Influence of some cytostatic drugs on semiconservative DNA-synthesis and DNA-repair in normal and cancer cells (author's transl)]

The action of cyclophosphamide, vincristine, vinblastine and procarbacine on the enzymes of the excision repair and on the semiconservative DNA-synthesis was investigated. To get a view of the total repair enzyme complexes the incorporation of 3H-thymidine into DNA after UV- and Gamma-irradiation was measured, and sedimentation profiles in alkaline sucrose were carried out. The drugs were also tested after being metabolized. The 4 drugs had no influence in an in vitro system on DNA-repair using spleen cells. Vinblastine and procarbacine showed an inhibitory effect on semiconservative DNA-synthesis. Using Yoshida ascites cells for the investigations we found an inhibition of the exonuclease-polymerase system by cyclophosphamide and procarbacine and a supression of ligase reaction by vinblastine and vincristine. Different degrees of inhibition of DNA-synthesis in Yoshida ascites cells could be seen after use of the 4 cytostatic drugs.     

Chirurgische Therapieoptionen nach Extravasaten systemischer Chemotherapie

Introduction

Extravasal application of chemotherapeutic agents may cause necrosis of the surrounding tissue. Often tendons, nerves and muscles are destroyed. In some cases, a surgical excision with additional coverage is indicated.

Surgical treatment

We report on 29 patients with necrosis after extravasation. In most cases, the lesion was localized to the hand or distal forearm, but the cubital fossa and thorax were also affected. Excision of the infiltrated tissue was performed and covered with local or free flaps, a split skin graft or primary closure.

Complications

Stable coverage was achieved in all cases. Patients with immunosuppression or comorbidity sometimes had wound healing difficulties. There were no important complications, such as flap necrosis, septicemia or infection.

Discussion

Chemotherapeutic extravasation is an important oncological complication that may cause permanent functional disability to the anatomical region involved. A variety of free and local flaps with tolerable donor morbidity can be used for coverage. Conservative treatment is often followed by a high rate of complications. Early radical debridement and coverage with an adequate flap offers a cure.     

Patupilone (epothilone B, EPO906) inhibits growth and metastasis of experimental prostate tumors in vivo

BACKGROUND: Microtubule agents appear promising for the treatment of prostate cancer. Patupilone (epothilone B), a highly potent non-taxane microtubule stabilizing agent, was evaluated in models of androgen-independent prostate cancer. METHODS: Patupilone was administered to athymic mice bearing human prostate cancer xenografts (subcutaneous DU 145 and PC-3M, orthotopic PC-3M). RESULTS: One 4 mg/kg patupilone administration produced transient regression of DU 145 tumors, while two weekly administrations of 2.5 mg/kg produced stable disease followed by protracted regression, however with more pronounced body weight loss. Taxol (15 mg/kg every other day) weakly inhibited tumor growth, but with less body weight loss. Patupilone (5 mg/kg) produced protracted growth inhibition of subcutaneous PC-3M tumors, with transient body weight loss. In mice with orthotopic PC-3M tumors, 4 or 5 mg/kg/week patupilone impaired primary tumor growth, abrogated metastases and enhanced survival, with only transient body weight loss. CONCLUSIONS: These data suggest that patupilone holds promise for prostate cancer treatment.     

Kr-81m ventilation imaging: clinical utility in suspected pulmonary embolism

The results of Kr-81m/Tc-99m ventilation-perfusion (VP) lung scintigraphy were correlated with the results of pulmonary angiography for 74 patients suspected of having pulmonary embolism (PE). Among patients having a diagnostic scan, the sensitivity and specificity of scintigraphy were 91% and 94%, respectively. Also, 157 consecutive cases of Kr-81m/Tc-99m VP lung scintigraphy were reviewed, and the frequency of an indeterminate scan was found to be 22%. A similar frequency was found for VP scintigraphy with xenon-133. Of eight patients who had indeterminate scans due to the presence of a single VP mismatch, four were demonstrated to have PE by angiography. Kr-81m is an excellent agent for VP scanning in cases of suspected PE, offering accuracy in diagnosis as well as favorable physical properties.     

Morphometric study of the rat duodenal epithelium during the initial six months of 1,2-dimethylhydrazine carcinogenesis

Male Wistar rats weighing 100 g received 1,2-dimethylhydrazine (25 mg/kg) s.c.) twice a week for 2 months and once a week thereafter for an additional 4 months. Groups of four to six rats were sacrificed monthly. Paraffin sections of duodenum were prepared and stained with periodic acid-Schiff and hematoxylin for cell counts and with toluidine blue for measuring nucleolar area. As an index of villus size and crypt size, the mean number of epithelial cells per representative sections of villi and crypts were used. Mitotic activity was assessed by counting the mean number of mitotic figures per representative crypt section. Nucleolar area was assessed from the analysis of drawn (camera lucida) images of nucleoli of columnar cells at six levels of the epithelium: lower, mid, and upper parts of the crypts and villi. Villus size increased progressively during the 6-month treatment, from 272 +/- 2 (S.E.) to 349 +/- 8. Crypt size increased from 118 +/- 2 in a wavy fashion, showing maximum (139 +/- 5, 143 +/- 2) at 3 and 6 months and minimum (123 +/- 3, 127 +/- 1) at 1 and 4 months. Mitotic number displayed a similar pattern of increase so that the percentage of mitotic figures in the crypts (mitotic index) remained constant (about 5%) in control and experimental animals. Nucleolar area in the controls decreased with age from 4.2 +/- 0.08 sq micron in lower crypt at 1 month to 2.8 +/- 0.04 sq micron at 6 months. During 1,2-dimethylhydrazine treatment, lower crypt nucleoli increased to 4.5 +/- 0.12 sq micron after 3 months and decreased slightly thereafter, reaching 4.0 +/- 0.14 sq micron by the sixth month. The nucleoli furthermore decreased gradually along epithelium (nucleolar compaction) by an average of 0.23% per cell position in control as well as treated animals. It appeared, then, that the main effect of 1,2-dimethylhydrazine was the enlarging of the four parameters measured. This effect seemed to relate in some manner to tumor formation as all the enlargements were attenuated in intestinal tissue adjacent to tumors.     

Spread of T lymphocyte immune responses to myelin epitopes with duration of multiple sclerosis

Although the primary cause of multiple sclerosis (MS) is unclear, evidence supports a role for autoimmune attack of myelin by T lymphocytes. However, it has been difficult to relate patterns of autoimmunity to pathogenesis. In mouse models, the case has been made for relapsing and remitting disease driven by epitope spread: an initial lesion leads to presentation of central nervous system antigens, in turn triggering the next wave of autoimmune T cells of different specificity, the response thus broadening. Few studies have been done to determine whether these events could be important over the longer time scale of human disease. We compared T cell responses with a panel of myelin epitopes in clinically isolated syndrome patients with a first attack, patients with MS with a mean disease duration of 0.95 years, and patients with MS having a mean disease duration of 15.9 years. T cells from patients with long-term disease recognize more myelin epitopes than patients with recent-onset disease. The epitope myelin basic protein 131-149, in particular, was more commonly recognized by patients with long-term disease. The data support the notion that the T cell response in MS broadens with time and is thus implicated in the ongoing pathogenic process. However, there was no clear correlation between disease severity and number of epitopes recognized. This may argue against a simple causal role of epitope spread in driving progression, as has been suggested in experimental allergic encephalomyelitis.