Scand.J. Dent. Res. 1978: 86: 346-356 (Key words: incisor; odontoblasts; rat; vincristine)

Effect of vincristine on odontoblasts in rat incisor TORBJORN STENE Department of Pathology, Dental Faculty, University of Oslo, Oslo, Norway

ABSTRACT- Vincristine in doses of 0.1, 0.3, 0.5 and 0.7 mg/kg was administered to 60 rats in four groups. Histomorphologic investigation of the odontoblast population in the maxillary incisors revealed dose-dependent reactions consisting of (1) swelling of the odontoblasts and an accumulation of abnormal mitotic cells in the germinative parts ofthe pulp after 5 h, (2) a supervening necrosis and destrucdon of some odontoblasts and ofthe mitotic cells after 24 h, and (3) after 3 d, a reversal to normal structure in some parts ofthe odontoblast population, but a further development ofthe vincristine-induced changes, with severe cellular derangement and irregular predentin production, in others. (Accepted for publication 27 April 1978)

The vinca-alkaloids vincristine (VCR) and vinblastine (VBL) are widely used antitumor agents. They are catharanthinevindoline dimers and belong to the microtubule-poisons. Biochemical and ultrastructural studies have shown that VCR and VBL interact with tubulinmolecules. These are complex protein subunits of microtubules, and in some cell types the alkaloids cause them to aggregate into large cytoplasmatic crystalloid structures (WiLSON 1975), with the effect that the number of normal microtubules within the cells diminishes

stopped in metaphase, which assumes abnormal appearances in the light microscope (KLENER 1974), secretory activity diminishes (EKHOLM et al. 1974,

(EKHOLM, ERICSON, JOSEFSSON & MELANDER 1974, KOVACS, HORVATH, SZABO, DZAU, FELDMAN, CHANG & REYNOLDS 1974, KOVACS, HORVATH, SZABO, DZAU, CHANG, FELDMAN ^&; REYNOLDS 1975). As a result, cellular

1975) indicate that the alkaloids interfere with other cellular mechanisms as well. A previously published report on the effects of VCR on the dentinogenesis in the rat incisor indicated that this drug has varied and dose-dependent effects on several stages in the dentinogenesis (STENE ?c KOPPANG 1976). The purpose of the

functions dependent on the microtubules suffer; cells in mitosis are irreversibly

CHERTOW,

BUSCHMANN 8C HENDERSON

19 75), and cell motility and shape change (KLENER 1974). Some ofthe effects caused by VCR and VBL cannot be explained by interaction with the microtubules alone; inhibition of collagen and general protein synthesis (EHRLICH, ROSS & BORNSTEIN 1974) and increased autophagic activity as well as necrotic changes (HiRSlMAKi, ARSTILA

^

TRUMP

1975,

NEVALAINEN

VINCRISTINE AND ODONTOBLASTS AIE

ASE

Fig. 1. Schematic presentation of longitudinal section of maxillary incisor from rat showing the different sectors of the odontoblast layer. Dotted lines indicate position and direction of transversal sections. AIE, acid insoluble enamel. ASE, acid soluble enamel. D, dentin. P, pulp. A, apically. I, incisally.

present study was to investigate the immediate effects of various doses of VCR on the odontoblast population in the rat incisor, in order to find out which stages in the differentiation and function of these cells are most sensitive to the drug.

Material and methods Of 75 female Wistar rats with a mean weight of 185 g, 60 constituted the experimental group, and the remaining 15 served as controls. The experimental animals were divided in four groups of 15 animals (Groups I-IV), and each animal received a single intravenous injection of VCR (Oncovin®, Lilly) dissolved in bacteriostatic sodium chloride solution (Diluting Solution for Oncovin®, Lilly). The animals in Group I received 0.1 mg/kg, those in Group II 0.3 mg/kg, those in Group III 0.5 mg/kg, and the animals in Group IV 0.7 mg/kg. The injected volume was 0.5 ml/200 g body weight, -fhe control animals received the equivalent volume of pure diluting solution. Five animals from each experimental group and five from the control group were decapitated under ether anesthesia after 5 h, after 24 h and after 3 d. The heads were divided by a midline incision, and the maxillae were freed from soft tissue and immediately fixed in 496 aqueous formaldehyde. After demineralization in an aqueous solution prepared from equal amounts of 4496 formic

347

acid and 2096 sodium citrate, the specimens were embedded in paraffin, and 80-120, 5-nmthick longitudinal sections were cut from each maxillary right incisor and stained with hematoxylin-eosin. Also, the maxillary left incisor from one animal from each of Groups 11, III and IV decapitated after 24 h and from one animal from each of the same groups decapitated after 3 d were cut transversally at three different apico-incisal levels, as indicated in Fig. 1, and 10-20, 5-nm-thick, hematoxylineosin-stained sections from all three levels were prepared. The sections were investigated by light microscopy.

Results THE CONTROL ANIMALS

A varying morphology of the odontoblasts at different apico-incisal levels of the incisors from the control animals made it possible to divide the odontoblast population into five labial longitudinal and four lingual longitudinal sectors (Fig. 1). Labial sector 1 extended from the apical end of the odontogenic epithehum and incisally to the point where dentin production started. In this sector the mesenchymal cells in the pulp differentiate into early and late, cuboidal to columnar preodontoblasts (Fig. 2). Labial sector 2 included the young and late mantle dentin-producing odontoblasts and extended incisally approximately to the level where the enamel production started. The odontoblasts in this sector were columnar and ot even length, and most of them had a clearly visible negative Golgi-image (Fig. 3). Labial sector 3 extended from sector 2 to a level approximately 1 mm apically to where the enamel turned acid soluble. The odontoblasts were tall columnar but of somewhat uneven length (Fig. 4). Labial sector 4 extended incisally about 1 mm past the level where the enamel

STENE

348 W

M

^^

«

Fig. 3. Odontoblasts (O) in labial sector 2 in control animal decapitated after 5 h. OE, odontogenic epithelium. P, pulp. I, incisally. H &E, xl60.

D Fig-. 2. Longitudinal section from labial sector 1 in control animal decapitated after 5 h. PO, preodontoblasts. P, pulp. OE, odontogenic epithelium. I, incisally. H & E, xl60.

turned acid soluble. The odontoblasts were of even length and somewhat wavy. Pulpal to the odontoblasts a distinct cellrich zone was seen. Labial sector 5 included the entire odontoblast population incisal to sector 4; the odontoblasts were taller and their cytoplasm was more granular and stained less intensively than those in sector 4. The cell-rich zone was well developed. Lingual sectors 1 and 2 were analogous to labial sectors 1 and 2, but their apicoincisal length was smaller. Lingual sector 3 extended from sector 2 to approximately where the dentin had twice the width of the predentin. The odontoblasts were of uneven length, as in labial sector 3, but they were generally shorter than those in labial sector 3. Lingual sector 4

Fig. 4. Odontoblasts (O) in labial sector 3 in control animal decapitated after 5 h. D, dentin. P, pulp. I, incisally. H & E, xl60.

VINCRISTINE AND ODONTOBLASTS

349

included the whole odontoblast population incisal to sector 3; the odontoblasts were tall columnar and of even length, but they stained less intensively and were more granular than those in sector 8. The cell-rich zone was poorly developed. These features were observed in all control animals after 5 h, 24 h, and 3 d. However, the intercellular spaces between the odontoblasts in labial and lingual sectors 2 and 3 in three control animals decapitated after 24 h were dilated, and the odontoblasts were dark and somewhat compressed. The same change, but less pronounced, was also seen in labial sector 4.

VCR-INJECTED ANIMALS

The observed effects of VCR on the odontoblasts in the different sectors were varied and both dose- and timedependent. Labial sector i-After 5 h an accumulation of mitotic cells was observed in the pulp in labial sector 1 in all experimental groups. The majority of these were in metaphase, and their mitotic figures were abnormal in that they showed irregular or ring-shaped distribution of their chromosomes (Fig. 5). Some metaphases were also observed among the cuboidal and columnar, juxtaepithelial preodontoblasts. The number of metaphases increased with increasing doses of VCR, and in Group IV animals (0.7 mg/kg VCR) the pulp tissue was replete with them. After 24 h only minor effects were observed in the animals from Group I (0.1 mg/kg VCR); the only difference from the control animals sacrificed after 24 h was the presence of a few abnormal metaphase cells. Their number was, however, smaller than after 5 h. In the

Fig. 3. Longitudinal section from labial sector 1 in animal injected with 0.3 mg/kg VCR 5 h prior to sacrifice. Note the abnormal metaphase cells in pulp and among preodontoblasts (arrows). PO, preodontoblasts. P, pulp. OE, odontogenic epithelium. I, incisally. H & E, xl60.

incisors from Groups II, III and IV marked changes were observed; there was disintegration of the tissue and a pronounced edema in an area of the pulp strictly confined to sector 1 (Fig. 6), and in and around this edematous area there were numerous necrotic cells and metaphases. The normally neady aligned preodontoblasts had disappeared, and the incisal limit of the part of this area that involved the preodontoblasts was very distinct; the mantle dentin-producing odontoblasts in labial sector 2 were clearly recognizable. Serial longitudinal sections as well as transversal sections in this region revealed that the edematous area

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Fig. 7. Hydropic changes in majority of odontoblasts (0) in labial sector 2, 5 h after injection of 0.7 mg/kg VCR. OE, odontogenic epithelium. P, pulp. I, incisally. H & E, xl60.

effect on the odontoblasts in labial sector 2. Higher doses, however, had marked effects; after 5 h an increasing number of odontoblasts became progressively paler, wider and more granular with increasing doses of VCR, and in the Group IV animals (0.7 mg/kg VCR) the majority of /""jg. 6A. Longitudinal section to show the them exhibited these hydropic changes edematous area in labial sector 1, 24 h after injection of 0.5 mg/kg VCR. B, transversal (Fig. 7). After 24 h the effect of VCR was section from the same region to show the difficult to ascertain. As in the controls medio-lateral extension of the area. OE, decapitated after 24 h, the odontoblasts odontogenic epithelium. P, pulp. A, were separated by dilated intercellular edematous area. I, incisally. L, laterally. H & spaces, and some of them therefore E, x25. looked compressed. The hydropic changes seen after 5 h were not observed. Thus, extended approximately halfway down the the odontoblasts in this sector seemed to medial and lateral aspects of the teeth, be unaffected by VCR 24 h after and that its pulpal extension was smallest administration. in the median plane (Fig. 6). Three days after the injection of VCR After 3 d the pulp and the pre- the odontoblasts in the Group II animals odontoblasts in the median part of the (0.3 mg/kg VCR) appeared slightly swollen sector appeared normal. However, in and hydropic. The two highest doses (0.5 Groups II, III and IV the remains of the and 0.7 mg/kg VCR) produced the same edematous area observed after 24 h were changes in the median region of the still recognizable laterally and medially, sector, but laterally and medially the but the tissue surrounding these appeared odontoblasts were more severely changed. normal and contained no necrotic or They were short, irregular and pyknotic, and some of them were markedly swollen mitotic cells. Labial sector 2-0.1 mg/kg VCR had no (Fig. 8). Pulpal to these cells an irregular

VINCRISTINE AND ODONTOBLASTS

351

,* r -*

fi^. (?. Longitudinal section from lateral part of labial sector 2 in animal sacrificed 3 d after injection of 0.5 mg/kg VCR. Note the degenerated odontoblasts (0) and predentinoid tissue (PT) in the pulp (P). I, incisally. H & E, X160.

mass of an eosinophilic, homogeneous or slighdy fibrous substance containing round and ovoid, degenerated cells, was seen. Its structure and staining properties were similar to those of predentin. In two of the animals from Group III (0.5 mg/kg VCR) and in two from Group IV (0.7 mg/kg VCR) diese changes also involved the apical part of the median region of the sector. Labial sector J - The effects of VCR on the odontoblasts in this sector were in some ways similar to those in labial sector 2. No observable changes were produced by 0.1 mg/kg VCR. After 5 h a slight increase in the granularity of the odontoblasts' cytoplasm was observed in Groups II and III, whereas the odontoblasts in the Group IV animals (0.7 mg/kg VCR) were markedly changed. They were paler and considerably more granular than in the controls, and most of them had a clear, basal, perinuclear halo (Fig. 9). After 24 h enlarged intercellular spaces, similar to those in the control animals, were seen between the odontoblasts in all the experimental groups. These seemed to

Fig. 9. Pale, swollen and granular odontoblasts (0) in labial sector 3, 5 h after injection of 0.7 mg/kg VCR (cf. Fig. 4). I, incisally. H & E, xl60.

increase in size and number with increasing doses of VCR, and the odontoblasts looked dark and wavy in the incisors from Groups I, II and III. In Group IV, however, the intercellular spaces were less conspicuous and the odontoblasts looked like those in the Group IV animals decapitated after 5 h; in addition, some cuboidal and apolar cells were observed close to the predentin. In Groups III and IV necrotic cells were also seen among the odontoblasts and in the peripheral part of the pulp. After 3 d no changes were seen in the apical part of the sector in any of the experimental groups. In the incisal twothirds, however, there were severe derangements in the odontoblasts after

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STENE

PD

Fig. 10. Longitudinal section from lateral part of labial sector 5 in animal sacrificed 3 d after injection of 0.5 mg/kg VCR, with irregular predentin (PD) and a zone of predentinoid tissue (PT) in the odontoblast layer. 0, odontoblasts. I, ineisally. H & E, xl60.

injection of the three highest doses of VCR. In the Group II animals (0.3 mg/kg VCR) the median region of the sector was morphologically similar to the controls, but towards the lateral and medial aspects of the teeth the pulpal border of the predentin was uneven, with round, globular masses protruding between the apical parts of some of the odontoblasts. The dentinal tubules were twisted and irregular, and the predentin contained inclusions with necrotic and degenerated cells. In association with these irregularities swollen, granular and apolar odontoblasts were seen. The majority of the odontoblasts were, however, morphologically normal. Further laterally and medially the changes were more pronounced; the predentin was irregular as described and bordered pulpally by pale, irregular and short columnar odontoblasts with hydropic and pyknotic changes. Between and pulpal to these cells a zone of predentinoid tissue was seen, and the odontoblasts pulpal to this were dark and separated by numerous small vacuoles

Fig. 11. Transversal section from incisal part of labial sector 3 in animal decapitated 3 d after injection of 0.7 mg/kg VCR. The derangements, with irregular predentin and abnormal odontoblasts, are seen to involve the median as well as the lateral (L) and medial (M) regions of the sector. T, tearing artefact. E, enamel. D, dentin. O, odontoblasts. H &: E, x25.

(Fig. 10). The Group III animals (0.5 mg/kg VCR) exhibited the same derangements, but the irregularities were seen closer to the median plane of the incisors, and hence the median zone ofthe sector without changes was narrower. In two of the animals from Group IV (0.7 mg/kg VCR) the derangements even involved the median part of the sector (Fig. 11), whereas the remaining three animals from this Group showed changes similar to those in Group III in addition to a few small irregularities in the predentin in the median part of the sector. These were, however, few and separated by wide areas of normal structure. Labial sectors 4 and 5 - After 5 h a slight

swelling of the odontoblasts was evident in labial sectors 4 and 5 in the incisors from Groups III and IV (0.5 and 0.7 mg/kg VCR). This was also observed after 24 h, but now the odontoblasts and cell-rich zone also contained necrotic and disintegrated cells. Some intercellular

VINCRISTINE AND ODONTOBLASTS vacuoles were seen in sector 4, but they were less pronounced than in labial sector 3, and they also involved the cell-rich zone pulpal to the odontoblasts. After 3 d the observed reaction to VCR was similar to that in the incisal part of labial sector 3. However, serial longitudinal sections and transversal sections showed that the normal appearing median zone was relatively wider than in sector 3, and that the most severe derangements only involved the most medial and lateral parts of the sectors, close to the medial and lateral walls of the pulp. Furthermore, a distinct zone of predentin in the odontoblastema, such as seen in sector 3, was not observed. Lingual sector 1 - The reaction to VCR in this sector was analogous to that in the corresponding labial sector, the only difference being that the metaphase cells were less numerous and seemed to be somewhat concentrated in the incisal part of the sector, near the columnar preodontoblasts. After 24 h and 3 d a slight edema developed in the incisal part of the sector. Lingual sector 2 - After 5 and 24 h the changes observed in this sector were identical to those in labial sector 2, and after 3 d the only difference from labial sector 2 was that the predentinoid tissue observed in Groups III and IV was globular in outline and situated further away from the median plane. Lingual sector J - The odontoblastic reaction to VCR in this sector was similar to that in labial sector 3 after 5 and 24 h. After 3 d the apical part of the sector appeared normal in all experimental groups, but in the incisal part an increasing number of the odontoblasts became round, swollen and apolar with increasing doses of VCR, and in the Group IV animals (0.7 mg/kg VCR) small irregular masses of predentin were seen between

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these cells. Lingual sector 4 — ln lingual sector 4 the effect of VCR after 5 h was similar to that observed in labial sector 5; the two highest doses (0.5 and 0.7 mg/kg VCR) produced some swelling of the odontoblasts, particularly of their basal parts. This was also seen after 24 h, and in addition, some of the odontoblasts turned into granular masses containing karyorrhectic fragments. After 3 d marked changes were observed in Groups II, III, and IV; most of the odontoblasts appeared degenerated and swollen, with irregular predentin interspersed between these and the few remaining normal odontoblasts. Transversal sections showed that these changes continued up the lateral and medial aspects of the teeth and were continuous with those in labial sectors 3, 4 and 5. However, the more or less distinct zone of predentinoid tissue in the odontoblastema in the incisal two-thirds of labial sector 3 was unique to this sector and was not observed in any other part of the incisors.

Discussion With all doses applied, VCR produced an accumulation of numerous abnormal metaphases among the preodontoblasts and in the apical part of the pulp near the terminal odontogenic epithelium (labial and lingual sectors 1). This was the only derangement caused by the lowest dose (0.1 mg/kg VCR), and it reflects the wellknown, irreversible stathmokinetic and lethal effect of VCR on cells in the early phases of mitosis, caused by VCR's interference with the microtubular mitotic spindle (KLENER 1974). Although the mitotic cells were not counted, it was evident that their number increased with

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increasing doses of VCR and that it was greatest after 5 h with all doses applied. The accumulation of metaphases reflects the high mitotic activity in the mesenchymal stem cells in these regions, preceding their differendation into juxtaepithelial preodontoblasts. It is worth noting that the area of highest concentration of metaphases coincides with that previously found to attain the greatest number of tritiated thymidine-labeled pulpal nuclei in rat incisors (ROBINS 1967). Metaphases were not observed among the fully developed odontoblasts in any part of the incisors; this indicates that the odontoblasts lose their proliferative capacity as soon as they reach sector 2 and start dentinal matrix production. This is in agreement with the results of RoBlNS's (1967) study using tritiumlabeled thymidine. The three highest doses also affected the rest of the odontoblast population, and after 5 h this was seen as unspeciflc hydropic changes in the odontoblasts. This was also evident after 24 h in labial sectors 4 and 3 and in lingual sector 4 after injection of the two highest doses. In labial and lingual sectors 2 and 3, however, the morphologic derangements now were of a different nature, in that the odontoblasts were dark and separated by dilated intercellular spaces, i.e. changes similar to those observed in some of the control animals sacrificed after 24 h. These changes could be attributed to the injection procedure or inadequate fixation, and an evaluation of VCR's effect in these regions after 24 h was therefore difflcult to make. A lethal action of the two highest doses of VCR on the odontoblasts was also evident after 24 h; the odontoblasts in labial sectors 3, 4 and 5 and in lingual sectors 3 and 4 contained numerous necrotic cells, especially lingual sector 4, indicative of cellular destruction.

A lethal action of the vinca-alkaloids on non-dividing cells has also been observed in pancreatic acinar cells in mice (NEVALAINEN 1975). After 3 d the odontoblasts in the median part of labial sectors 3, 4 and 5 were histomorphologically normal, whereas all the remaining odontoblasts incisally to the apical part of sectors 3 exhibited severe changes, with marked shortening and swelling of the cells and irregular predentin production. The cellular changes could be expressions of an unspeciflc, sublethal injury, or of a speciflc effect of VCR. The latter seems as probable as the former, considering the role of microtubules in maintaining cellular shape and morphology (WiLSON 1975). The irregularities in the predentin are probably caused by inhibidon or complete cessation of matrix production in the degenerated odontoblasts. It is known that the vinca-alkaloids inhibit collagen synthesis in, among others, embryonic osteoblasts (EHRLICH et al. 1974), and colla.gen is quantitatively the most important constituent of the predendnal matrix. Furthermore, the apolar, cuboidal odontoblastic cells associated with the predendnal derangements could, because of VCR's detrimental action on the microtubules and on the structure and intercellular arrangements of organelles, have a greatly changed secretion mechanism which results in the observed matrix deposidon not only apically, as in normal odontoblasts, but also laterally and basally to the cells. Ultrastructural changes of the above-mentioned nature have been observed in a variety of cells after administration of vinca-alkaloids, such as parathyroid, adrenal and pancreatic cells in addition to osteoblasts and chondrocytes (EHRLICH et al. 1974, CHERTOW et al. 1975, KOVACS et al. NEVALAINEN 1975, MOSKALEWSKI,

1975, THY-

VINCRISTINE AND ODONTOBLASTS BERG, LOHMANDER 8c FRIBERG 1975). It

must be stressed, however, that these are mere assumptions and that an elucidation of the genesis of the observed derangements in the predentin production requires other and more refined techniques. The odontoblasts medially and laterally in labial and lingual sectors 2 also exhibited severe degenerative changes after 3 d, and pulpal to these cells an irregular mass of predentinoid tissue containing cells in lacunes was seen. It is assumed that this predentinoid tissue was produced by cells in the pulp, as it had no connection with the ordinary mantle dentin. It thus seems to represent a reparative phenomenon induced by the cellular destruction observed in these regions after 24 h, and its genesis therefore appears to be completely different from that of the derangements observed further incisally. Between the changes in sector 2 and the apical termination of the derangements observed further incisally there was a zone with normal odontoblasts surrounding the pulp encompassing the apical part of lingual sector 3, the corresponding lateral and medial aspects of the incisors, and the apical part of labial sector 3. This zone was continuous with the normal appearing median parts of labial sectors 3, 4 and 5. As degenerative changes were seen at all levels after 5 h, it seems that the odontoblasts in these areas are more resistant to VCR than those in the remaining parts of the odontoblasts. It is worth noting that the median, labial zone of normal structure got progressively narrower with increasing doses of VCR, which suggests that the odontoblasts in the median plane for some unknown reason are more resistant to VCR than the morphologically similar cells located laterally and medially in the same sectors. 24

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The position of the most resistant odontoblasts at the time of exposure to VCR, i.e. immediately after the intravenous injection, is difficult to deduce because VCR's effect on the incisors' growth rate is unknown. Assuming that the growth rate is unaffected, i.e. about 2.1 mm/week (PINDBORG 1950) and therefore somewhat less than 1 mm in 3 d, the apical limit of the derangements seen in sector 3 after 3 d would correspond to the transition between sectors 2 and 3 at the time of injection. This is based on the fact that the distance between these two hallmarks was measured to be approximately 1 mm in several animals sacrificed after 3 d. It then appears that the severely changed cells observed in sector 2 after 3 d were positioned in sector 1 at the time of injection, probably being early and late preodontoblasts. It is worth noting that this part of the odontoblastema also has been found to be the most sensitive to irradiation and the cytostatic drug cyclophosphamide (KoPPANG 1973a, b), but in order to find out whether the VCR-induced changes in this region will develop into a dentinal niche, such as seen after irradiation and cyclophosphamide exposure, longer obset-vation time is needed. It appears, however, from a preliminary investigation on VCR's effects (STENE & KOPPANG 1976), that such is the case. The zone of unaffected cells seen in the apical part of labial and lingual sectors 3 after 3 d would correspond to sector 2 at the time of injection, i.e. the area occupied by the mantle dentin-producing odontoblasts, again assuming an unimpaired growth of the incisors. Why these and the odontoblasts occupying the median region of the labial sectors are less vulnerable to VCR than the remaining odontoblasts is difficult to explain. The most obvious possibilities include

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tion on the effect of cyclophosphamide on variations in VCR exposure and uptake in dentinogenesis of the rat incisor. Scand. J. different parts of the odontoblast layer, Dent. Res. 1973b: 81: 397-405. differing structural and functional roles of KOVACS, K., HORVATH, E., SZABO, S., DZAU, the microtubules, and varying effects of V.J., CHANG, Y. C , FELDMAN, D . & REYNOLDS, E. S.: Effect of vinblastine on the VCR on other cellular structures, aspects fine structure of the rat adrenal cortex. into which further investigation obviously Horm. Metab. Res. 1975: 7: 365-366. is needed. It also remains to be seen KovAGs, K., HORVATH, E., SZABO, S., DZAU, whether VCR affects the growth rate of V. J., FELDMAN, D., CHANG, Y. C. & the incisors, and whether the observed REYNOLDS, E. S.: Effect of vinblastine on neurohypophyseal and adenohypophyseal derangements are permanent or of a microtubules. Steroids Lipids Res. 1974: 5: transient nature. 167-172.

MOSKALEWSKI, S., THYBERG, J., LOHMANDER, S. & FRIBERG, U . : Influence of colchicine and

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mechanisms of parathyroid hormone secretion. Ultrastructural changes in response to calcium, vitamin A, vinblastine, and cytochalasin B. Lab. Invest. 1975: 32: 190-200. EHRLICH, H . P., Ross, R. & BORNSTEIN, P.: Efiects of antimicrotubular agents on the secretion of collagen. J. Cell Biol. 1974: 62 : 390-405.

vinblastine on the Golgi-complex and matrix deposition in chondrocyte aggregates. Fxp. Cell Res. 1975: 95: 440-454. NEVALAINEN, T . J.: Cytotoxicity of vinblastine

and vincristine to pancreatic acinar cells. Virchows Arch. Cell Fathol. 1975: 18: 119-127. PINDBORG,

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jeorganet. Thesis. Munksgaard, Copenhagen 1950. ROBINS, M . W . : The proliferation of pulp cells EKHOLM, R., ERICSON, L. E., JOSEFSSON, J . - O . in rat incisors. Arch. Oral Biol. 1967: 12: & MELANDER, A.: In vivo action of 487-501. vinblastine on thyroid ultrastructure and STENE, T. & KOPPANG, H . S.: The effect of hormone secretion. Fndocrinology 1974: 94: vincristine on dentinogenesis in the rat 641-649. i n c i s o r . Scand. J. Dent. Res. 1 9 7 6 : 8 4 : HiRSiMAKi, Y., ARSTILA, A. U. & TRUMP, B. F. : 342-344. Autophagocytosis: In vitro induction by WILSON, L.: Action of drugs on microtubules. microtubule poisons. Exp. Cell Res. 1975: 92: Life Sci. 1975: 17: 303-310. 11-14. KLENER, P.: Vinca-alkaloids. Experimental and clinical trials. Acta Univ. Carol. 1974: 58: Address: 1-157. KOPPANG, H . S. : The radiosensitive stages of the Department of Fathology rat incisor odontoblast as demonstrated by Dental Faculty auioradiography. Scand.J. Dent. Res. 1973a: University of Oslo 81:303-314. Blindem, Oslo 3 Norway KOPPANG, H . S.: Autoradiographic investiga-

Effect of vincristine on odontoblasts in rat incisor.

Scand.J. Dent. Res. 1978: 86: 346-356 (Key words: incisor; odontoblasts; rat; vincristine) Effect of vincristine on odontoblasts in rat incisor TORBJ...
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