Wiskott-Aldrich syndrome and Epstein-Barr virus-induced lymphoproliferation.
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Biomedical subjects
Publications and source records attributed to M Okano.
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A 6-year-old girl was admitted for cervical lymphadenopathy. She was diagnosed histologically as having Burkitt's lymphoma with partial involvement of follicles. Immunological study of a biopsy specimen demonstrated that many cells were surface immunoglobulin (lambda light chain)-positive, and chromosomal analysis revealed a translocation of (8;14) (q24;q32) in all blastic cells. Her serum antibody titers to Epstein-Barr virus (EBV) capsid antigen and to early antigen were 1:320 and 1:160, respectively, and most of the cells from the lymphoma biopsy specimen were EBV-associated nuclear antigen (EBNA)-positive. In addition, EBV DNA/DNA reassociation kinetic analysis showed 22 EBV genome equivalents per cell. Complete remission was obtained by CHOP therapy (consisting of cyclophosphamide, adriamycin, vincristine, and prednisolone) combined with cervical irradiation. She is in complete remission now (17 months after the onset).
A total of 24 patients with urothelial cancer were treated with a combination chemotherapy consisting of vincristine (1 mg, i.v., day 1), bleomycin (15 mg, or peplomycin, 10 mg, i.m. day 2), mitomycin-C (4 mg, i.v. day 3), tegafur (600-750 mg, p.o., every day) and OK-432 (2-4 KE, i.m., day 1, 3, 5). This one-week course was repeated for an average of 4.6 courses. Of these cases, 13 patients with early stage treated as adjuvant chemotherapy after radical operation showed strong suppressive effects against tumor recurrence or metastasis except 3 cases. However, in advanced cancer this regimen was less effective. Therefore, we modified this regimen: VCR 2mg and PEP, 10 mg on days 2, 4 and 6. This modified regimen was given to two patients and one showed partial response and I-A according to Karnofsky's criteria. Mild side effects such as slight leukopenia, fever up, gastrointestinal symptoms or alopecia were observed. These results suggest that this regimen could be used as an adjuvant chemotherapy after radical operation of urothelial malignancy for the purpose of protecting tumor recurrence or metastasis.
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A series of quassinoids were observed to be potent inhibitors of induced inflammation and arthritis in rodents. Brusatol afforded the most potent activity followed by brucein-D. A 3-hydroxy-delta 3-2-oxo moiety in brusatol or a 1-hydroxy-delta 3-2-oxo moiety in brucein-D, as well as a C-15 ester-bearing delta-lactone ring in brusatol and C-11 and C-12 free hydroxyl groups are required in both quassinoids for potent anti-inflammatory activity. Preliminary studies indicate that one of the modes of action of quassinoids as anti-inflammatory agents is to stabilize lysosomal membranes, reducing the release of hydrolytic enzymes that cause damage to surrounding tissues.
Serum prostate-specific antigen (PA), a new tumor marker of prostate cancer, was evaluated with an eznyme immunoassay (EIA) in various urologic cancer patients and benign prostatic diseases in Japanese. Sera of prostate cancer patients before treatment (n = 27) revealed a range of PA concentrations from 0.12-23 ng/ml with a mean (+/- SD) of 5.78 +/- 6.85 ng/ml, while that of patients with benign prostatic hypertrophy (BPH) (n = 27) showed from less than 0.10 to 2.6 ng/ml with 0.84 +/- 0.81 ng/ml (mean +/- SD). The mean serum PA levels in nonprostatic cancers were calculated as follows: bladder cancer (n - 21), 0.77 +/- 0.55 ng/ml; renal pelvis or ureteral cancer (n = 6), 0.46 +/- 0.47 ng/ml; renal adenocarcinoma (n equal to 6), 1.07 +/- 0.77 ng/ml; other urologic cancers (n = 6), 0.55 +/- 0.52 ng/ml. Serum PA ranged from less than 0.10 to 1.1 ng/ml in patients with prostatitis (n = 5). A significant statistical difference in serum PA levels between prostate cancer and other groups was recognized. These results suggested that an elevation of serum PA value was highly specific to prostate cancer in urological malignancies. The evaluation of serum PA may be of great value in the detection of prostate cancer.
The stratified squamous epithelium of the skin, the epidermis, is a renewing cell population. In order for epidermis to remain the same size, each dividing basal cell must produce on an average, one daughter cell that will remain as a germinative cell and another that will perform terminal differentiation (differential mitosis). In order to investigate cell kinetics in the epidermis, the information obtained from in vivo study is limited, and offers only indirect evidence for the determination of cell cycle time and cell proliferation pattern. Keratinocytes in cell culture are unique in formation of a multilayered cellular sheet in which the keratinocytes form a structure resembling the epidermis in vivo, and keratinize at the top. In the early days of the primary culture of human keratinocytes, when the cells proliferate to form a monolayer sheet, direct access to cell proliferation pattern and measurement of interdivision time can be done using techniques of time-lapse cinemicrography. The primary cultures at 8-20 days of incubation were employed for cinemicrographic observation when small polygonal cells appeared in groups, when numerous mitotic figures were observed, and when stratification of the cells had not yet occurred. The appropriate field was marked and followed for up to 6 days. Photographic prints were made from the 16 mm cine film, and dendrograms were made and analyzed for pattern of cell proliferation and interdivision time. Most cells in the field divided two or three times during the period of observation. Sister-sister pairs of the second and third generations divided after approximately the same interdivision times. However, some cells have never divided. Some of the sister-sister pairs differed considerably in their interdivision times. In some cultures synchronous division was quite evident. The average interdivision time was about 26 hr in the majority of cultures, and it is suggested that the estimated long cell cycle time in vivo might be overestimated due to the existence of non-cycling cells in the germinative population.
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With an enzyme-labeled antibody technique, prostate antigen (PA) was studied immunohistochemically. PA was found to localize at epithelial cells and secretary materials in the lumen of prostatic tissue regardless of histological type. However, PA could not be detected in the interstitial area of the prostate. This technique may become useful for detection of local extension or distant metastasis of prostate cancer. An immunoelectronmicroscopical study of PA is now underway.
Peplomycin, a new derivative of Bleomycin, was evaluated clinically for treatment of prostate cancer patients. Peplomycin was injected intramuscularly, 5 or 10 mg every other day, to 8 patients with prostate cancer. Total dose ranged from 30 to 200 mg. According to Karnofsky's criteria, only one case was I-B, other cases were in group 0. Pulmonary fibrosis, one of the major side effects of this drug, was experienced in 2 cases. This anticancer agent was injected directly into the prostate, 20 mg once a week for 5 weeks, to 2 patients who were refractory to estrogen treatment and had lower urinary obstruction for relief of local symptoms. One case was I-A, and the other was I-B. No severe side effect was observed. Serum concentration of Peplomycin after administration was measured by a bioassay. Serum levels of Peplomycin after a local injection of 20 mg and after one intravenous shot of 10 mg were almost equal.
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Herein we report a case of primary paraganglioma of the urinary bladder. A 21-year-old woman was admitted to an emergency hospital, because of gross hematuria, dysuria and complete urinary retention. Pelvic CT scan and ultrasonic examination revealed a bladder tumor and coagulated blood mass, then she was referred to our clinic for further treatment. On cystoscopy a dark brown lobular tumor was seen on the anterior wall. The bladder tumor was removed by partial cystectomy. The operative specimen measured 6 X 4 X 3 cm and weighed 50 g. Histological examination showed it to be a paraganglioma of the urinary bladder, which was chromaffin positive. Her serum and urinary catecholamine level were within the normal range after operation. She is now ten months postoperative, free from hematuria, and showing no other symptoms or signs of disease including metastasis.
Bisbrusatolyl malonate, which was shown previously to be active against P-388 lymphocytic leukemia cell growth, was investigated for inhibitory effects on nucleic acid and protein synthesis. DNA and RNA synthesis as well as protein synthesis were markedly inhibited at 10,25, and 50 mu mole final concentrations in vitro. The major sites of inhibition of nucleic acid synthesis appeared to be DNA polymerase, messenger and transfer RNA polymerases, orotidine-5'-monophosphate decarboxylase, phosphoribosyl pyrophosphate amino transferase, and dihydrofolate reductase. Moderate inhibition of nucleotide kinase activities and oxidative phosphorylation processes occurred after drug treatment. Cyclic adenosine monophosphate levels were reduced. Protein synthesis was inhibited during the elongation step of peptide synthesis. The data suggested that bisbrusatolyl malonate interfered with the peptide bond formation. However, the ongoing polypeptide synthesis must be completed before the drug can bind to the ribosome effectively.
A series of new bisbrusatolyl and brusatolyl esters and related compounds were synthesized and tested for in vivo antileukemia activity against a quassinoid sensitive strain of P-388 lymphocytic leukemia in BDF1 mice. The bisbrusatolyl malonate, succinate, glutarate, adipate, and sebacate were as active or more active than brusatol. The C-3 esters of brusatol and bruceantin were also found to be as active or more active than brusatol or bruceantin in general. The free hydroxyl groups at C-11 and C-12 as well as the enone double bond in ring A of both bisbrusatolyl and brusatolyl esters are required for antileukemic activity. The presence of a double bond in the ester side chain contributes to the enhanced activity of these esters.
A series of esters of brusatol, bisbrusatol, and bruceantin were shown to have potent antileukemic activity. Antineoplastic activity was correlated with the ability of the compounds to suppress DNA and protein synthesis in P-388 lymphocytic leukemia cells. Compounds with high T/C% values successfully inhibited DNA polymerase activity and purine synthesis. The ability to inhibit protein synthesis during the elongation process also correlated positively with high antileukemic activity in this series of quassinoids. Dihydrofolate reductase activity and basal and adenosine diphosphate stimulated respiration of P-388 cells were also inhibited.