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J Wennerberg

Publications and source records attributed to J Wennerberg.

At least 55 records · Page 3Linked to original sources
PubMed1995

Radiation effects on S-phase duration, labelling index, potential doubling time and DNA distribution in head and neck cancer xenografts.

The effect of irradiation on S-phase duration (Ts), labelling index (LI), potential doubling time (Tpot), and cell cycle phase distributions was determined by DNA flow cytometry in xenografted human squamous cell carcinoma of the head and neck (SCCHN). Tumours were treated with a single dose of 3 Gy, and excised at intervals over a 90-h period. Six hours before each excision the tumours were labelled in vivo with bromodeoxyuridine (BrdUrd). Although the growth rate of irradiated tumours was comparable with that of untreated controls, analysis of BrdUrd uptake revealed a transient reduction of LI and a prolongation of Ts in irradiated tumours. Maximum mean Tpot was 931 days in irradiated tumours as compared to 13 days in untreated controls. The variations in Ts, LI and Tpot all occurred within the first hours after irradiation; during the remainder of the observation time, the values of the variables did not differ from those of untreated controls. In irradiated tumours the distribution of cells according to DNA content changed significantly on three occasions during the observation period: 1) Parallel to the initial lowering of LI and prolongation of Ts there was a transient increase in the proportion of cells in G0/G1 and a decrease in the proportion of cells in S and G2; 2) At 18 h, the most pronounced cell cycle phase redistribution occurred when the G0/G1 fraction decreased and the S and G2 phase fractions increased; 3) At 66 h (i.e., approximately one cell cycle later), the pattern was the same as that after 18 h. The findings suggest that the transient prolongation of DNA replication seen in SCCHN cells immediately after a single radiation dose is a symptom of DNA damage inflicted during late G1 or early S-phase, and that this disturbance in DNA synthesis is associated with the subsequent accumulation of cells in G2 phase.

Animals↗
PubMed1994

Characteristic karyotypic features in lacrimal and salivary gland carcinomas.

Short-term cultures from 12 non-squamous cell carcinomas (NSCCs) of the head and neck were cytogenetically investigated. Three tumours were acinic cell carcinomas, two adenoid cystic carcinomas, three mucoepidermoid carcinomas, two carcinomas in pleomorphic adenoma, and two adenocarcinomas. Clonal chromosome aberrations were detected in all but one adenocarcinoma. Including our data, a total of 40 head and neck NSCCs with clonal aberrations have been described. Deletions of the long arm of chromosome 6 are the most common aberrations (11/40 cases); they have been detected in all types of NSCC except carcinoma in pleomorphic adenoma. Two aberrations seem to be closely associated with tumour type: t(6;9)(q21-24;p13-23), which has been seen in three of 11 adenoid cystic carcinomas (in two as the sole aberration), and structural rearrangements of 8q12-13, which have been detected in three of four carcinomas in pleomorphic adenoma.

Adenocarcinoma↗
PubMed1993

Chromosome abnormalities in eighty-three head and neck squamous cell carcinomas: influence of culture conditions on karyotypic pattern.

Short-term cultures from 115 squamous cell carcinomas (SCC) of the head and neck were cytogenetically investigated. Thirty-six of the tumors have been reported previously, whereas 79 are new cases. The material was divided into two series based on the medium used. The 80 tumors of series I were cultured in RPMI 1640 supplemented with fetal calf serum, glutamine, antibiotics, insulin, cholera toxin, and epidermal growth factor. The 35 tumors of series II were cultured in a chemically defined, serum-free medium with a low calcium concentration, MCDB 153, which stimulates epithelial growth while inhibiting fibroblasts. A total of 83 tumors with clonal karyotypic abnormalities were detected in the two series. Series II had a higher proportion of tumors with complex karyotypic changes than series I (43% versus 15%), a lower proportion of tumors with pseudo- or neardiploid clones characterized by simple rearrangements (3% versus 34%), and a lower frequency of unrelated clones (3% versus 24%), indicating that the different culture conditions favored growth of different cell populations. Except for rearrangements of 1p22, which were mainly found in series I, the distribution of breakpoints in structural aberrations was similar in the two series and clustered to several chromosomal bands or regions, in particular 11q13, 1p22, 1p11-12, 3p11-q11, 5q13, 1q25, 15q10, and 8q10. Unbalanced structural aberrations were more common in series II, frequently leading to loss of segments from chromosome arms 3p, 7q, 8p, 11q, 13p, 14p, and 15p, whereas gain of genetic material often involved chromosome arms 1q, 3q, 8q, and 15q.

Aged↗
PubMed1993

DNA analysis as a predictor of the outcome of induction chemotherapy in advanced head and neck carcinomas.

We investigated whether flow cytometric DNA index and/or ploidy status are predictors of response to chemotherapy and survival. Fifty consecutive patients with previously untreated locally advanced squamous cell carcinomas of the head and neck received induction chemotherapy consisting of three courses of cisplatin (100 mg/m2) and a subsequent 120-hour infusion of fluorouracil (1000 mg/m2 per 24 hours) repeated every 3 weeks. Chemotherapy was followed by radiotherapy to a median target dose of 65 Gy and subsequent surgery for residual tumor. The median observation time was 27 months (range, 24 to 57 months). Flow cytometric DNA analysis was based on formalin-fixed and paraffin-embedded tissue from pretreatment tumor biopsy specimens. Complete response after induction chemotherapy was achieved in only 12% (2/17) of patients with diploid tumors compared with 39% (13/33) of those with nondiploid tumors. Among patients with nondiploid tumors, DNA index was higher for those responding to chemotherapy compared with the nonresponders. Complete response to chemotherapy was apparently a prerequisite for survival in the nondiploid group. Of the patients not responding to chemotherapy but responding to subsequent radiotherapy, survival was better among those with diploid tumors than among those with nondiploid tumors.

Adult↗
PubMed1993

T3N0 glottic carcinoma: DNA S-phase as a predictor of the outcome after radiotherapy.

In consecutive series of 326 laryngeal cancer patients, of 29 (9%) with stage T3N0 glottic carcinomas, 23 achieved complete local remission after curative radiotherapy and form the basis of the present investigation. Flow cytometry determinations of DNA-ploidy status and the S-phase fraction, and a "histopathological malignancy grading system" were evaluated as possible patient- and/or tumor-related predictors of local recurrence. Twelve patients (52%) were continuously disease-free after radiotherapy, whereas 10 (43%) manifested local recurrence, and one distant metastasis. The radiotherapy delivered to patients who later suffered from a local recurrence did not differ from those being continuously disease-free. The frequency of local recurrence was significantly correlated to patients whose primary tumours manifested a low S-phase fraction (p < 0.05). A low S-phase fraction may indicate slowly proliferating tumour-cells, which become more radioresistant on exposure to a series of fractionated doses, as their reassortment into sensitive phases will be proportionately slower.

Adult↗
PubMed1992

Comparison of BrdUrd and [3H]TdR incorporation to estimate cell proliferation, cell loss, and potential doubling time in tumor xenografts.

In this study, two different methods of estimating cell proliferation were compared: cell loss and potential growth rate of xenografted head and neck cancer grown in nude mice based on the detection of DNA incorporation of bromodeoxyuridine (BrdUrd) in one method, and [3H]thymidine ([3H]TdR) in the other. The 21-d-old xenografts were labelled in vivo, either with BrdUrd or [3H]TdR and excised at intervals during 65.5 h. In tumors containing BrdUrd, the percent labelling was measured in mid-S and mid-G1 phase windows of cytograms from bivariate DNA flow cytometry (FCM). In [3H]TdR-labelled tumors, the percent labelled mitoses (PLM) was determined by light microscopy evaluation of autoradiographs. With a computer program based on a theoretical model, the percent labelling versus time after injection was used to analyze cell cycle time, cell loss, tumor growth fraction, and potential doubling time. The values calculated from DNA incorporation with BrdUrd agreed well with those obtained from labelling with [3H]TdR, i.e., cell cycle time 2.3 vs. 2.4 d, and growth fraction 67 vs. 70%. The estimated potential doubling time was 3.1 d and cell loss factor 40% by both methods. Flow cytometry analysis of BrdUrd-labelling is considerably faster than the evaluation of [3H]TdR-labelling, and the present results provide further support for the BrdUrd labelling method as a promising alternative to the PLM method in cell cycle studies designed to evaluate the relevance of cell proliferative properties in relation to biological behavior in xenografted head and neck cancer.

Animals↗
PubMed1992

Clonal structural chromosome aberrations in nonneoplastic cells of the skin and upper aerodigestive tract.

Cytogenetic analyses of tumors of the skin and upper aerodigestive tract have repeatedly revealed small, pseudodiploid clones characterized by balanced structural rearrangements and a high frequency of cells with nonclonal structural aberrations. However, the lack of common cytogenetic denominators within the different histologic subtypes, the discrepancy between cytogenetic findings and data obtained from flow cytometric DNA content studies, and the occasional identification of tumors with massively rearranged karyotypes indicate that the chromosome rearrangements present in pseudodiploid cells have little to do with the tumorigenesis or progression. Further support for this conclusion, and indirect evidence that the pseudolipid clones probably do not represent the tumor cell populations, derives from the present study in which clonal and nonclonal structural rearrangements were also found in short-term cultures from nonneoplastic skin and pharyngeal mucosa. It is possible that the aberrations are present in subepithelial fibroblast that have accumulated DNA damage due to extensive exposure to potentially carcinogenic agents.

Adult↗
PubMed1992

Near-haploid clones in a malignant fibrous histiocytoma.

Near-haploid solid tumors are very rare. In a storiform-pleomorphic malignant fibrous histiocytoma (MFH) of bone, we found three cell populations: one with a near-haploid, a second with a near-diploid, and a third with a near-tetraploid chromosome number. The near-haploid cells had few structural rearrangements: i(12p) and t(13q21q) in one clone, and these two and an additional t(19;?)(p11;?) in another clone. One structurally normal copy of all chromosomes was also present, except that the only chromosome 13 was involved in the t(13q21q). There were also two near-diploid clones, one without the t(19;?) and one with a single copy of this derivative chromosome. This is the first tumor with i(12p) among bone and soft tissue tumors.

Chromosome Inversion↗
PubMed1992

Growth of xenografted squamous cell carcinoma of the head and neck--possible correlation with patient survival.

Tumor biopsies from 100 cases of squamous cell carcinoma of the head and neck (HNSCC) were xenografted to athymic nude mice. To ascertain whether xenograft take might be a factor of clinical significance, it was compared with patient survival, the patients being divided into two groups (take and non-take) according to the results of transplantation. The tumor take rate was 29%. Median survival time with respect to cancer death was 18 months in the take group, as compared with over 74 months in the non-take group (p = 0.06). No significant differences were observed between the two groups with respect to age, tumor size, nodal status, clinical stage or histological differentiation. The findings suggest that take of HNSCC xenografts in nude mice may reflect the malignant potential of the original tumor. Moreover, the possibility cannot be excluded of a selection bias favoring the use of such malignant xenografts in therapeutic studies in nude mice.

Animals↗
PubMed1992

Normal tissue reactions in mice after combined treatment with metoclopramide and ionizing radiation.

We have previously shown that metoclopramide potentiates the effect of ionizing radiation and cisplatin treatment of human squamous cell carcinomas from the head and neck region xenografted to nude mice. In the present tumor study, the dose scheduling of metoclopramide in combination with radiation was evaluated, and metoclopramide was shown to be most effective in potentiating the cytotoxic effect of radiation when administered one hour before radiation. The effect of radiation in combination with metoclopramide on normal tissue was also studied in two well-established models. Acute skin reactions to radiation exposure were studied in 129-type mice, and metoclopramide did not enhance the acute skin reaction in this in vivo model. Survival after whole body irradiation was studied in heterozygote Balb/c nu/+ mice as a measure of bone marrow toxicity. Metoclopramide was not found to affect the LD50/30 in this in vivo model. The absence of potentiation of radiation damage to normal tissue in these animal studies, makes metoclopramide an interesting possibility for future clinical evaluation.

Animals↗
PubMed1991

Cytogenetic analysis of 33 basal cell carcinomas.

Cytogenetic analysis of short-term cultures from 33 basal cell carcinomas (BCC), a type of neoplasm for which no previous karyological data exist, revealed clonal chromosome aberrations, all of them different, in 8 tumors. In 2 cases, 2 cytogenetically unrelated clones were detected, suggesting a multicellular origin in at least a subset of BCC. A remarkably high level of nonclonal structural rearrangements, mostly in the form of seemingly balanced translocations, was found in 23 tumors; namely, in 6 of 8 BCC with clonal karyotypic abnormalities and in 17 of 25 without. It is possible that some of these aberrations represent additional neoplastic clones, thus indicating an even higher level of cytogenetic heterogeneity in BCC. We think that the most likely interpretation of the results is that BCC may have a multicellular origin, reflecting field cancerization of the skin. During subsequent tumor development, the selection pressure narrows down the number of clones that infiltrate the surrounding tissue. The finding by karyotypic analysis of some apparently monoclonal, some polyclonal BCC, may reflect that different tumors have been examined at different points in the clonal evolution of the neoplastic cells.

Aged↗
PubMed1991

Rearrangement of 9p13 as the primary chromosomal aberration in adenoid cystic carcinoma of the respiratory tract.

Two adenoid cystic carcinomas, one of the nasal cavity, the other a bronchial tumor, were cytogenetically analyzed. The former had a t(6;9)(q21-22;p 13-21) as the sole karyotypic abnormality. The latter had two related abnormal clones, resulting in the mosaic karyotype 46,XY,t(9;17)(p13;p13)/46,Y,t(X;6)(p22;q23),t(9;17)(p13;p13). The karyotypic profiles of the two cases, the only respiratory tract adenoid cystic carcinomas that have been cytogenetically characterized, differ little from those of previously reported adenoid cystic carcinomas of the major salivary glands, underscoring the fundamental biologic similarity among these tumors even when they develop from different structures and in different anatomical sites and organs. Because in the second case the t(9;17) obviously must have preceded the t(X;6), we conclude that both tumors had rearrangement of 9p13 as the primary cytogenetic change. The data thus add to the evidence that 6q changes are frequent, albeit at least sometimes secondary, aberrations in malignant salivary gland tumors. A subset of adenoid cystic carcinomas instead have rearrangement of 9p as the primary, and presumably pathogenetically essential, abnormality.

Adult↗
PubMed1991

Dose schedule evaluation of metoclopramide as a potentiator of cisplatin and carboplatin treatments of xenografted squamous cell carcinomas of the head and neck.

The potentiating effect of metoclopramide on the tumor growth inhibition of cisplatin has been studied on human squamous cell carcinomas xenografted to nude mice. In this system, the optimal time interval for intraperitoneal administration of metoclopramide was 8 h after intraperitoneal administration of cisplatin. The optimal single dose level of metoclopramide in this study was 2 mg/kg. Metoclopramide enhanced the cytotoxic effect of cisplatin at all cisplatin doses tested between 2.5 and 7.5 mg/kg body weight. Under experimental conditions that gave optimal sensitization of cisplatin-induced cytotoxicity, there was no potentiation of the cytotoxic effect with metoclopramide in combination with carboplatin. There is great similarity in the cytotoxic action of cisplatin and carboplatin, with the main difference being a much slower rate of formation of DNA crosslink formation following carboplatin exposure. Hence the data reported here support an important role for the kinetics of formation and reparability of DNA damage as part of the mechanism of metoclopramide sensitization of platinum-containing drugs.

Animals↗
PubMed1991

Growth of xenografted head and neck cancer in nude mice pre-treated with whole body irradiation.

In an attempt to enhance the primary acceptance rate of human squamous cell carcinoma of the head and neck (HNSCC), nude mice (BALB/c) were given whole body irradiation (WBI) prior to heterotransplantation of tumour specimens. A total of 27 fresh HNSCC biopsies were transplanted, with a take rate of 15%. No difference in primary tumour acceptance rate was found between irradiated and non-irradiated mice. Only one of the accepted tumours established growth both in irradiated and non-irradiated mice. In a second experiment, three previously established tumour lines of HNSCC were re-transplanted to irradiated and non-irradiated mice. As compared with non-irradiated mice, the growth rate was lower in all tumours transplanted to irradiated mice, the difference being statistically significant in two out of the three tumour lines. The results of the study show that attempted immunosuppression by WBI of nude mice prior to tumour implantation does not improve the growth conditions of HNSCC. These findings further emphasise the complexity of the transplantation barrier against human tumour xenografts in nude mice.

Animals↗
PubMed1991

Induction chemotherapy (cisplatin + 5-fluorouracil) and radiotherapy in advanced squamous cell carcinoma of the head and neck.

A phase II study was made of 58 consecutive patients with previously untreated locally advanced squamous cell carcinomas of the head and neck. The induction chemotherapy consisted of 3 courses of cisplatin (100 mg/m2) and a subsequent 120-h infusion of 5-fluorouracil (1,000 mg/m2/24 h) repeated every 3 weeks. It was followed by radiotherapy to a median target dose of 66 Gy and surgery for residual tumour. A total of 91 per cent received all 3 courses of chemotherapy, which was well tolerated. Complete response (CR) was obtained in 20 patients (35%) after chemotherapy and in 40 patients (69%) after subsequent radiotherapy. The median observation time was 28 months (range 15-57). The actuarial survival at 2 years for complete responders to chemotherapy was 83 per cent, implying a prolonged survival (p = 0.002) compared to those with less than CR. Complete responders after chemotherapy had also a significantly longer recurrence-free survival, though 19 out of 20 did not undergo surgery. Complete response after this induction therapy is thus an important prognostic predictor.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Squamous cell carcinoma of the head and neck heterotransplanted to nude mice. Take rate in relation to patient survival.

Biopsy specimens from 62 human single primary squamous cell carcinomas (SCC) of the head and neck were xenografted into nude mice. To evaluate the prognostic significance of successful heterotransplantation, the 62 cases were retrospectively examined for survival, adjusting for possible confounders by multivariate analysis. The recorded take rate in the first passage was 24%. Median survival in the take group was 25 months versus 74 months in the nontake group, which is not statistically significant in this material. However, the numerical difference in survival between the take groups is in accordance with the concept that human tumors accepted as xenografts on nude mice may constitute a selected group of malignancies. This has to be considered when using heterotransplanted human tumors for in vivo investigations of SCC of the head and neck.

Aged↗
PubMed1990

Cisplatin-fluorouracil interaction in a squamous cell carcinoma xenograft.

Patients with squamous cell carcinoma of the head and neck are treated with cisplatin and fluorouracil according to a schedule based on the findings of clinical studies. A similar schedule showed a supra-additive effect in the treatment of xenografted human squamous cell carcinoma of the head and neck. We sought to ascertain whether this schedule was optimal. A single intraperitoneal injection of cisplatin (7.5 mg/kg) was combined with three injections of fluorouracil given during a 24-hour period (total dose, 150 or 80 mg/kg) before, during, or after cisplatin administration. The combined effect of cisplatin and fluorouracil on tumor growth and toxic effects was schedule dependent. Consideration of both toxic effects and tumor growth inhibition, as assessed by reduction of the area under the growth curve, the optimal administration interval was found to be fluorouracil given 3 days after cisplatin administration.

Animals↗