Biomedical subjects
Publications and source records attributed to U Ringborg.
Some basic principles of adjuvant chemotherapy are discussed as mode of action, molecular mechanisms, drug resistance, patient selection, and early and late toxicity. It is assumed that in the future improved methods for selecting patients will increase the possibilities to cure patients with micrometastases of solid tumors by adjuvant chemotherapy.
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This study was based on 15,376 patients in Sweden with cutaneous malignant melanoma diagnosed during the 25-year period 1960-1984. Trunk melanoma increased substantially during that period among men, with age-standardized rates rising from 1.1 to 7.0 per 10(5). Among women, the greatest increases occurred in melanoma of the upper extremity (rising from 0.4 to 2.3), lower extremity (rising from 1.6 to 4.4), and trunk (rising form 0.6 to 3.1), but the rates for the latter two sites seemed to level off after 1978. Multivariate analyses showed that models based on a common parameter ("drift"), including linear birth cohort and/or time periods effects, were significantly superior to simple age models for explaining incidence trends for each separate site. Further, in men with melanoma of the trunk and upper and lower extremities, birth cohort effects had significant effects compared with drift. In contrast, in women, time period effects were a significant improvement on drift for melanoma of the trunk and lower extremity. The relative risk of malignant melanoma among men leveled off in later-born cohorts for all separate sites. A similar trend was found in women, except for melanomas of the trunk, in which the increase in relative risk persisted. The results indicate sex-specific differences in temporal trends of exposure to factors causing malignant melanoma.
Dacarbazine-vindesine-cisplatin treatment was evaluated in a phase II study of patients with disseminated malignant melanoma after the dose of cisplatin had been determined in a phase I study. Dose of dacarbazine was 250 mg/m2 X V every 4 weeks, vindesine 3 mg/m2 once every week, and cisplatin 100 mg/m2 every 4 weeks. Forty patients with advanced disseminated malignant melanoma are available for response. Complete remissions were obtained in three patients (8%) and partial remissions in 12 patients (30%). The total response rate was 38%. Median response duration was 4 months. Toxicity was unacceptable in five cases (nephrotoxicity, one patient; ototoxicity, two patients; hypotonia, one patient; gastrointestinal toxicity, one patient). The conclusion is that the combination dacarbazine-vindesine-cisplatin gives rise to a high response rate in patients with advanced disseminated malignant melanoma. Despite its considerable toxicity, the regimen should be tested on patients with a limited tumor burden.
The interaction of 5-fluorouracil (5-FU) and cisplatin (CDDP) was studied in Bp8 ascites sarcoma cells growing in mice. By density gradient centrifugation in Percoll solution, non-viable cells were separated from viable cells. Single drug treatment with doses of 12 and 36 mg/kg body weight of 5-FU and 0.4 and 0.8 mg/kg body weight of CDDP did not yield non-viable cells during the time period studied (96 h). Combination of the drugs increased the non-viable cells to about 10-25% depending on the doses given. This indicates a supra-additive cytotoxic effect. Analysis of the distribution of viable cells in the different cell cycle phases by flow cytometry showed an accumulation of cells in the S-phase after 5-FU and in the S- and G2-phases of the CDDP or combined 5-FU-CDDP treatment. Similar analysis of non-viable cells showed a similar cell cycle distribution, which suggests that supra-additive cytotoxicity is not cell cycle specific. By labeling the DNA of the tumor cells with [125T]-deoxyuridine and using whole body measurement, the cell loss was studied. No changes in cells loss after single drug and combined treatment were found during the observation time. The molecular basis for the interaction between 5-FU and CDDP should be elucidated.
A case-control study of cutaneous malignant melanoma (CMM) was based on 523 incident cases and 505 age- and sex-matched controls selected from the general population. The purpose was to investigate the relative risk of developing CMM associated with different sun habits and indicators of pigmentation, such as skin type, eye colour and hair colour. Compared to people with black hair, blonde subjects had a relative risk of 74.4 (95% confidence interval, 45.8-120.8). Associations with skin type and eye colour were considerably weaker. Relative risks of about 1.5-2.5 were found for certain sun habits. The results suggest that in a population of Caucasian origin with a predominantly fair complexion, pigmentary status characterized by hair colour is a far more important aetiological factor than sun habits.
The anatomical location of the squamous cell carcinoma (SCCA) within the oral cavity and oropharynx influenced the association of SCCA with the biomarker in vitro hyperdiploidy in human dermal fibroblast cultures (IVH). There was a strong association of IVH with the occurrence of SCCA in the anterior 2/3 of the tongue, floor of the mouth and lower alveolar ridge of the oral cavity and in the base of the tongue and pharyngeal wall of the oropharynx. There was a lower association of SCCA with IVH in the tonsillar region of the oropharynx. IVH showed no association with SCCA located in other anatomical parts of the oral region. The patient group whose diagnosis of SCCA in the anterior 2/3 of the tongue occurred prior to the age of 50 years were invariably IVH-, whereas those diagnosed after the age of 50 years were IVH+, providing evidence for heterogeneity. There was no such correlation of biomarker subgrouping with age of diagnosis demonstrated for SCCA at any other anatomical location within the oral cavity or oropharynx.
Glutathione is the most abundant low molecular mass thiol in human cells. It is involved in the inactivation of genotoxic electrophilic compounds, and a variety of glutathione-linked enzymes catalyze such detoxication reactions. Within this group, the enzymes occurring in highest intracellular concentrations are the glutathione transferases, which catalyze the detoxication of a broad spectrum of alkylating and oxidizing compounds such as epoxides, reactive alkenes and organic hydroperoxides. Multiple forms of glutathione transferase with distinct substrate specificities exist, and their differential expression in cells contributes to differences in detoxication capacities in tissues. Glyoxalase I catalyzes the inactivation of 2-oxoaldehydes and may also be considered as part of the cellular detoxication system. Characterization of the different enzymes and their differential expression in normal and tumor cells will help to clarify their cellular functions and their significance to human cancer. Clear differences in the occurrence of the various enzyme forms in normal and tumor cells have been demonstrated and variations between different tumors appear to be linked to their degree of resistance to alkylating cytostatic drugs. Modulation of catalytic activities in vitro by administration of enzyme inhibitors may help to overcome this resistance.
Trends in incidence of and mortality and survival from malignant melanoma in Sweden for 1960 through 1982 were analyzed. Incidence rates increased annually by 5.4% for females and by 5.8% for males, whereas mortality rates increased annually by 2.7% for females and 3.3% for males. For females, the 5-year relative survival (RS) rates increased by approximately 15 percentage points before 1970. In contrast, males before 1970 had a successive improvement in RS rates of 4.6-8.2 percentage points for each 5-year period of diagnosis. Multivariate analyses revealed that during the study period the malignant melanoma-specific hazard decreased by 71% [95% confidence interval (CI) = 59%-79%] for females and by 64% (95% CI = 54%-73%) for males during the first 5 years of follow-up.
In a phase II study 119 patients with disseminated malignant melanoma were randomized to receive treatment with dacarbazine alone or in combination with vindesine. The study was designed to reveal an additive response rate when the drugs were combined. Dacarbazine was given i.v. at 250 mg m-2 per day X V every 4 weeks. In the combination regimen vindesine given at 3 mg m-2 per week was included. One hundred and ten patients were available for evaluation of response. With dacarbazine 4/51 patients obtained a complete remission (8%) and 5/51 patients a partial remission (10%). Overall response rate was 18%. With dacarbazine-vindesine 8/59 patients obtained a complete remission (13%) and 7/59 patients a partial remission (12%). Overall response rate was 25%. The difference in response rates observed between the treatment arms is not statistically significant. Median response duration was 123 days for dacarbazine patients and 171 days for patients receiving dacarbazine-vindesine (difference not statistically significant).
The relationship between site and survival in cutaneous malignant melanoma was investigated by a follow-up of 12,353 Swedish patients diagnosed in 1960-1982. In males, the poorest prognosis was found for tumors located on the scalp-neck region (5-year relative survival rate, RS51%), followed by the lower extremity (RS66%) and trunk (RS68%). Among females, the poorest prognosis was noted for tumors located on the external ear (5-year RS 71%), trunk (RS 78%) and scalp-neck (RS 78%). The prognosis varied considerably between the sites of the head-neck region--for eyelid and facial lesions the prognosis was good, but for external ear and scalp-neck tumors it was poor. Multivariate analysis taking into account age and year of diagnosis showed the highest relative hazards (RH) for female lesions of the trunk (1.40) and male scalp-neck tumors (1.65), with the upper extremity used as reference (RH = 1.00). Except for lesions of the trunk, no significant differences in RH were found between the various sites after 4 years of observation.
From January 1981 to February 1986, a total of 240 patients with primary, malignancy-grade III or IV soft tissue sarcoma were entered into an adjuvant chemotherapy multicenter trial conducted by the Scandinavian Sarcoma Group (SSG). Of these patients, 181 were evaluable. The tumor was located in the extremities in 155 patients. After radical surgery (wide and compartmental) the patients were randomized to treatment with single-agent doxorubicin 60 mg/m2 administered as an intravenous (IV) bolus once a month for 9 months (group 1, n = 77) or to control (group 2, n = 77). If the surgical procedure was marginal, the patients initially received postoperative radiotherapy, followed by doxorubicin (group 3, n = 16) or control (group 4, n = 11). The control groups did not receive any adjuvant chemotherapy. Adjuvant therapy was initiated within 6 weeks of surgery (group 1) or within 10 weeks of surgery for patients receiving postoperative radiotherapy (group 3). With a median follow-up of 40 months, there was no significant difference between the four treatment groups in overall survival (group 1, 75%; group 2, 70%; group 3, 69%; group 4, 73%), disease-free survival (group 1, 62%; group 2, 56%; group 3, 62%; group 4, 64%), or local tumor control (group 1, 92%; group 2, 92%; group 3, 87%; group 4, 90%). The conclusions were the same whether the total group or evaluable patients only were included in the analysis. The local recurrence rate for patients undergoing radical surgery was 8% and for patients undergoing marginal surgery followed by radiotherapy was 12%. This study indicates that the use of single-agent doxorubicin as postoperative adjuvant chemotherapy has no significant clinical benefit in patients with high-grade soft tissue sarcoma.
124 patients with keloids were treated with surgical excision followed by postoperative X-ray radiation, begun within 24 hours after surgery. Only patients with a two-year keloid history were included in this study. The treatment results were evaluated 6 and 24 months after treatment. There was good correlation agreement between subjective and objective evaluations. Good or excellent results were observed in 92% of the patients. Side effects were moderate. Slight hyperpigmentation was found in 31% of the patients and telangiectasis in 15%. It was concluded that excision and early postoperative irradiation constitute effective keloid treatment.
The effects of D,L-buthionine-S,R-sulfoximine (BSO) on cytotoxicity and DNA cross-linking induced by bifunctional DNA-reactive cytostatic agents in a human melanoma cell line (RPMI 8322) were investigated. RPMI 8322 cells were exposed to 0.01 mM BSO for 24 h, which resulted in a decrease in cellular glutathione to 14% without any reduction of cell proliferation or plating efficiency. BSO pretreatment significantly enhanced cytotoxicity of melphalan with a dose modification factor (DMF) of 3.4 and nitrogen mustard (HN2) (DMF 3.3). The increased cytotoxicity was paralleled by similar increases in DNA cross-linking (melphalan: DMF 2.2, HN2: DNF 2.5). A small but significant potentiation by BSO of cis-diamminedichloroplatinum(II) toxicity was seen (DMF 1.5), with a corresponding minor but significant increase in DNA cross-linking (DMF 1.1). Similarly, the potentiation of bis-chloroethylnitrosurea toxicity was small but significant (DMF 1.1), with no significant increase in DNA cross-linking (DMF 1.0). No effect of BSO pretreatment on the rate of removal of HN2-induced DNA cross-links was observed. Thus, the observed sensitization of RPMI 8322 cells to melphalan, HN2, cis-diamminedichloroplatinum(II), and bis-chloroethylnitrosourea was correlated to similar changes in drug-induced DNA cross-linking. Despite the increased cytotoxicity and DNA cross-linking BSO did not significantly increase the intracellular concentration of intact melphalan. These findings support the hypothesis that the potentiation of the cytotoxicity of bifunctional alkylating agents by BSO is due to an increased DNA cross-linking caused by a reduced intracellular conjugation of drug with glutathione, which results in an increased binding of drug to DNA targets.
Peripheral lymphoblasts were exposed either to different initial concentrations of the alkylating agents (melphalan, chlorambucil or phenylacetic acid mustard) using a fixed incubation time or a constant [3H]methylthymidine incorporation into the trichloracetic acid-insoluble fraction of the cells. The concentration-time relationships were evaluated by calculating the amount of drug which had chemically reacted in the incubation system. Melphalan showed lower cytotoxicity at short exposure times and high drug concentrations, while chlorambucil exhibited higher cytotoxicity at longer exposure times. In the latter case the effect could be accounted for by the cytotoxic activity of monohydroxy chlorambucil which was formed in the incubation system.
The cytotoxic effect of cis-diamminedichloroplatinum(II) (cis-DDP), as measured by a dye exclusion assay was much more pronounced in bone marrow cells and phytohemagglutinin (PHA)-stimulated lymphocytes than in a human melanoma cell line. DNA synthesis measured by incorporation of 3H-thymidine was much more sensitive to cis-DDP in PHA-stimulated lymphocytes than in melanoma cells. These differences were not caused by a difference in drug accumulation since measurements of cellular platinum content gave similar results in both cell types. The total amount of DNA cross-links and DNA interstrand cross-links induced by cis-DDP was measured with alkaline elution of DNA. In both PHA-stimulated lymphocytes and melanoma cells low total levels of DNA cross-links and DNA interstrand cross-links were found immediately after drug exposure, followed by a protracted increase in DNA cross-linking for 6-12 hours during further incubation after removal of cis-DDP. The relationship between the concentration of cis-DDP and peak levels of total DNA cross-links as well as DNA interstrand cross-links was linear in both cell types. Cis-DDP was found to induce 5.6 times higher total levels of DNA cross-links 6.1 times higher levels of DNA interstrand cross-links in PHA-stimulated lymphocytes than in melanoma cells. The incorporation of 3H-thymidine was much more reduced in PHA-stimulated lymphocytes than in melanoma cells at similar levels of DNA cross-linking. Thus, both reduced DNA cross-linking and lower effect of DNA cross-links on the DNA synthesis may contribute to the greater resistance of melanoma cells to cis-DDP.
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The formation and removal of nitrogen mustard (HN2)- and melphalan-induced DNA cross-links (DNA interstrand and DNA-protein cross-links) in a human melanoma cell line (RPMI 8322), as determined by alkaline elution of DNA, was compared and related to the cytotoxic effect of each drug. HN2 was considerably more cytotoxic than melphalan as determined by inhibition of colony formation. Immediately following exposure to HN2 maximum levels of DNA cross-links were found. Melphalan, in contrast, caused a protracted induction of DNA cross-links with maximum levels obtained 6-12 h following drug exposure. HN2 induced approximately 13 times higher peak levels of DNA cross-links compared to equal concentrations of melphalan. Removal of DNA cross-links following exposure to both drugs followed an exponential time course. The rate of removal of HN2-induced DNA cross-links was, however, 1.5-2.4 times more rapid than that of melphalan-induced cross-links. A strong correlation was obtained between the cytotoxicity of both drugs and the total area under the curve for DNA interstrand cross-links, indicating that both the initial induction of as well as the rate of removal of DNA interstrand cross-links are important for the cytotoxic effects of bifunctional alkylating agents.