Association of macrophage activation with antitumor activity by synthetic and biological agents

Treatment of normal BALB/c mice i.p. with a number of adjuvants, including pyran copolymer, the copolymer of polyinosinic and polycytidylic acids, Bacillus Calmette-Guérin, glucan, and dextran sulfate, rendered macrophages nonspecifically cytostatic for syngeneic tumor cells. Macrophage activation was highly dose dependent. The validity of the inhibition of DNA synthesis assay for measuring macrophage-induced cytostasis of target cells was proven by demonstrating a concurrent decrease in RNA synthesis and a reduction in viable tumor cell number. Moreover, conditioned supernatants from pyran-activated macrophages did not significantly decrease [3H]thymidine incorporation by freshly added leukemia cells. Biological or synthetic agents that activated macrophages were generally effective systemic antitumor agents against the M109 lung carcinoma. Drugs that did not activate macrophages, such as typhoid vaccine, tilorone, levamisole, WY-13876, and thymosin, were ineffective in prolonging the life of tumor-bearing mice. Pyran treatment i.p. was the most effective antitumor adjuvant in two separate tumor models, and suppression of tumor growth appeared to be related not only to an increase in macrophage tumoricidal function, but also to a larger influx of macrophages responding at the tumor site.     

Aza and diaza bioisosteric anthracene-9,10-diones as antitumor agents

We compared 115 female and 115 male Brazilian alcoholics in terms of their social and demographic characteristics, as well as other characteristics associated with alcohol consumption. Women both began drinking and increased their consumption later than men. The incidence of attempted suicide was higher among women. Females used less illicit drugs. Male alcoholics were more frequently born in the city of S?o Paulo. As for adherence to treatment in an out-patient clinic, no significant differences were found between the sexes 3, 6, 9 and 12 months after initiation of treatment.     

Therapy of resistant psoriasis with topical corticosteroids and dimethylsulfoxide

The sequential application of full-strength dimethylsulfoxide (DMSO) and potent topical corticosteroid preparations was very effective in resistant plaque-type psoriasis. Complete clearing may be achieved in 3-4 weeks. Lower strengths of DMSO were less beneficial. Irritation from the solvent was effectively controlled by corticosteroids and was limited to transient burning or stinging. Resistance to topical corticosteroids may be overcome by the concomitant use of DMSO.     

Effect of selected antimutagens on the genotoxicity of antitumor agents

Cyclophosphamide (CP), bleomycin (BL), doxorubicin (DOX) and cisplatin (CISP) are potent antitumor drugs used worldwide against many forms of human cancer. As with most such agents, there can be physiological side-effects and the possible induction of mutations and other genotoxic effects in non-tumor cells. It is common for patients to ingest a host of food supplements to diminish the discomforting side-effects of therapy. Because these food supplements are often also rich in antimutagens that could also affect the biological efficacy of the antitumor drugs, we investigated if such antimutagenic agents were indeed antimutagenic to these antitumor drugs. Using the Salmonella/microsome bioassay, we tested CP, BL, DOX, and CP for mutagenicity in the presence and absence of the antimutagens ascorbic acid (AA), chlorophyllin (CHL) and (+)-catechin (CAT). AA was a very effective antimutagen against CISP and less effective against BL and DOX. It was not antimutagenic to CP. CHL was effective as an antimutagen against all four antitumor drugs, and CAT was a strong inhibitor of DOX mutagenicity, but had little effect on BL, CP and CISP. These data now provide a basis for future in vivo antitumor/antimutagen combination studies to determine if these antimutagens function in a manner to reduce genetic effects without having concomitant effects on intended antitumorogenicity of these therapeutic agents.     

Characterization and responsiveness of the Madison 109 lung carcinoma to various antitumor agents

The Madison 109 (M109) tumor was discovered in 1964 in the lung of a BALB/c mouse. This experimental carcinoma is maintained in vivo by sc passage in the right axillary region. When implanted im (5 X 10(5) cells) into the right hind leg of BALB/c mice for testing, the primary progresses with metastases to the lung, spleen, and liver. The metastases to the lung are visible within 3 weeks and result in the death of the host in about 35 days after tumor implant. Implantation of a lung nodule is tumorigenic and lethal. Pyran polymer therapy delayed the appearance of lung metastases, inhibited the growth of the primary tumor, and significantly increased the lifespan of BALB/c mice inoculated with the M109 tumor. No spontaneous regression has been observed and very few "no takes" have occurred in untreated BALB/c mice inoculated with at least 500 M109 cells. Of the 82 agents tested so far, the M109 model has selected active agents such as actinomycin D, adriamycin, daunorubicin, DNA, procarbazine, and pyran polymer. It has not shown sensitivity as tested to several standard therapeutic agents including cytosine arabinoside, BCNU, hydroxyurea, mechlorethamine, melphalan, triethylenemelamine, and vincristine.     

Treatment of Herpes simplex virus infections with topical antiviral agents

Clinical studies of topical therapy against Herpes simplex virus (HSV) infections have been reviewed. Idoxuridine (IDU) 15% in dimethyl sulfoxide (DMSO), interferons, and penciclovir result in significant clinical benefit against this virus. IDU reduced pain duration and decreased time to loss of crust in a study of 301 patients. Alpha-interferon has shown synergism with other anti-HSV drugs such as caffeine, trifluorothymidine (TFT), DMSO, and nonoxynol-9. Finally, in a study of over 2,000 patients, application of penciclovir cream, both early and late in the course of HSV infection, decreased the duration of lesions, pain, and viral shedding. Acyclovir (ACV)-resistant strains of HSV are susceptible to (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine (HPMPC), and ascorbic acid shows promising effects against HSV. Using a vehicle that enhances skin penetration of a drug or possibly further exploring combination therapy may result in efficacious treatment of HSV. The possibility of topical vaccination or topical gene therapy may also prove beneficial in the future.     

Interaction of alpha-tocopherol with model human high-density lipoproteins

The effects of alpha-tocopherol on the properties of model high-density lipoproteins (HDLs), composed of human apolipoprotein A-I and dimyristoylphosphatidylcholine, were investigated by physicochemical methods. The intrinsic fluorescence of alpha-tocopherol and its effects on the polarization of fluorescence of 1,6-diphenyl-1,3,5-hexatriene, which probes the hydrocarbon region of the lipids, and 4-heptadecyl-7-hydroxycoumarin, which is a probe of lipid surfaces, suggest that alpha-tocopherol is located at the lipid-water interface. Relative to cholesterol, alpha-tocopherol in lipid surfaces is virtually inert physicochemically. Incorporation of alpha-tocopherol into HDLs induces only a modest increase in particle size, no change in the transition temperature, and little change in lipid polarity and lipid-lipid interactions. Moreover, alpha-tocopherol has only a negligible effect on the kinetic parameters of the lipophilic enzyme lecithin:cholesterol acyltransferase, which binds to phosphatidylcholine surfaces and forms cholesteryl esters. However, alpha-tocopherol has a dramatic inhibitory effect on the rate of association of apolipoprotein A-I with dimyristoylphosphatidylcholine, a process that occurs through the insertion of the protein into preformed defects in the lipid surface. It is proposed that alpha-tocopherol inhibits the rate of association of apolipoprotein A-I with dimyristoylphosphatidylcholine by inserting into defects within the lipid surface, thereby reducing the size and/or number of sites for insertion of apolipoprotein A-I.     

Reaction of alpha-tocopherol with alkyl and alkylperoxyl radicals of methyl linoleate

The common cytogenetic finding characteristic of human malignant testicular germ-cell tumors is the presence of an isochromosome of the short arm of chromosome 12, i(12p), suggesting alterations in the proto-oncogenes (e.g., c-Ki-ras2) or putative tumor suppressor genes (TSG) that are localized here. However, to date there is no proof for such alterations. Conversely, alterations in expression of the retinoblastoma gene, a classical TSG, have been reported for the majority of testicular tumors. Other molecular genetic alterations have been described, affecting genes that are involved in the normal regulation of spermiogenesis, such as the c-kit gene product and its ligand SCF, as well as hst1, which is normally expressed in embryonal tissues only. The well-documented sensitivity of testicular tumors to chemotherapeutic agents may be caused by decreased activity of the glutathione S-transferase detoxification enzymes, as well as alterations of the expression of this gene family.     

Azidothymidine resistance of H9 human T-cell lymphoma cells is associated with decreased sensitivity to antitumor agents and inhibition of apoptosis

Biology of HIV-1 associated neoplasias is modulated by viral and host factors. In addition the development of tumors and their response to therapy may be further influenced by long-term treatment of HIV-1 patients with nucleoside analogs such as AZT (3'-azido-3'deoxythymidine), ddI (2',3'-dideoxyinosine), ddC (2',3'-dideoxycytidine), d4T (2',3'-didehydro-2'3'-dideoxythymidine), and 3TC [(-)-beta-L-2',3'-dideoxy-3'-thiacytidine] alone or in combination. As these compounds can trigger mechanisms involved in chemoresistance, we tested whether prolonged in vitro treatment of H9 cells (T-cell lymphoma) with AZT alters sensitivity of lymphoma cells to antitumor agents used for AIDS-associated malignancies. H9 cells grown for more than two years in medium containing 250 microM AZT developed resistance to the toxic effects of AZT while retaining sensitivity for other nucleoside analogs including ddC or cytosine arabinoside (ARA-C). These cells designated H9rAZT250 were 2 to 10-fold less sensitive to the toxic effects of antitumor agents, including cisplatin (CDDP), vincristine (VCR), doxorubicin (DOX) and etoposide (VP-16), when compared with parental H9 cells. The resistance of H9rAZT250 cells to antitumor agents was associated with inhibition of apoptosis as demonstrated by ultrastructural investigations and DNA-fragmentation assay (ELISA). The expression of the antiapoptotic gene bcl-2 was increased in H9rAZT250 cells while expression of other genes involved in the regulation of apoptosis such as c-myc, p53 and Fas was not changed. These results demonstrate that prolonged in vitro treatment of H9 lymphoma cells with AZT results in the development of resistance to antitumor agents in association with inhibition of apoptosis and increased expression of bcl-2. Therefore AZT long-term treatment of some HIV-1 patients with malignancies may have affected behavior of tumor cells including response to therapy.     

Treatment of mucositis with vitamin E during administration of neutropenic antineoplastic agents

Mucositis represents one of the most frequent complications during chemotherapy or radiotherapy. Few studies have showed effective prevention against mucositis in this setting. In this randomized study, we tested the efficacy of vitamin E in the treatment of chemotherapy-induced mucositis. Twenty patients with malignant haemopathies were included; 19 patients were evaluable for the prevention of mucositis. Ten patients were treated with induction therapy for acute myelogenous leukaemia and 9 were treated with intensive therapy followed by autologous bone marrow transplantations. The severity of mucositis was evaluated according to World Health Organization classification. Our results showed that vitamin E may be of therapeutical value in the prevention of mucositis especially during induction therapy for acute myelogenous leukaemia.     

Nonoperative treatment of major blunt renal lacerations with urinary extravasation

PURPOSE: We determined whether nonoperative treatment of major renal lacerations with urinary extravasation adversely affects patient outcome. MATERIALS AND METHODS: We reviewed all nonoperatively treated patients who presented between 1983 and 1994 with blunt renal trauma with major lacerations on initial staging computerized tomography. Patients with major lacerations associated with (31) and without (15) extravasation were compared for complications, blood transfusions and length of hospital stay. RESULTS: Urinary extravasation spontaneously resolved in 27 of 31 patients (87.1%), while 4 (12.9%) required a ureteral stent for persistent extravasation. No complications occurred in patients without extravasation. Mean hospitalization was 8.3 and 7.7 days for patients with isolated renal injuries with and without extravasation, respectively. Blood transfusions were required in 4 patients with and none without extravasation. CONCLUSIONS: Nonoperative treatment of major renal lacerations with urinary extravasation is safe and effective. Although delayed intervention may be required, complications can often be treated with endourological or percutaneous methods.     

Photodynamic antitumor agents: beta-methoxyethyl groups give access to functionalized porphycenes and enhance cellular uptake and activity

Porphycene photosensitizers bearing two or four methoxyethyl side chains were synthesized in nine steps from commercially available starting materials. Ether cleavage led to (hydroxyethyl)- and (bromoethyl)porphycenes that were converted to vinyl and benzo derivatives. Five of the side chain-functionalized porphycenes were biologically studied in comparison with two tetra-n-propylporphycenes. Porphycenes were incorporated in small unilamellar liposomes and incubated with cultivated SSK2 murine fibrosarcoma cells. Cellular uptake and phototoxicity 24 h after 5 J/cm2 laser light treatment were determined. The porphycenes tested were between 17 and 220 times more photodynamically active than the currently clinically used sensitizer Photofrin, although extinction coefficients of the porphycenes' irradiated bands are only approximately 10-fold higher. The LD50 concentration for SSK2 cells in the incubation medium was as low as (8.5 +/- 2.8) x 10(-9) M for tetrakis(methoxyethyl)porphycene. Two methoxy or hydroxy groups enhanced cellular uptake, three or four methoxy groups both enhanced and accelerated cellular uptake of tetraalkylporphycenes. Half-life times of the uptake processes varied between (0.14 +/- 0.04) and (14 +/- 4) h and cellular saturation levels between (1.2 +/- 0.2) and (26 +/- 3) pmol/10(5) cells. When individual uptake rates were accounted for, all porphycenes had a similar "cellular" phototoxicity, pointing toward a common mechanism of action. Evidence is presented for the assumption that cell membranes are the primary targets of the tested porphycenes and that membrane solubility may play a critical role in their photodynamic efficiency. The results show that nonionic polar side chain functionalities can strongly enhance cellular uptake and antitumor activity of lipophilic porphyrinoids and thus that the known lipophilicity/activity relationship can be reversed for very hydrophobic sensitizers.     

In vitro and in vivo studies on the role of dimethylsulfoxide (DMSO) in resensibilization of bacterial strains resistant to antibiotics and chemotherapeutic agents

Resensibilization in vitro to seven antibiotics under the influence of DMSO was studied in 624 resistant strains of five species of bacteria (E. coli, S. typhi, S. pyogenes, S. viridans, S. aureus), 61 strains of tubercle bacilli resistant to isonicotinic acid hydrazide (INH) and 19 strains of tubercle bacilli resistant to rifampicin (RMP). DMSO in concentrations of 0.1-10.0% caused reversion of sensitivity in strains of E. coli, S. pyogenes and S. viridans. Reversion in vivo of sensitivity to INH of tubercle bacilli was studied in experimental tuberculosis of guinea pigs. Tubercle bacilli previously resistant to INH recovered complete sensitivity to the drug, enabling animals infected with the INH-resistant strain of bacilli to be treated with INH.     

Effect of side chain location in (2-aminoethyl)-aminomethyl-2-phenylquinolines as antitumor agents

New equipment facilitating the use of spontaneous ventilation with positive expiratory pressure (PEP) has become available in France since January 1996. This technique was applied in 38 patients with severe cardiogenic pulmonary oedema and persistent respiratory distress despite high flow classical oxygen therapy and standard treatment. After 1 hour of ventilation with a flow of 220 l/min of 100% oxygen with an average PEP of 7.7 cm H20, a significant improvement of clinical (heart and respiratory rate) and biological parameters (arterial gases) was observed. There were no side effects. Four patients died during the hospital period and only 1 was intubated. Spontaneous ventilation with PEP is a simple technique for coronary care units and, compared with conventional oxygen therapy, it rapidly improves arterial oxygenation, reduces respiratory work and improves conditions of cardiac load. Acute severe cardiogenic pulmonary oedema seems to be an indication of choice, especially in the elderly, where it may help avoid an often controversial intubation.     

Treatment of advanced colorectal cancer with doxorubicin combined with two potential multidrug-resistance-reversing agents: high-dose oral tamoxifen and dexverapamil

On the basis of the overexpression of the MDR1 gene in human colorectal cancer, which may constitute a molecular basis for intrinsic drug resistance that can be reversed, and because of the limited therapeutic value of conventional cytotoxic treatment in this common disease, the present phase II study of P-glycoprotein-directed double modulation was initiated. Fifteen patients with measurable metastatic colorectal cancer, all of whom were refractory to first-line chemotherapy with 5-fluorouracil/leukovorin, were entered in this trial. Treatment consisted of 80 mg tamoxifen twice daily on days 1-9, oral dexverapamil every day on days 7-9, and 60 mg/m2 doxorubicin given by intravenous bolus injection on day 8. Courses were repeated every 4 weeks. After a median of three (between one and six) courses, none of the 14 evaluable patients had objective response, and 4 had stable disease. Adverse reactions consisted mainly of myelosuppression (WHO grade IV granulocytopenia was noted in 40%), and mild and reversible dexverapamil-related cardiovascular side-effects, specifically hypotension (47%). Our results suggest that, despite the histological demonstration of high levels of P-glycoprotein in colorectal cancer and administration of two potentially synergistic chemosensitizers, we were unsuccessful in circumventing its primary resistance to chemotherapy.     

5-substituted 2-bromoindolo[3,2-b]quinoxalines. A class of potential antitumor agents with cdc25 phosphatase inhibitory properties

Several derivatives of 5-substituted 2-bromoindolo[3,2-b]quinoxaline were synthesized and characterized. The synthesized compounds were evaluated for their antitumor activity using the National Cancer Institute-in vitro-disease oriented antitumor screen and two biochemical mechanism-based screens (cdc2 kinase and cdc25 phosphatase). Compound 19 showed broad spectrum antitumor activity with full panel (MG-MID) GI50. TGI, and LC50 of 14.2, 31.6- and 66.2 microM, respectively. In addition it inhibited cdc2 kinase and cdc25 phosphatase with IC50's of 70 and 25 microM, respectively. Thus, compound 19 represents a model for compounds with potential antitumor activity and cdc25 phosphatase inhibitory properties.