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Über die Wirkung von 4-Hydroxypentenal auf die nicht karzinomatös und die karzinomatös veränderte Portio uteri

Authors
Journal
Experimentelle Pathologie
0014-4908
Publisher
Elsevier
Publication Date
Volume
11
Identifiers
DOI: 10.1016/s0014-4908(75)80076-7
Keywords
  • 4-Hydroxypentenal
  • Portio Vaginalis Cervicis
  • Carcinoma Of The Cervix
  • Dna-Synthesis
  • Cancer Chemotherapy
  • Tumor
  • Cytostatic Compounds
  • Carcinoma In Situ
  • Cancer Of The Vulva
Disciplines
  • Biology
  • Chemistry
  • Ecology
  • Medicine

Abstract

Abstract Problem: 4-hydroxy-2,3-transpentenal (HPE) represents the 5-C-homologue of a series of hitherto unknown α,β-unsaturated aldehydes. The marked inhibition of DNA-biosynthesis by these chemical compounds, particularly by HPE, suggests blocking of mitosis by HPE due to direct action.on the S-phase. It is known that DNA-biosynthesis as well as energy metabolism are generally more disturbed by HPE in animal tumor cells (Ehrlich ascites and solid tumors, NK/Ly sarcoma 37, sarcoma 180, plasmocytoma G, murine Harding-Passey melanoma) than in normal cells (liver, kidney, jejunum, spleen, thymus); for details see Bickis et al. 1969; Rindler et al. 1970; Kapfer et al. 1972). After systemic administration of HPE the concentration of the cytotoxic agent in the blood caused a noticeable but merely selective inhibition of the metabolism in experimental animal tumors; however, it was not sufficient to produce therapeutic results. The low stability of HPE in the blood and in the peritoneal cavity is to be attributed to its affinity to SH-groups. Therefore the biological tests had to be confined to the local administration of HPE. In this histological study of the action of HPE the substance was administered directly to the human portio vaginalis uteri (ecto- and endocervix) in cases of carcinomatous alterations, in cases of non-carcinomatous affections as well as in normal portiones. Material and methods: In this test 42 women were treated with HPE. 3 patients were observed clinically only, the other 39 cases were investigated also histologically. The histological studies were performed on the extirpated uterus (36 cases), the resected portio (1 case) and only on a conus (2 cases). In 17 of these patients examined histologically the portio was clinically free of pathological symptoms. They suffered from such more or less commonplace gynecological disorders as displacement of the uterus, incontinentia urinae relativa, uterus myomatosus, endometriosis and cystical adnexal tumors. 7 patients suffered from ectopies, 8 from Ca colli uteri, 7 were affected by invasive cancer of the cervix. 8 of the patients were older than 50 years, the others were aged between 25 and 50 years. Mode of HPE administration: 1. Application of a small HPE-soaked linen patch fixed on a Sta Seal impression of the vagina (Sta Seal = dental silicon impression paste). 2. Application by means of a small linen patch, in a portio cap. The inner surface of a portio cap corresponding to the vaginal uterus in shape and size was coated with a circular linen, patch. The unneeded segment was cut off. After moistening with the aldehyde (HPE) it was fit tightly to the inner surface of the cap and, in situ, to the portio surface as well. In several cases the portio did not fill the cap completely and did not contact the tissue in the region of the os uteri. Consequently, there the aldehyde effect was lower than in the lateral regions of the portio. Therefore 3. the linen patch was mounted into a cap pessary containing the Sta Seal impression of the portio with all its superficial details. The HPE-soaked linen was gently pressed to the portio surface by the cap pessary partially filled with Sta Seal, provided that the pessary was exactly applied to the portio vaginalis cervicis. 4. Application of the aldehyde in Algin at pur (Fluka AG) in a portio cap. Alginate is a convenient carrier substance owing to its consistency which enables a coating of all structures of the portio surface. It penetrates to the external os uteri and can also be injected into the cervical canal with a syringe. 5. Application with a Dermo Jet. Injection of fluids into the skin with jet syringes usually does not injure the blood vessels. The depth of the effect and the distribution vary dependent on, the distance between the jet and the surface. At a small distance a minute jet penetrates to relatively deep layers of the tissue, at greater distance the fluid distribution is more superficial and its pattern resembles more or less a truncated cone. 6. Application by needle injections. The sucessful destruction of experimental animal tumors by circular injections of aldehyde solution ( Schauenstein and co-workers 1969, 1971a, b) initiated application of this technique to the portio as well. In our tests we used aqueous HPE-solutions of different concentration (101, 2% and 3%) or HPE in alginate gel (0.5 %, 3% and 5%). The portiones were locally treated with HPE by one of the techniques described above. During application by means of a small linen patch or in alginate gel (see 1-4 in table 1) the contact periods varied between 1 hour and 48 hours in the individual cases. At first the different times of application were intended to determine the duration of HPE's effectiveness. Later the period of application was never less than 3 hours. In some cases an abnormally long time of application was determined by external circumstances, i. e. by the night or by an irregular clinical schedule. HPE was administered once or subsequently up to 5 times. In one case (no. 39) HPE administration was repeated 13 times. The total duration of treatment varied between one hour and more than 7 days. Intervals from 42 hours up to 19 days between termination of HPE treatment and surgical intervention enabled different times of observation. In the majority of patients the termination of HPE treatment coincided with the extirpation of the uterus indicated by the primary gynecological disorder. The therapeutic effect of HPE was examined macroscopically, by colposcopy and, in nearly all cases, also histologically. Table 1 gives a survey of the techniques applied and of the frequency of HPE administration. The table is supplemented by one case of developed cancer of the vulva in a 84 years-old woman included in the discussion. Results: HPE causes severe tissue damage, which is not always linearly dependent on time and concentration, and which is followed by serous to necrotizing inflammation of the mucous membranes. Tissue death occurs quite uniformly in the normal and carcinomatous epithelium, the superficial parts of the tissue glands and the stroma, including blood vessels and connectivetissue cells. The slight cellular reaction accompanying the initial damage and the moderate suppuration in the paranecrotic demarcation zone, and further the rapid regeneration of the stroma and the cancerous and noncancerous epithelium with still extended necrosis, may be explained in part by the rapid metabolism of HPE. Repeated treatments with the convenient mode of application (aldehyde in alginate gel) led to successive tissue necroses to a depth of more than 9 mm. It was thus possible to destroy completely 2 of 8 carcinomas in situ restricted to the surface of the portio. 7 glandular ectopies and the 6 remaining carcinomas in situ which had grown deeply into the glands, in all 7 invasive cancers, could only be destroyed in the superficial layers owing to the limited depth of the effect of maximally 9 mm, and the pronounced inflammatory reaction. On the periphery of the total necrosis, i. e. in the inflammatory demarcation zone, marginal tissue damage could be observed which affected the cancerous epithelium alone and not the cellularly infiltrated stroma. This inconsistent necrosis and necrobiosis may be concentration dependent and extended only slightly, 1.5 mm maximally, beyond the total necrosis. In all, with the use of HPE on invasive cancers a favorable effect could not be obtained owing to the insufficient depth of the effect and the considerable regenerative capacity of the cancer.

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