enhancement with IL 2 indicating the possibility of immunotherapy in this neoplasm.

Circulating immune complexes in Hodgkin's disease. Reactivity of IgG isolated from circulating immune complexes.

In our earlier report on circulating immune complexes (CIC) from sera of patients with Hodgkin's disease (HD), we demonstrated disease-associated increase in the intensity of a 40kD (pl 5.6) polypeptide in the CIC. In extension of these investigations, we now report that the 40kD moiety exists in CIC as a complex with IgG, and that IgG isolated from such CIC samples from sera of patients with HD shows preferential reactivity with the typical large binucleate Reed-Sternberg (R-S) cells in the sections of disease-involved lymph nodes from HD patients.

Expression of p43 associated placental isoferritin (PLF) correlates inversely with cell growth in breast cancer cell lines MCF-7 and T47-D.

We have previously demonstrated that the expression of the recently described immunosuppressive antigen p43 in breast cancer patients correlates with early stages of the disease and a low degree of proliferation of the tumors. Attempts were made to evaluate the expression of p43 in two breast cancer cell lines (MCF-7 and T47-D) stimulated to proliferation by 17-beta estradiol and fetal bovine serum (FBS). p43 expression was determined by RIA technique using the new monoclonal antibody CM-H-9, the rate of proliferation was assessed by [3H]thymidine incorporation during 72 hours of incubation. Induction of proliferation by addition of 17-beta estradiol and FBS to serum-free tissue culture medium correlated with a decrease of p43 synthesis in both cell lines. The level of p43 expression in nonstimulated cells was low in comparison to that in cells cultivated routinely (15% FBS, no estrogen). However, the drop of p43 synthesis was significantly stronger in cell lines with estrogen stimulated proliferation. Our in vitro results confirmed previous clinical observations describing an inverse correlation between p43 synthesis and degree of proliferation and differentiation in breast cancer for the first time. However, the pathologic mechanisms leading to this phenomenon need to be elucidated.

In vitro cytotoxicity and mode of action of 1-alkylpyrrolidine N-oxides.

A new class of nonaromatic amine oxides was synthesized and tested for cytotoxic activity in vitro. The aim of this study was to find if there is any correlation between the cytotoxic activity of the investigated 1-alkylpyrrolidine N-oxides and their structure (as a structural parameter the number of carbon atoms m in the alkyl chain was used). Maximum activity was achieved with 1-tetradecylpyrrolidine N-oxide (C14) which was chosen for further biochemical studies. Further lengthening led to decrease in activity. The drug inhibited the incorporation rate of [14C] precursors (adenine, thymidine, uridine, valine) into appropriate macromolecules of Ehrlich ascites cells, the extent of inhibition being dependent on both time and concentration of the compound in the incubation medium.

Effects of daunomycin and its macromolecular analog daunophilin on the proliferation of mammalian cells.

Effects of daunomycin and daunomycin bound to an HPMA copolymer (daunophilin) on the proliferation of mammalian cells cultivated in vitro were compared. One line of non-tumor cells (LEP human cells) and two tumor cell lines (human HeLa cells and C6 rat cells) were used. It was found that both daunomycin and daunophilin had an inhibitory effect on the proliferation of the three cell lines and that the effect was irreversible. Daunophilin had to be used in concentrations by two orders of magnitude higher (> 1 micrograms/ml) than daunomycin (> 0.01 micrograms/ml) to produce comparable effect on cell growth.

Involvement of NOR-bearing chromosome in Rb-fusion: evidence from an in vivo murine sarcoma cell line.

The involvement of NOR-bearing chromosome in the formation of two stable and transmissible Robertsonian markers is reported in ascitic form of mouse Sarcoma 180 (S180) adapted in vivo to outbred strain of Swiss albino mice. The chromosomes involved in Robertsonian fusion included t(8;12) and t(16;17).

Correlation of steroid receptors in synchronous tissues with survival in breast cancer patients.

Estrogen and progesterone receptors (ER and PR) were estimated in 129 synchronous (primary and metastatic lymph node) breast cancer tissues, of which 40% were premenopausal and 60% were postmenopausal. ER and PR accordance was seen in 68% and 70% patients, and ER and PR discordance was seen in 32% and 30%, respectively. The mean level of ER in patients having ER accordance was higher in responders than in nonresponders. In patients having steroid receptors in accordance, there was a trend towards gain of receptors (type II) in responders, and loss of receptors (type I) in nonresponders. In ER discordant cases 48% were of type I while in PR discordant cases 46% were of type I. In postmenopausal patients, survival was lower in patients showing accordance than in those showing discordance. In nonresponders showing loss of receptors in lymph node, the survival was shorter than in those who showed gain of receptors in lymph node. No such trend was seen in premenopausal patients. Our study suggests that in postmenopausal patients, survival was better related to ER accordance than ER discordance and PR accordance or discordance. However, a larger patient series is needed for confirmation.

ROC analysis of benefit and limitation in radiotherapy for cancer of the oral cavity.

The ROC analysis of optimalization of radiation treatment of cancer of the oral cavity was carried out. Material of 210 patients with squamous cell carcinoma (SCC) of the oral cavity was included into the study. Based on dose-response curves for tumor and late mucosal reactions, iso-utility curves and optimal k values were estimated. Optimal k values decreased from 0.792 to 0.584 with extension of overall treatment time from 35 to 49 days. It may suggest that the planning of additional dose to compensate tumor clonogens repopulation during prolonged treatment time does not improve therapeutic gain in radiotherapy for cancer of the oral cavity. The ROC is a useful model to estimate optimal radiation treatment for a given tumor because it is independent of any arbitrary consensus or theoretical assumption.

Effectiveness of moderate dose combination chemotherapy in Burkitt's lymphoma.

Twenty-five evaluable pediatric patients with histologically proven Burkitt's lymphoma were treated with moderate dose combination chemotherapy consisting of cyclophosphamide, vincristine, methotrexate and cytosine arabinoside (COMA regime) without central nervous system prophylaxis. Complete remission was achieved in 94.1% (16/17) of patients with Stage I, I R, II and III A disease, with disease-free survival of more than 3 years. This protocol was attended by minimal chemotherapeutic toxicity. This combination chemotherapy was ineffective in more advanced disease (Stages III B, IV), major cause of failure being progressive disease with central nervous system involvement. This study showed the effectiveness of moderate dose chemotherapy without CNS prophylaxis in early stage Burkitt's lymphoma including Stage III A and needs for aggressive chemotherapy with CNS prophylaxis in more advanced disease.

Role of sputum cytology in the diagnosis of mediastinal germ cell tumor.

A rare case of germ cell tumor of the mediastinum infiltrating the lung and metastasizing to the supraclavicular lymph node in a 25-year-old male is presented. The patient presented with a history of superior vena cava syndrome and chest roentgenograms revealed an abnormal mediastinum. Primary positive diagnosis was made cytologically on sputum specimens. The peculiar cell type found in the Papanicolaou stained sputum smears were correlated with fine needle aspiration cytology of lung and lymph node, and confirmed the histologic pattern of the tumor metastasizing to the lymph node. To our knowledge, the present case is the first report of a primary mediastinal seminoma (germinoma) infiltrating the lung and diagnosed by sputum cytology. These results suggest the usefulness of sputum examination as an adjunctive diagnostic procedure in the detection of patients with possible lung infiltrated germinal neoplasms.

Cigarette smoke exposure of school children: effect of passive smoking and vitamin E supplementation on blood antioxidant status.

Despite similar vitamin E concentrations, erythrocytes of 25 children of smoking parents had an increased tendency (p < 0.01) to peroxidize in vitro as compared with those of 28 children of nonsmoking parents. This difference was abolished by vitamin E supplementation (100 mg alpha-tocopherol acetate/day for 14 days). The increased susceptibility to erythrocyte peroxidation in the smokers may reflect lower erythrocyte glucose-6-phosphate dehydrogenase, glutathione peroxidase and superoxide dismutase activities (p < 0.001, p < 0.005, and p < 0.02, respectively) in children of smoking parents. Children of smoking parents seem to be under sustained oxidant stress with increased plasma-conjugated dienes (p < 0.01) and dehydroascorbate (p < 0.002) concentrations. Total plasma cholesterol was similar in children of smoking and nonsmoking parents, and was unaffected by vitamin E supplementation. Indices of sustained oxidant stress in children of smoking parents were partially ameliorated by vitamin E supplementation.

Elastin metabolism parameters in sera of patients with lung cancer.

Elastin metabolism parameters (elastin-derived peptides and elastase-like activity) were determined in sera of patients with lung cancer and in healthy controls. The concentration of elastin-derived peptides was statistically significantly elevated in the lung cancer group. There was no statistically significant difference in the serum elastase-like activity between the groups studied. These data seem to indicate an enhanced metabolism of elastin in patients with lung cancer.

Immunocytochemical reactivity of a mouse monoclonal antibody CDI 315B raised against human breast carcinoma.

Our previous report revealed the production of monoclonal antibody (MoAb) CDI 315B by immunization of mice with tumor extract proteins of human invasive ductal breast carcinoma. In the present study we report on the immunocytochemical reactivity of this MoAb with formalin or methacarn fixed, paraffin embedded tissue sections and also with cell cultures. Among breast tissues, positive staining was detected in 88% (64 of 73) of primary breast carcinomas, 77% (7 of 9) of metastatic lymph nodes, 24% (8 of 33) of benign breast disease and 15% (2 of 13) of normal breast tissue. No immunostaining was detected with several other tumors, with the exception of melanoma, where 63% (5 of 8) of positive staining was found. On in vitro cell lines, positive reaction was detected only with breast carcinoma and melanoma cells, but not with other examined cell lines. On benign breast disease tissue sections, positive reaction was detected in areas with cell hyperplasia. On normal breast tissue sections MoAb 315B stained the epithelial cells of terminal ductuli. Since the MoAb 315B recognized some antigen present in the cytoplasm of most breast carcinoma cells, this MoAb may have potential application in diagnosis and management of breast cancer.

IL-1 alpha induced, TNF alpha mediated HLA class II (DR) antigen up-regulation in a human ductal breast carcinoma cell line ZR-75-1.

The IL-1 alpha induced up-regulation of HLA class I and HLA class II (DR) antigen expression on the cell surface of the human breast cancer cell line ZR-75-1 was demonstrated. This was associated with a concomitant increase in TNF alpha production. Coincubation with an anti-TNF alpha neutralizing antibody partially inhibited the IL-1 alpha induced up-regulation of HLA DR antigen but had no effect on IL-1 alpha induced HLA class I up-regulation. These data indicate that IL-1 alpha induced HLA class II (DR) antigen up-regulation in ZR-75-1 cells is partially mediated by TNF alpha and that IL-1 alpha induced HLA class I and class II (DR) antigen up-regulation in ZR-75-1 human breast cancer cells in vitro are mediated by different mechanisms.

Inhibition of intercellular gap junctional communication by alkyl ethers and its modulation by cAMP.

The inhibition of intercellular gap junctional communication (IGJC) by alkyl ethers (ethylene glycol, monomethyl ether, polyethylene glycol 1,000 and polyethylene glycol 6000) was examined using V79 Chinese hamster cells in vitro. Ethylene glycol and monomethyl ether inhibited IGJC very strongly, whilst the other agents inhibited IGJC only insignificantly. When the cells were treated with the combination of two agents, ethylene glycol and monomethyl ether, a significant increase in the inhibition of IGJC occurred. This was probably the result of potentiation rather than an addition effect. The effect of ethylene glycol was antagonized by dibutyryl cyclic adenosine monophosphate (DbcAMP). This effect was most intensive when the cells were treated with both agents at the same time and, in other experimental combinations, the effect was lower but also significant. Caffeine did not influence IGJC either in combination with DbcAMP or by itself.

Determination of the synthesis and uptake of alpha 2-macroglobulin by cultured human glioma cells.

Using immunological techniques, the synthesis of alpha 2-macroglobulin was studied in established cell lines derived from human glioblastomas multiforme. alpha 2-Macroglobulin was detected in cytoplasm and in the culture medium of the analyzed cell lines. Radioimmunoprecipitation revealed a protein with M(r) corresponding to alpha 2-macroglobulin in the medium conditioned by U-118MG and U-343MG cells. On the other hand, using immunoblot analysis, alpha 2-macroglobulin was detected in all of the analyzed lines. In immunofluorescence test, alpha 2-macroglobulin was determined also in all four cell lines, but with different staining pattern. Conditioned culture medium (CCM) of U-536MG cells with the lowest level of alpha 2-macroglobulin exerted the lowest mitogenic activity for human fibroblasts.

Increase in the concentrations of brain serotonin and 5-hydroxyindoleacetic acid during growth of a transplanted murine lymphoma.

The concentrations of serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) were studied in discrete brain areas of mice bearing transplantable Dalton's lymphoma (DL). Marked rise in 5-HT level (p < 0.05) was observed in serotonin secreting cell rich area--raphe region--as well as in hypothalamus and caudate putamen. High 5-HT level in these discrete areas was maintained throughout the period of tumor growth. Appreciable increase in 5-HT concentration was also observed in midbrain at the late stage (day 15 post-transplantation) of tumor growth. Unlike 5-HT, there was little change in 5-HIAA levels at the early stage (day 7) of tumor growth, and this was followed by a fall in 5-HIAA level around day 10 post-transplantation. However, the concentration of this 5-HT metabolite increased considerably at the late phase of tumor proliferation. The results suggest a close relationship between serotonin level in discrete brain regions and growth of an experimental tumor in mice.

Palliative treatment of esophagogastric cancer by laser photocoagulation.

Over a 7-year period 158 nonsurgical patients with an advanced esophageal cancer were treated by palliation. The initial success rate was 79% and the complications rate was 2.3%. Average improvement duration was 136 days. Tumors were mostly situated in lower and middle part of oesophagus.

Endoscopic ND:YAG laser treatment of rectosigmoidal cancer.

Over a period of 7 years 126 patients with rectosigmoid carcinoma considered unsuitable for surgery underwent endoscopic Nd:YAG laser treatment for palliation of symptoms and tumor eradication, if feasible. Altogether 72 (59%) of the lesions had distal margins less than 7 cm from the anus and 32 (23%) above the peritoneal reflection. In 14 patients with tumor less than 3 cm in diameter, symptomatic improvement was achieved in all. In the remaining 112 patients with larger tumors (81 greater than 3/4 circumferential, mean length 5.5 cm) symptomatic improvement was achieved with repeated treatments (average 3.7) in 58 (71%). All treatment failures occurred in patients with extensive tumors (17 initial, 12 late). Bowel perforation did not occur and there was no treatment related mortality. The average stay in hospital for all laser patients was 9 days (32% of patients were outpatient attendance). These results suggest that laser therapy may be the palliative treatment of choice in patients with rectosigmoid carcinoma unsuitable for surgery.

Characterization of a pan-lymphocyte monoclonal antibody useful in differentiating leukemic from normal myeloid progenitors and monocytes from macrophages.

A monoclonal antibody (McAb) designated 3A2 that recognizes a 51 kDa epitope having surface density of 37 x 10(8) per MOLT-4 cells is described. This epitope appears to be expressed on (i) lymphocytes at all stages of differentiation; (ii) leukemic myeloid progenitors; (iii) peripheral blood monocytes (MO). The epitope is specifically absent from normal myeloid progenitors and macrophages. The McAb may, therefore, be useful in studying myeloid lineage leukemias and, as a marker for monocyte to macrophage (MO + MAC) differentiation.

Circulating epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) in patients with epithelial ovarian carcinoma.

Circulating epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) were estimated in 58 patients with epithelial ovarian cancer and were correlated with clinically and biochemically important prognosticators. IGF-I levels were significantly low in patients as compared to controls. The relation of growth factors with clinically important prognosticators was non-significant. Moreover, the levels of EGF and IGF-I in the ER+/PR+ and ER-/PR- groups and in the low and high EGFR+ tumors did not differ significantly. Patients with EGF < 1.0 ng/ml had significantly better survival than those with EGF > 1.0 ng/ml.

Biochemical analysis of breast cyst fluid as a possible predictor of breast carcinoma development.

The occurrence of breast cancer in patients with gross cystic disease is 2-5 times higher as compared to control group of women. During 3 years, 183 cyst fluid samples were analyzed in 129 females, in 30 patients of them the samples were analysed repeatedly. The distribution of the Na+/K+ ratio, considered as the measure of cancer risk, was found to be bimodal. In repeated analyses the type I cyst fluid markedly predominated (Na+/K+ < or = 4.0). A direct dependence on this ratio was found in the concentration of glucose, albumin, carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA) and its specific form, TPS; an indirect dependence was found for the level of uric acid, phosphates, alkaline phosphatase (ALP) and alpha-amylase (AMS). The predominance of apocrine metaplasia cells released into the cyst fluid is characteristic of type I cysts. A definitive assessment of significance of these parameters will be enabled by a long-term follow-up of the disease in the respective patients.

Antitumor, nephrotoxic and clastogenic effect of cis-DDP with DDTC or NAC.

Diethyldithiocarbamate (DDTC) and N-acetylcysteine (NAC) are nucleophile sulfur-containing compounds which can protect the platinum-induced nephrotoxicity. Combinations of cis-diamminedichloroplatinum(II) (cis-DDP) and DDTC or NAC were tested on the leukemia L1210 and melanoma B 16 tumor models. Nephrotoxicity of cis-DDP alone and in combination with DDTC or NAC was evaluated. On both of the investigated tumor models clastogenic effects in bone marrow cells were detected. DNA synthetic and mitotic activity of L1210 cells in vivo were evaluated by 3H-thymidine incorporation and cytogenetic analysis. Amelioration of the platinum induced nephrotoxicity and preservation of the antitumor activity of cis-DDP through combined application with DDTC or NAC were obtained at the L1210 model. Maximal inhibition of the DNA synthesis in L1210 cells was detected with the cis-DDP treatment. The sulfurcontaining nucleophiles DDTC or NAC could modulate the inhibitory effect of cis-DDP on the incorporation of 3H-thymidine into the nuclei of L1210 cells. Enhanced mitotic activity was detected during cytotoxic therapy with cis-DDP. Cis-DDP alone and in combination with DDTC or NAC caused a significant growth inhibition on the s.c. tumor of the melanoma B16 bearing mice. Two times better therapeutic results at this model were obtained with cis-DDP alone (T/C = 234.09%, T/C = 136.36% for cis-DDP+DDTC and T/C = 151.14% for cis-DDP+NAC). The usefulness of DDTC or NAC as adjuvants in the platinum based chemotherapy of human cancers have been discussed. Clastogenic effect and antitumor activity are probably connected and it is supposed that the reduction of the genotoxicity could lead to a decreased antitumor activity of the platinum complex.

Drug-resistance associated alterations of cell surface antigen expression in a human anthracycline-resistant ovarian carcinoma cell line.

The anthracycline uptake and cell surface expression of plasma membrane antigens (HLA class I, c-erbB-2, protectin-CD59, integrin beta 1-chain-CD29, etc.) were compared on a parental anthracycline sensitive and an anthracycline-resistant subline of the human ovarian carcinoma cell line A2780. The anthracycline-resistant (A2780/ADR) subline incubated for 30 min in the presence of daunomycin displayed two subpopulations with different anthracycline cell content as determined by flow cytometry. The subpopulation with lower daunomycin cell content was absent in the parental anthracycline sensitive cell line. The most predominant antigenic changes on the resistant subline as compared with the sensitive one were as follow: Loss of HLA class I and a twofold increase in the expression of CD59 antigen and a slight decrease of integrin beta 1-chain on the cell surface of the resistant subline.

Systemic chemotherapy for muscle invasive bladder cancer.

A total of 60 patients with muscle invasive transitional cell carcinoma of the bladder were entered into the nonrandomized study. The 1st group consisted of 30 patients treated by M-VAC neo-adjuvant chemotherapy followed by radical cystectomy when a residual tumor had been detected by biopsy made after the treatment. The overall clinical response was 70%. Fifteen (50%) out of 30 patients achieved clinical complete response (cCR). Objective pathologic response was attained in 6 (66.7%) of 9 evaluable patients who underwent radical cystectomy, pathologic complete response (pCR) was observed in two (22.2%) patients. Ten (33.3%) patients are still alive at a median follow-up of 22+ months. There were three (10%) drug-related deaths. The 2nd group consisted of 30 patients treated by CMV (with carboplatin) neo-adjuvant chemotherapy followed by radical pathologic response was attained in 9 (47.4%) of 19 evaluable patients, with pCR in 6 (31.6%) patients. Twenty four (80%) patients are still alive at a median follow-up of 13+ months. There was one (3.3%) drug-related death. The authors recommend immediate radical cystectomy following neo-adjuvant chemotherapy in all patients if their total status it allows.

Hyperthermia in cancer treatment (I).

In recent years there have been numerous randomized and nonrandomized studies conducted to assess the efficacy of hyperthermia combined with either radiation therapy or chemotherapy especially in the treatment of superficially seated malignant tumors. The major impact of hyperthermia is currently on loco-regional control of tumor. Heat may be directly cytotoxic to tumor cells or inhibit repair of both sublethal and potentially lethal damage after radiation. These effects are augmented by the physiological conditions in tumor which lead to states of acidosis and hypoxia. Blood flow is often impaired in tumor relative to normal tissue, and hyperthermia may lead to a further decrease in blood flow and augment heat-sensitivity. Three major areas of clinical investigation have borne the greatest fruit for hyperthermia as adjunctive therapy to radiation therapy. These include recurrent and primary breast lesions, melanoma, and head and neck neoplasms. Thermal enhancement ratio was increased in all cases and is estimated to be 1.4 for neck nodes, 1.5 for breast and 2 for malignant melanoma. In general, the most important prognostic factors for complete response are radiation dose, tumor size and minimal thermal parameters (minimal thermal dose (t43min), mean minimal temperature (Tmin) or T90, i.e., temperature exceeded by 90% of thermal sensors). The number of heat fractions administered per week appears to have no bearing on the overall response, which may be indicative of the effects of thermotolerance. The total number of heat fractions delivered also appears irrelevant provided adequate heat is delivered in one or two sessions. The major prognostic factors for the duration of local control are tumor histology, concurrent radiation therapy, dose, tumor depth and Tmin.

Biological rationale for hyperthermia in cancer treatment (II).

Hyperthermia (HT) has gained a great interest in the past two decades. The nature of hyperthermia-induced cell lethality is quite different from that of radiation-induced killing. The G1-phase of the cell cycle is the most resistant to HT while S-phase cells are quite sensitive. In addition to heat-induced cytotoxicity, HT sensitizes cells to low LET ionizing radiation. The mechanism of heat cytotoxicity is distinct from that of ionizing radiation. Unlike the response to ionizing radiation, heat cytotoxicity is influenced by thermotolerance, low pH and nutritional deprivation, but is independent of acute hypoxia. Also, blood flow influences the heating characteristics of a tumor relative to normal tissue, and vascular collapse may occur after heating. Thermotolerance is a nonheritable resistance to HT induced by exposure to heat and other cytotoxic agents. Thermotolerance develops within 2-3 h during exposure to temperatures less than 43 degrees C. Cells exposed for a brief period to temperatures higher than 43 degrees C are sensitized to exposure to temperatures below 43 degrees C. This is called "stepdown heating, SDH". SDH results from the inhibition of thermotolerance development by exposure to the high temperature. Cells are sensitized to HT damage by acutely lowering pH, and thermotolerance development is reduced at low pH. Reduced pH also enhances thermoradiosensitization. Since much of a tumor population is at low pH, and these tumor cells are very likely to be hypoxic and radioresistant, this offers one of the strongest reasons for combining HT with radiation therapy in the treatment of human tumors. The neovasculature in tumors does not respond to increased temperatures as do blood vessels in normal tissues, and these differences in blood flow may lead to selective tumor heating. HT dramatically enhances the cytotoxicity of the electron affinic radiosensitizers in hypoxic cells. HT sensitizes the cell to many cytotoxic agents and even converts some drugs that are innocuous to highly toxic. HT chemosensitization may occur by an increased reaction rate, increased permeability, or decreased repair. The most promising chemosensitization by HT would seem to be with alkylating agents and cis-platinum since they are enhanced at all elevated temperatures.

Enhanced erythropoietin and suppression of gamma-glutamyl transpeptidase (GGT) activity in murine lymphoma following administration of vanadium.

Administration of vanadium as ammonium monovanadate (0.005 microgram/0.1 ml/mouse/day) was found to reduce the tumor cell proliferation in the host mice bearing Dalton's lymphoma. The high activity of gamma-glutamyl transpeptidase (GGT), a neoplastic marker, was seen in the host cells bearing lymphoma. Vanadium effectively prevented an increase in activity of gamma-glutamyl transpeptidase and maintained a sustained low activity of this enzyme. In addition, an improvement of the hematological aspects of the mice and almost fourfold elevation of erythropoietin (Epo) was obtained following vanadium treatment. This increase in Epo activity may play a vital role in regulating the growth of cellular neoplasia. The present study further confirms the antitumorigenic potential of vanadium in the control of tumor progression in lymphoma via modulating several factors involving erythropoiesis and may emerge as a new chemopreventive agent for the future.

Effect of pentoxifylline on P-glycoprotein mediated vincristine resistance of L1210 mouse leukemic cell line.

Effect of pentoxifylline (PTX) on vincristine (VCR) resistance of multidrug resistant L1210/VCR mouse leukemic cell line was studied. Reversal effect of PTX (in concentration 50-150 mg/l) on vincristine resistance, i.e. potentiation of vincristine cytotoxicity on L1210/VCR cells by PTX was found. PTX alone in the above concentration did not exert any significant cytotoxic effect on sensitive or resistant cell lines in the absence of vincristine. Resistance of L1210/VCR cell line was found previously to be accompanied with overexpression of drug transporting P-glycoprotein. Indeed, lower level of 3H-vincristine accumulation by resistant L1210/VCR cell line in comparison with sensitive L1210 cell line was observed. Accumulation of 3H-vincristine by L1210/VCR cell line was significantly increased in the presence of PTX. PTX in the same condition did not exert any considerable effect on accumulation of 3H-vincristine by nonresistant L1210 cells. Observable morphological damage was observed in L1210/VCR cells cultivated in medium containing vincristine (0.2 mg/l) and pentoxifylline (100 mg/l) in comparison with the non-damaged cells in the presence of vincristine or pentoxifylline alone. The results obtained indicate that pentoxifylline may be considered as a reversal agent in multidrug resistance.