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Biomedical subjects

P Alexander

Publications and source records attributed to P Alexander.

At least 73 records · Page 4Linked to original sources
PubMed1989

Enhanced growth of tumour cells in healing colonic anastomoses and laparotomy wounds.

In the past, it has been noted that experimental tumour cells inoculated into the peritoneal cavity or into the lumen of the bowel will grow at a recently formed colonic anastomosis. However, it has previously been unclear whether the healing process enhances tumour growth or whether the presence of a suture line merely allows the tumour cells to gain access to the tissues. In the present study, using the hooded Lister rat, we have confirmed these findings by showing that growth of the syngeneic MC28 sarcoma and OES5 breast carcinoma occurs preferentially at colonic anastomoses and laparotomy wounds after intraperitoneal injection, and at colonic anastomoses after intraluminal injection. In previous studies using the MC28 sarcoma and the OES5 breast carcinoma injected by the intracardiac route (so that tumour cells reach normal and healing tissues in approximately equal numbers) we have shown that tumour growth is enhanced in healing wounds but not in the surrounding normal tissues when cells reach a healing colonic anastomosis or laparotomy wound within 2 h of its formation. Furthermore, by studying the distribution of radiolabelled tumour cells after intracardiac injection, we have calculated that the probability of a tumour cell leading to a deposit in a healing anastomosis or laparotomy wound is increased 1,000 fold compared to normal tissue. No previous studies have combined the data for intracardiac, intraluminal and intraperitoneal injection of tumour cells using the same animal model. We conclude that the same phenomenon of tumour growth enhancement in colonic anastomoses and laparotomy wounds reported after intracardiac injection of tumour cells may well be enhancing tumour growth after intraperitoneal and intraluminal injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Anastomosis, Surgical↗
PubMed1988

Preferential growth of blood-borne cancer cells at sites of trauma--a growth promoting role of macrophages.

Carcinoma and sarcoma after gaining access to the venous circulation are completely trapped in the organs of first encounter, i.e. the lung and vertebrae for cancers draining into the vena cava, or liver for tumours with portal drainage. Systemic dissemination of carcinomas and sarcomas derives from cancer growing in the lung and can be mimicked in experimental rats by injecting cancer cells intra-arterially via the left ventricle. These emboli are arrested in different tissues in proportion to the cardiac output they receive, but the probability of a cancer embolus introduced in this way causing a lesion varies by several orders of magnitude for different tissues. Traumatising tissues by procedures such as surgical incision of the abdomen, gut anastomosis, placing a stitch in the kidney or chemical or surgical partial hepatectomy, greatly enhances the likelihood that a cancer cell trapped in the tissues develops into a metastasis. While several factors contribute to making a wound a more favourable "soil" for metastasis a major mechanism is the release of growth factors from macrophages that have infiltrated the wound.

Animals↗
PubMed1988

Preferential growth of bloodborne cancer cells in colonic anastomoses.

Intracardiac injection, in hooded Lister rats, of syngeneic MC28 sarcoma cells never induced tumour growth in normal bowel. Tumour growth occurred at the site of a colonic anastomosis if surgery preceded tumour injection but not if it followed tumour injection, even by as little as 1 h. Maximum enhancement of tumour growth occurred when the healing process had progressed between 2 and 8 days, with a peak at 5 to 7 days. The enhancing effect was largely over by the time the healing had progressed 14 days. The syngeneic OES5 breast carcinoma also grew at colonic anastomoses when surgery preceded tumour injection by 5 days, but not in normal colon. The MC28 sarcoma also grew at ileal anastomoses but not in the normal ileum after intracardiac injection. By injecting radiolabelled sarcoma cells, an estimate of the probability of a single bloodborne tumour cell lodging at a colonic anastomosis and leading to a tumour deposit was calculated to be of the order of 1:43 whereas the probability of the cell lodging in normal colon and causing a deposit is less than 1:4 x 10(4).

Anastomosis, Surgical↗
PubMed1988

Mechanisms of organ selective tumour growth by bloodborne cancer cells.

The sites of tumour development for 6 rat tumours injected into syngeneic rats via different vascular routes was determined. Xenografts of human tumours were also injected intra-arterially (i.a.) into immunosuppressed rats. Following intravenous (i.v.) and intraportal (i.ptl.) injection of cells tumour colonies localized in lung and liver respectively due to tumour cell arrest. Arterially injected radiolabelled cells disseminated and arrested in a similar distribution to cardiac output and did not 'home' to any organs. Following arterial injection of unlabelled tumour cells colonies grew in many organs. While the pattern of growth for a particular tumour varied with the cell dose, the 'arterial patterns' for all of the tumours studied followed a similar pattern. Some organs (eg adrenals, ovaries and periodontal ligament) were consistently preferred, others (eg skin and skeletal muscle) only supported tumour growth following the delivery of large numbers of cells, while in some tissues (eg spleen and intestines) tumour never grew. Viable tumour cells could be demonstrated by bioassay in many organs for up to 24h after i.a. injection. However tumour growth only occurred in certain organs and the pattern of this growth was not related to the number of tumour cells arrested or their rate of autolysis. This site preference could be expressed quantitatively as the probability of an arrested cell developing into a tumour and was considered a 'soil effect'. Site preference was not directly related to organ vascularity. Organ colonisation was promoted by steroid treatment but the mechanism was unclear and was not secondary to T-cell immunosuppression or prostaglandin synthesis suppression. The adrenal glands were preferred sites of tumour growth but pharmacological manipulation of adrenal function did not alter tumour growth to this organ. Sites of injury and healing were preferred sites of tumour colonisation and this could not be accounted for by increased delivery of tumour cells to these regions. The possibility that the macrophage component of the inflammatory response promoted tumour growth was suggested from studies in which the interval between trauma and inoculation of tumour cells was varied as well as by promotion of intraperitoneal (i.p.) tumour growth by a macrophage infiltrate.

Animals↗
PubMed1988

Chronic hyperdynamic sepsis in the rat: I. Characterization of the animal model.

We describe a new rat model of chronic hyperdynamic sepsis. After control values for weight gain, and food and water intake of each animal were obtained over a 5-day period, male Sprague-Dawley rats weighing 370-425 g were anesthetized, catheterized to allow chronic cardiac-output measurements, and a sterile subcutaneous cavity was formed over the flank area. The animals were allowed a 3-4 day postoperative recovery period. Body weight, food and water intake, and cardiac output were measured daily. Frequent blood samples were withdrawn for bacterial cultures and white cell counts (WBC). On the third and, in some cases, the fourth postoperative day, the subcutaneous cavity was inoculated with 10(9) colony-forming units of Escherichia coli and Bacteroides fragilis. The resulting sepsis was characterized by loss of body weight in spite of normal food and water intake, increased cardiac output, increased WBC, intermittent bacteremia, decreased muscle mass, and decreased cross-sectional area of skeletal muscle myofibrils. Two levels of septic response emerged--moderate and severe. Based on the above-mentioned measurements, it was possible to categorize all long-term septic animals into these two groups. Both groups exhibited cardiac-output, body-weight, and WBC data significantly different from sham controls. Repeated inoculations of the subcutaneous abscess initiated on the third postoperative day resulted in moderate sepsis with no long-term mortality, severe sepsis with 23% mortality over a 3-week period, or a 100% mortality within 4 days, depending on the virulence of the E. coli organisms used. The new model is ideally suited for pathophysiologic studies of sustained, hyperdynamic sepsis.

Animals↗
PubMed1987

Analogs of leukotriene B4: effects of modification of the hydroxyl groups on leukocyte aggregation and binding to leukocyte leukotriene B4 receptors.

The syntheses and agonist and binding activities of 5(S)-hydroxy- 6(Z), 8(E), 10(E), 14(Z)-eicosatetraenoic acid (12-deoxy LTB4), 5(S), 12(S)-dihydroxy-6(Z), 8(E), 10(E), 14(Z)-eicosatetraenoic acid (12-epi LTB4), 12(R)-hydroxy-6(Z), 8(E), 10(E), 14(Z)-eicosatetraenoic acid (5-deoxy LTB4), 5(R), 12(S)-dihydroxy-6(Z), 8(E), 10(E), 14(Z)-eicosatetraenoic acid (5-epi LTB4), 6(Z), 8(E), 10(E), 14(Z)-eicosatetraenoic acid (5, 12-deoxy LTB4) are described. These leukotriene B4 analogs were all able to aggregate rat leukocytes and compete with [3H]-leukotriene B4 for binding to rat and human leukocyte leukotriene B4 receptors with varying efficacy. The analog in which the 12-hydroxyl group was removed was severely reduced both in agonist action (aggregation) and binding. The epimeric 12-hydroxyl analog demonstrated better agonist and binding properties than the analog without a hydroxyl at this position. In contrast, in the case of the 5-hydroxyl the epimeric hydroxyl analog had greatly reduced agonist and binding activities while the 5-deoxy analog demonstrated potency only several fold less than leukotriene B4 itself. The dideoxy leukotriene B4 analog was more than a thousand fold less active than leukotriene B4 as an agonist and in binding to the leukotriene B4 receptor. These results show that binding to the leukocyte leukotriene B4 receptor requires a hydroxyl group at the 12 position in either stereochemical orientation but that the presence of a hydroxyl at the 5 position is less important. However, the epimeric C5 leukotriene B4 analog clearly interacts unfavourably with the binding site of the leukotriene B4 receptor.

Animals↗
PubMed1986

Pattern of spread of bloodborne tumour.

The pattern of bloodborne tumour spread has been studied experimentally in syngeneic rats. A variety of tumour types has been injected intravenously, intraportally and also intra-arterially via the left ventricle. Tumour cell arrest as a factor in the localization of metastases in the lung following intravenous injection of cells, and in the liver following intraportal injection, is emphasized. Once tumour cells have entered the arterial circulation they disseminate to almost all organs in similar proportions to the distribution of cardiac output. The dissemination and arrest of cells is not found to correlate with the later distribution of metastases. For example, certain organs (especially the adrenals) which receive only low fractions of injected cells, are always preferred sites for bloodborne metastasis. A strikingly similar pattern of 'arterial metastasis' is also seen for all the tumours used despite their very different histological and biological natures.

Animals↗
PubMed1986

Perforation of the colon in the immunocompromised patient.

Perforation of the colon in the immunocompromised patient is a catastrophic and usually fatal event. The immunocompromised patient, like all patients, may suffer from the more common causes of colonic perforation, including diverticulitis, chronic inflammatory bowel disease, presence of a foreign body, and trauma. There also appears to be in these patients the unusual occurrence of spontaneous perforation, particularly in patients with renal allografts or on dialysis. In a retrospective multi-hospital review, 10 cases of apparent spontaneous perforation were found. The pathogenesis is unclear, but predisposing factors include immunosuppressive medications, uremia, discrete colon ulcerations, and fecal impaction. The reported mortality rate approaches 100 percent due to delayed recognition and impaired host defense mechanisms. In our patients, mortality was 40 percent. We attribute this improved survival to prompt surgical intervention and aggressive postoperative management, including daily dialysis, parenteral hyperalimentation, broad-spectrum antibiotics, and a high index of suspicion for ongoing sepsis with early repeat exploration.

Adult↗
PubMed1986

Gene for an immunoglobulin-binding protein from a group G streptococcus.

The gene (spg) for an immunoglobulin G (IgG)-binding protein from a Streptococcus clinical isolate of Lancefield group G was cloned and expressed in Escherichia coli. The complete nucleotide sequence of the gene and 5'-flanking sequences was determined. The DNA sequence includes an open reading frame which encodes a hypothetical protein of 448 amino acid residues (Mr = 47,595). The 5' end of this open reading frame encodes a sequence resembling a typical secretion signal sequence, and the remainder of the encoded protein has features reminiscent of staphylococcal protein A and of streptococcal M6 protein, including repeated sequences and a similar C-terminal structure. Aside from this C-terminal structure, the encoded protein has little direct amino acid sequence homology to either protein A or M6 protein. In E. coli, the cloned gene directs the synthesis of a protein which binds to immunoglobulins, including rabbit immunoglobulin, goat IgG, and human IgG3(lambda). Its binding properties are similar to those of the protein G described by Björck and Kronvall (L. Björck and G. Kronvall, J. Immunol. 133:969-974, 1984), a type III Fc receptor from a group G streptococcus.

Amino Acid Sequence↗
PubMed1985

Inhibition of growth and spontaneous metastasis of syngeneic transplantable tumors by an aromatic retinoic acid analogue. 1. Relationship between tumour immunogenicity and responsiveness.

Aromatic retinoic acid analogues selected for their favourable therapeutic ratios were tested for their effects on the growth (in vivo and in vitro) and spontaneous metastasis of a variety of murine sarcomas and carcinomas. Ro 10-1670 (a trimethylmethoxyphenyl analogue of retinoic acid) was used in in vitro studies, while its corresponding ethyl ester Ro 10-9359 was used for oral administration. Four of six fibrosarcomas, one of three squamous cell carcinomas, and one of five mammary adenocarcinomas responded to retinoid treatment in vivo by reduced growth rates (first detectable after 8-10 days), and in some cases by complete regression. The magnitude of the response was directly proportional to tumour immunogenicity, and eight tumours which failed to respond to retinoids did not evoke detectable transplantation immunity in syngeneic recipients. Retinoid administration did not significantly inhibit the development of spontaneous metastasis of non-immunogenic tumours, but decreased the incidence of secondary disease in the case of tumours of moderate immunogenicity. In vitro, retinoid treatments were generally without significant effects on tumour cell growth rate or morphology, and where growth inhibition was obtained it did not correlate with in vivo tumour responsiveness. No evidence of increased differentiation of retinoid-treated tumours was obtained either in vitro or in vivo. Taken together, the data suggest that in the 14 transplantable syngeneic tumours studied the inhibitory effects of retinoids on tumour growth and metastasis in vivo were mediated indirectly by potentiation of cell-mediated immunity directed against antigenic determinants on the tumour cell surface.

Animals↗
PubMed1985

Inhibition of growth and metastasis of syngeneic transplantable tumours by an aromatic retinoic acid analogue. 2. T cell dependence of retinoid effects in vivo.

An aromatic retinoic acid analogue (Ro 10-9359) previously shown to be capable of inhibiting the growth and metastasis of immunogenic sarcomas and carcinomas (see accompanying paper) was tested for its anti-tumour effects in various categories of immune-deprived mice. 'Non-specific' immunosuppression evoked by sub-lethal whole-body X-irradiation abolished the inhibition of tumour growth induced by Ro 10-9359 in immunocompetent syngeneic hosts. Also, retinoid treatment of three categories of T-lymphocyte-deprived mice (nu/nu; thymectomized-irradiated; and cyclosporin A-treated) was ineffective in reducing the local growth rate or inhibiting spontaneous metastasis of their tumours; in fact, regardless of retinoid treatment the tumours grew faster and metastasized more widely in immunosuppressed animals than in controls. Silica and carrageenan (which are toxic to mononuclear phagocytes) did not interfere with the inhibitory effects of Ro 10-9359 on tumour growth, and did not themselves potentiate metastasis; however, both agents prevented the abolition of DM6 carcinoma metastasis by retinoids. APD, which inhibits the 'accessory cell' function of macrophages did not reduce the effectiveness of Ro 10-9359 against local tumours. However, in contrast to silica and carrageenan this agent did increase the incidence of metastasis of DM6 carcinoma from 40% to 60%, but in the presence of retinoids only 20% of mice succumbed to secondary disease. These results suggest an essential role for T lymphocytes in retinoid-induced local tumour growth inhibition, and a further contribution of mononuclear phagocytes to the prevention of metastatic disease.

Animals↗
PubMed1985

Studies on the development of human acute myeloid leukaemia xenografts in immune-deprived mice: comparison with cells in short-term culture.

Human AML cells from the blood of a series of patients have been implanted subcutaneously into mice immune-suppressed by thymectomy and total-body irradiation. Solid tumours resulted from 18 out of 19 samples and their growth was compared with the proliferation of AML cells in culture. In 17 cases tumours grew to a maximum size and then spontaneously regressed. Cells from one patient produced tumours which did not regress and could be retransplanted into freshly immune-suppressed mice. Cells from a human promyelocytic cell line (HL60) also produced nonregressing and retransplantantable tumours. Normal human mononuclear bone marrow cells implanted s.c. produced a growth pattern similar to that of the majority of AML cells. A second inoculum of AML cells into animals with regressing tumours also produced tumours and thus regression cannot be accounted for on the basis of returning immunity. AML cells placed into short-term suspension culture invariably matured to monocyte/macrophage type cells and/or granulocytic cells as identified by cytochemical staining. However, no correlation was observed between proliferation or maturation of cells in culture, and tumour growth in vivo. Cells derived from disaggregated AML tumours also showed evidence of myeloid differentiation suggesting that tumour regression is due to maturation of leukaemic cells.

Animals↗