Antibody responses to membrane antigens in monkeys infected with Herpesvirus saimiri.

The antibody response to Herpesvirus saimiri (HSV)-induced membrane antigens (MA) was followed in HSV-infected owl monkeys using the membrane immunofluorescence (MF) and antibody-dependent lymphocyte cytotoxicity (ADLC) assays. These responses were correlated with the loss of T-cell responsiveness to general mitogens. Antibody titers to MA as determined by ADLC but not MF increased to remarkably high titers in those monkeys that developed malignant disease following virus infection, while remaining at relatively low and constant levels in those monkeys that developed a chronic virus infection in the absence of malignant disease. This disease-related antibody response pattern was paralleled by the loss of T-cell function in diseased animals. The development of leukemia in HVS-infected owl monkeys did not suppress the ability of peripheral blood lymphocytes to act as effector cells in the ADLC assay. The relationship of these immune response patterns to the development of malignant disease in this system is discussed.     

EB-virus associated serology in malignant disease: antibody levels to viral capsid antigens (VCA), membrane antigens (MA) and early antigens(EA) in patients with various neoplastic conditions

Two hundred and forty-nine sera derived from African donors suffering from a variety of malignant diseases were examined for EBV-related antibody levels. When divided into three major subgroups (lymphoproliferative tumours, carcinoma and sarcoma) none of the mean titres approached the high anti-VCA, anti-MA or anti-EA levels characteristic for Burkitt's lymphoma (BL) or nasopharyngeal carcinoma (NPC). On breaking down the material further into specific diagnostic or pathological subgroups, similar low mean values were found, except for small groups of plasma cell tumours and carcinomas of the palate (with high anti-VCA and anti-MA) and osteogenic sarcoma (with moderately high anti-MA). The data do not support a regular association of high anti-EBV titres with malignant disease in general and thus reaffirm the special position of BL and NPC in this respect.     

Effect of local radiotherapy on the antibody levels against EBV-induced early and capsid antigens (EA and VCA) in patients with certain malignant tumours

Antibodies to tumour-related and EBV-associated intracellular antigens were studied in 14 cases of Burkitt's lymphoma, 50 of nasopharyngeal carcinoma, 10 of maxillary carcinoma and 95 cases of other tumours, all of whom received radiotherapy in Nairobi. For up to 1 month after radiotherapy the cases of Burkitt's lymphoma recorded an increase in antibodies to early antigens (EA) amounting to, on average, about one titre step (p<0.001). During the same interval there was a small but significant increase in antibodies to viral capsid antigen (VCA) (mean 0.6 titre step; p<0.001). The patients with nasopharyngeal and maxillary carcinoma, too, showed a small but statistically significant increase in antibodies to VCA 2-6 months after radiotherapy (p<0.01 and 0.001, respectively), but no increase in antibodies to EA. On the contrary, in nasopharyngeal carcinoma patients there was a significant decrease in antibodies to EA 2-3 months after radiotherapy. In the group of other tumours there was no evidence of a change in antibodies to the intracellular antigens studied during any of the relevant intervals.     

Prevalence of antibody to adult T-cell leukemia virus-associated antigens (ATLA) in Japanese monkeys and other non-human primates

The prevalence of adult T-cell-leukemia virus (ATLV) infection was examined in Japanese monkeys living naturally in various parts of Japan and in other species of non-human primates imported into and kept in Japan. Sera of 2,650 Japanese monkeys from 41 troops throughout Japan were tested. High incidences of anti-ATLV-associated antigen (ATLA)-positive monkeys were found in most troops, not only in the endemic area of human ATL(Southwestern Japan), but also in non-endemic areas. The incidence of sero-positive individuals increased gradually with age, reaching a maximum when the animals became adult, indicating age dependency, like that found by epidemiological studies on humans. Anti-ATLA antibodies were also detected in 90 of 815 sera of imported non-human primates of 33 species other than Japanese monkeys. All the anti-ATLA sero-positive monkeys were Catarrhines (Old World monkeys), mainly macaques of Asian origin. Some sero-positive monkeys were also found among animals of African origin, but no antibody was detected in Prosimians and Platyrrhines (New World monkeys). The clear-cut difference between the geographical distribution of sero-positive simians and that of humans indicates the improbability of direct transmission of ATLV from simians to humans.     

Skin reactions to human papillomavirus (HPV) 16 specific antigens intradermally injected in healthy subjects and patients with cervical neoplasia

We have tested the safety and feasibility of a synthetic long peptide-based HPV16-specific skin test to detect cellular immune responses to HPV16 E2, E6 and E7 in vivo. Women with cervical neoplasia (n = 11) and healthy individuals (n = 19) were intradermally challenged with 8 different pools of HPV16 E2, E6 and E7 peptides. The skin test was safe as the injections were perceived as mildly painful and no adverse events were observed. The majority of skin reactions appeared significantly earlier in HPV16+ patients (<8 days) than in healthy subjects (8-25 days). The development of late skin reactions in healthy subjects was associated with the appearance of circulating HPV16-specific T cells and the infiltration of both HPV16-specific CD4+ Th1/Th2 and CD8+ T cells into the skin. These data show that the intradermal injection of pools of HPV16 synthetic long peptides is safe and results in the migration of HPV16-specific T cells into the skin as well as in an increase in the number of circulating HPV16-specific T cells. The use of this test to measure HPV16-specific immunity is currently tested in a low resource setting for the measurement of spontaneously induced T-cell responses as well as in our HPV16 vaccination trials for the detection of vaccine-induced immunity.     

Kaposi's sarcoma and its relationship to cytomegalovirus (CMV) III. CMV DNA and CMV early antigens in Kaposi's sarcoma

DNA-DNA reassociation kinetics, anti-complement immunofluorescence (ACIF) and ACIF-blocking tests were used to search for cytomegalovirus (CMV) gene products in Kaposi's sarcoma (KS) biopsies and early cell cultures deriving from them. Three of eight tumor biopsies were positive for CMV DNA; two of them at 0.35 genome/cell and one at one copy of 25% genome/cell. CMV-related antigens, mainly localized in the nucleus, were found in cryostat sections of seven of 31 tumor biopsies and four of 12 KS cell lines at early passage level. It appears that the antigen is present in a high number of tumor cells, like the Epstein-Barr virus nuclear antigen (EBNA) in EBV-transformed cells. Inevitably, the increasing data concerning the oncogenic potential of CMV lead on to consideration of the increasing evidence of its association with Kaposi's sarcoma, a multiple hemorrhagic sarcoma with an epidemiologic distribution in Africa similar to that of Burkitt's lymphoma.     

Pharmacokinetics and metabolism of O-(chloroacetyl-carbamoyl) fumagillol (TNP-470, AGM-1470) in rhesus monkeys

 The metabolic disposition and pharmacokinetics of TNP-470 were investigated in rhesus monkeys following intravenous administration of 5 mg/kg of [³H]-TNP-470. Rapid and extensive metabolism of parent drug to six metabolites occurred as demonstrated by the absence of unchanged drug in plasma and urine at time points as early as 6 min after administration. Substantial, yet variable, plasma levels of M-IV were detected in all three monkeys with a mean C_max value of 3.54μM. Five other metabolites, labeled M-I, M-II, M-III, M-V and M-VI, were also detected in biological fluids of monkeys. M-II, M-V and M-VI exhibited similar kinetic profiles with apparent plasma elimination half-life values of 0.91 ±0.37, 2.42 ±0.13 and 1.19 ±0.29 h respectively. In contrast, M-I, M-III and M-IV exhibited much shorter apparent plasma half-life values of 30 min or less. Urinary recovery within 36 h represented only 19.90±6.09% of the total administered dose. No radioactivity was detected beyond 36 h and during a 15-day sample collection period, suggesting that nonrenal (biliary) elimination of TNP-470 metabolites is a predominant excretion route in nonhuman primates. This study provides the first detailed in vivo analysis of TNP-470 metabolism and disposition using an animal model highly predictive of humans, consistent with the detection of the same TNP-470 metabolites in human tissues. A detailed understanding of TNP-470 metabolism and disposition is critical to fully elucidate the pharmacodynamic properties of this new anticancer drug as clinical investigations proceed. Received: 17 May 1995 / Accepted: 9 October 1995     

Expression of Lewis(a), Lewis(b), and sialated Lewis(a) antigens in early and advanced human gastric cancers

An immunohistochemical analysis of the expression of Lewis(a), Lewis(b), and sialated Lewis(a) blood group antigens was performed on specimens of human non-involved stomach (n = 91), early gastric cancers (n = 41), and advanced gastric cancers (n = 50). In non-involved stomach, Lewis(a) and Lewis(b) were detected mainly in surface epithelium, although sialated Lewis(a) was scarcely expressed. These blood group-related antigens were rarely observed in deep glands. In gastric cancers, Lewis(a) showed a tendency to be expressed in well or moderately differentiated carcinomas, and this was observed to be more marked in advanced tumors. There was no obvious difference in positive ratios of Lewis(b) between degrees of differentiation of the cancers. Sialated Lewis(a) was not detected in early cancers, and its frequent expression in well- or moderately differentiated, advanced carcinomas suggested an association with both cancer differentiation and progression. These results indicate that knowledge of the expression of blood group antigens may help interpret the antigenic alterations occurring in the course of carcinogenesis, differentiation, and progression of gastric cancers.     

Selective protection against cis-diamminedichloroplatinum(II)-induced toxicity in kidney, gut, and bone marrow by diethyldithiocarbamate

Diethyldithiocarbamate (DDTC) has been shown to inhibit nephrotoxicity induced by cis-platinum (DDP) without inhibition of tumor response in the rat. We report here that DDTC at doses of 25-300 mg/kg inhibits DDP-induced nephrotoxicity and bone marrow toxicity in C57BL/6 X DBA/2F1 (hereafter called B6D2F1) mice, F344 rats, and beagle dogs and is also antiemetic in the dog. DDTC doses which afford excellent protection do not decrease median survival time following DDP treatment in L1210 and P388 leukemias, B16 melanoma, and Lewis lung and colon 26 carcinomas in B6D2F1 mice when DDTC is given 2 h after DDP. Preliminary experiments indicate that DDTC does not alter median survival time after treatment of P388 leukemia with the platinum analogues diammine(1,1-cyclobutanedicarboxylato)platinum(II) and cis-diisopropylamine-cis-dichloro-trans-dihydroxyplatinum(IV ). Maximum blood urea nitrogen levels after DDP treatment are reduced significantly by DDTC in all species; blood urea nitrogen elevation, total kidney platinum, weight loss, and leukopenia correlate with DDP-DDTC interval in the rat and indicate optimum protection at 2 h, the shortest interval examined. Bone marrow toxicity was assessed by peripheral white blood cell counts in all species and by marrow cellularity in the mouse. White blood cell nadirs were higher and bone marrow recovered more rapidly after DDTC compared with DDP given alone. DDP reduced marrow cellularity 50-60% in the mouse; administration of DDTC 2 h after DDP afforded no protection to the lymphocytes in the marrow but maintained the granulocyte + precursor population near control levels. DDTC plasma pharmacokinetic values have been determined after s.c., i.p., and i.v. administration in the mouse, rat, and dog. Peak plasma levels of 0.3-1.2 mM are observed after a 250-mg/kg dose, with a plasma half-life of 10-20 min. Our data indicate that DDTC may provide protection against most clinically significant toxicities arising from cis-platinum at doses which do not inhibit tumor response.     

Infection with Kaposi's sarcoma-associated herpesvirus (KSHV) and human immunodeficiency virus (HIV) in relation to the risk and clinical presentation of Kaposi's sarcoma in Uganda

A case-control study from Uganda found that the risk of Kaposi's sarcoma increased with increasing titre of antibodies against Kaposi's sarcoma-associated herpesvirus (KSHV) latent nuclear antigens, independently of HIV infection. Clinically, widespread Kaposi's sarcoma was more frequent among patients with HIV infection than in those without, but was not related to anti-KSHV antibody titres.     

Response of T lymphocytes to phytohaemagglutinin (PHA) and to cancer-tissue-associated antigens, measured by the intracellular fluorescence polarization technique (SCM test).

Human peripheral-blood mononuclear cells, separated by Isopaque-Ficoll flotation and E-rosette formation, were tested by the fluorescein fluorescence polarization method of Cercek & Cercek (the SCM test). The response to stimulation with PHA or cancer tissue leads to a decreased polarization value TP). The responding cells were present in the T-cell fraction (E-rosette-forming cells), which contained less than 10% macrophages and less than 1% cells with surface-bound Ig. Control experiments with the non-T-cell fraction gave different response patterns. The response of T cells from apparently healthy donors and patients with and without cancer were compared. All of the group of 16 healthy persons had a polarization value (P) which decreased (mean +/- s.e. = 23% +/- 2) after PHA stimulation, compared with no or little decrease after stimulation with cancer tissue, giving cancer indices (P cancer/PPHA) of 1.15--1.56. In 13 patients with carcinoma of the colon, stimulation with PHA produced little decrease of polarization, while stimulation with colonic cancer tissue decreased the polarization in all cases (mean +/- s.e. = 25% +/- 2). The corresponding cancer indices were 0.61--0.86. Seven of 10 colonic-cancer patients tested against ovarian cancer tissue did not respond, whilst 3 patients in this group responded and had a cancer index less than 1.0. Three patients with non-malignant diseases had response patterns similar to those of healthy persons, except for the lack of PHA response in the patient with ulcerative colitis. This method seems to open up new possibilities for evaluation of cancer patients, although further studies including many more patients are needed before any conclusion can be drawn as to the validity of the test.     

Prospective Study of Antibody to Human Papilloma Virus type 16 and Risk of Cervical, Endometrial, and Ovarian Cancers (United States)

Objective: Human papilloma virus (HPV) is frequently detectable in cancers of the cervix, vagina, and vulva, but its role in endometrial and ovarian cancers is less certain. This analysis aimed to examine the association of presence of HPV type 16 (HPV-16) antibodies with subsequent risk of cervical, endometrial, and ovarian cancers. Methods: In a prospective study enrolling over 15,000 pregnant women, pre-cancer sera from women who developed cervical (n = 83), endometrial (n = 34), and ovarian (n = 35) cancers were compared with sera from 172 control women frequency-matched by age group and race. Results: HPV-16 seropositivity (OR = 2.0, 95% CI 1.0–3.4) was associated with cervical cancer, with the association more prominent for cancers occurring within 10 years of serum sampling (OR = 2.3, 95% CI 1.0–5.3) than cancers occurring later (OR = 1.6, 95% CI 0.75–3.6). Overall, the associations between HPV-16 seropositivity and endometrial (OR = 1.6, 95% CI 0.64–3.8) and ovarian cancers (OR = 1.1, 95% CI 0.43–2.8) were not significant, although the odds ratios for those cancers occurring within 20 years after serum sampling were similar to that for cervical cancer (OR = 2.2 for both). Conclusions: Our results confirm that HPV-16 infection precedes the development of cervical cancer. Predictability of HPV-16 seropositivity for risk of other female cancers warrants further investigation.