Evidence for Mononuclear Phagocytes in Solid Neoplasms and Appraisal of Their Nonspecific Cytotoxic Capabilities

Flavone Acetic Acid (FAA) is a synthetic flavonoid compound with potent activity against a variety of transplantable murine tumours including many which are resistant to conventional cytotoxic drugs (Corbett et al., 1986;Bibby et al., 1988a). FAA possesses several features unusual for an anticancer agent. Thus FAA's activity appears to be confined to tumours growing subcutaneously (s.c.) as solid lesions; its effect on tumour cells in culture or against leukaemia models being minimal (Bibby et al., 1987;Finlay et al., 1988;. These characteristics, coupled with a toxicity profile unlike that of most antineoplastic drugs (Zaharko et al., 1986), suggest that the drug may have an indirect mode of action.A possible way whereby FAA might exert its antineoplastic effects is via interruption of the tumour blood supply. A number of authors, using techniques as varied as magnetic resonance spectroscopy, dye perfusion and pointcounting of vascular channels, have shown that FAA administration rapidly effects a dramatic reduction in tumour blood flow (Evelhoch et al., 1988;Bibby et al., 1989a;Zwi et al., 1989). Most recently, by means of a radioactive-tracer clearance assay, we have confirmed this inhibition of tumour blood flow by FAA and provided evidence that tumour necrosis factor cz (TNFx) is responsible for this effect (Mahadevan et al., 1990).For a given tumour, FAA appears to be less effective against early stage disease than against its more advanced, better established counterpart (Bibby et al., 1988b). Certainly the studies on blood flow inhibition cited above were conducted on overt, palpable tumours which possess a functional microvasculature (Folkman & Cotran, 1976). We are unaware of any studies on the effects of FAA on the early development of tumour microcirculation. Accordingly the present study, using the clearance of locally-injected '33Xe as an indication of blood flow (Mahadevan et al., 1989(Mahadevan et al., , 1990, was undertaken to examine the possible effects of FAA on this early stage of neoplastic growth. Protamine, an argininerich basic protein which is capable of inhibiting tumour neovascularisation (Folkman, 1985;Taylor & Folkman, 1982), was used as a positive control. We show here that the inhibition of tumour blood flow achieved by FAA administration depends on an established tumour microvasculature with no evidence that the drug inhibits new vessel formation. Fluanisone; Janssen Pharmaceuticals) and Hypnovel (5 mg ml-1 of Midazolam Hydrochloride; Roche), each at a dose of 0.5 ml kg-' of body weight.A 1 cm dorsal, vertical, midline skin incision was made aseptically immediately proximal to the base of the tail and a dorsal subcutaneous pouch was fashioned 4-5 cm cephalad to the incision by gentle, blunt dissection. A sponge disc was then introduced through the incision and placed flat in this subcutaneous pouch. The skin incision was closed with two interrupted 5-0 silk sutures and the animal allowed to recover.

Section: Discussionmentioning

confidence: 99%

Divergent effects of flavone acetic acid on established versus developing tumour blood flow

Mahadevan

Hart²

1991

“…This can be exploited for obtaining separate populations of tumour cells and TAM (Russell et al, 1980). Single cell suspension in MEM with 10% FBS was prepared from SCCVII tumour as described above.…”

Section: Facs Analysismentioning

confidence: 99%

Distribution of Photofrin between tumour cells and tumour associated macrophages

Korbelik¹,

Krosl²,

Olive³

et al. 1991

Photofrin levels in cells derived from SCCVII tumours, excised from mice that previously received the drug, were measured using a fluorescence activated cell sorter (FACS). Concomitantly, in the same cells the FACS was used to measure fluorescein isothiocyanate (FITC) fluorescence that originated from FITC-conjugated antimouse IgG added to the cell suspension before sorting. This later measurement enabled discrimination between IgG negative tumour malignant cells and IgG positive host cells (primarily macrophages). In addition, cellular Photofrin content in 'tumour' and 'host' cells sorted by FACS was determined by chemical extraction. The measurements were performed for the time intervals 1-96 h post Photofrin administration. The data showed consistently higher Photofrin levels in the 'host cells', i.e., tumour associated macrophages (TAM), than in 'tumour' cells. On a per cell basis, at any time point studied there was a minimum of 1.7 times more Photofrin in 'host' than in 'tumour cells', while at 4-12 h postadministration, ratios of up to 3.0 times were observed. This corresponds to ratio values greater than 9, when based on Photofrin content per micrograms cell protein.

“…Although the mean augmentation of activity was (Underwood, 1974;Ioachim, 1976). In an attempt to delineate the role played by various effector mechanisms in situ, numerous studies have been reported in which tumour infiltrating cells have been isolated from highly immunogenic animals tumours (Russell et al, 1980;Herberman et al, 1980;Haskill et al, 1979Haskill et al, , 1978 as well as from human tumours (Mantovani et al, 1979;Klein et al, 1980;Werkmeister et al, 1979;Totterman et al, 1980;Vose & Moore, 1979). Several studies have investigated the in vitro activity of TILs from human tumours but none have attempted to find an association between effector-cell presence and survival.…”

Section: Effect Of Interferon On Blood and Ascites Lymphocyte Reactiomentioning

confidence: 99%

“…Because blood represents essentially the sole source by which immune competence can be followed, it is important to determine whether activity in patient peripheral-blood leucocytes is representative of what is actually taking place in the tumour. There have been numerous reported investigations of the tumour-and ascites-isolated macrophages and lymphocytes from both animals (Russell et al, 1980;Herbermann et al, 1980;Haskill et al, 1979Haskill et al, , 1978 and humans (Mantovani et al, 1979;Klein et al, 1980;Werkmeister et al, 1979;Vose & Moore, 1979;Totterman et al, 1980) with various results in animals, but most of the clinical studies have failed to detect intratumour activity. In addition, many of these studies have not focused on a particular cancer type, making the results more difficult to compare.…”

mentioning

confidence: 99%

Mononuclear-cell infiltration in ovarian cancer. II. Immune function of tumour and ascites-derived inflammatory cells

Haskill¹,

Koren²,

Becker³

et al. 1982

Summary.-Mononuclear cell fractions were isolated from blood, ascites and solid tumours of patients undergoing surgery for Stages III and IV PHA responses of patient blood and ascites fractions were about half that of normal blood. Tumour-infiltrating lymphocytes (TIL) were less than 10% as responsive as normal blood. The depressed PHA responses of the TIL were not due to the presence of a suppressor cell population. NK activity of patient blood was less than that of normal blood, but not as much as the ascites or TIL cells. The activity of the ascites-derived lymphocytes was enhanced by treatment with interferon. ADCC activity against both CRBC and SB cells was normal or higher than controls in patient blood, and depressed in the ascites-derived fractions. TIL responded to <10% of the patient blood values.The results indicate a lack of response by ascitic and TIL cells in assays dependent on FcR -bearing effector cells and a greater loss of PHA-reactive cells from the tumour than from blood and ascites. These data could result from intratumour inactivation, or a failure of the particular subset to localize either In the ascites or the tumour site.