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Biological Research

versión impresa ISSN 0716-9760

Biol. Res. v.35 n.1 Santiago  2002 

Vincristine induces somatic segregation, via mitotic crossing-over, in diploid cells of Aspergillus nidulans


State University of Maringá, Department of Cell Biology and Genetics, Maringá PR Brazil

Corresponding Author: Dra. Marialba Avezum Alves de Castro-Prado. Universidade Estadual de Maringá. Departamento de Biologia Celular e Genética. Av. Colombo 5790. 87020-900. Maringá, Paraná, Brazil. Telephone: (44)-2614679; e-mail:

Received: November 12, 2001. In revised form: January 28, 2002. Accepted: February 1, 2002


Vincristine is an alkaloid widely used as an antineoplastic agent. In eukaryotic cells the drug causes blockage in the G2 phase of the cell cycle and an increase in the frequency of sister chromatid exchanges. Due to the fact that germinating Aspergillus nidulans cells spend most of their cycle in G2 phase, they provide an excellent system for the study of mitotic crossing-over. Taking into account that mitotic crossing-over occurs during G2 period, the evaluation of recombinagenic and aneugenic potential of vincristine is provided with regard to two diploid strains of A. nidulans: a wild strain (uvsH+//uvsH+) and a defective one in DNA repair (uvsH//uvsH). Drug toxicity and its effect on the asexual cycle of A. nidulans has been evaluated as well. Treatment of both strains with vincristine did not change colony growth in the culture, however cytological analyses showed aberrant conidiophores. Recombinagenic potential of vincristine was evaluated by induction of gene homozygosis originally present in heterozygosity diploid strains (Homozygotization Index). Results show that vincristine induces mitotic crossing-over and higher frequency of aneuploid mitotic segregants. The results also show the recombinagenic and aneuploidogenic potential of vincristine and suggest its participation in the induction of secondary malignancies

Key terms: aneuploidy, antineoplastic drug, Aspergillus nidulans, recombinagenic activity.


Vincristine is an alkaloid from the bark or root of the pervinca plant (Vinca rosea Linn.). It inhibits mitosis as do colchicine derivatives as well the formation of mitotic fuses by means of specific bonding with tubuline. The compound is used as a antineoplastic agent in the treatment of leukemia, lymphomas, and breast and uterine cervix cancer (23, 38).

Studies with in vitro sarcoma cells demonstrated that vincristine causes a transient arrest in cells at G2. Treatment of brown marrow cells with low doses of vincristine demonstrated that the drug also promotes an increase in the frequency of sister chromatid exchange (22, 25, 37, 40).

The aneuploidogenic potential of vincristine has been demonstrated by means of micronucleus analyses in human lymphocyte cells. As the drug significantly increased micronucleus frequency, vincristine has been considered a powerful aneugenic. Such an effect is due to the drug's interaction with microtubular proteins, resulting in an abnormal distribution of chromosome (11, 32).

Initially described in Drosophila melanogaster (35), mitotic crossing-over has an important function in the detection of recessive mutations in heterozygous diploid cells. Mitotic exchange occurs during segregation of sister chromatids in mitosis in which homologous chromatids may come into contact and trigger the mitotic crossing-over process. The segregation of a paternal chromatid and a recombinant toward the same mitotic pole results in homozygosis of distal genes to the point of exchange (2). Mitotic crossing-over-induced homozygosis of recessive genes may have carcinogenic effects due to a decrease in the constitutional heterozygosity of tumor-suppressing genes (41, 42).

Mitotic crossing-over has already been recorded in many other organisms, such as Aspergillus nidulans, Schizophyllum commune, Verticillum albo-atrum, Saccharomyces cerevisiae and others. It is currently thought to be a commonly occurring process in diploid cells (7, 12, 14, 21, 29, 31, 34).

The study of recombinagenic potential of chemical compounds is of the utmost importance in detecting other compounds that may cause neoplasms. A great number of chemical and physical agents, such as UV, ionizing radiation, DNA synthesis inhibitors, mitomycin C and norfloxacin, are known to be inductors of mitotic exchange (8, 9, 24, 28).

Among the many organisms in which mitotic crossing-over has been reported, ascomycete Aspergillus nidulans is especially indicated due to the fact that it spends most of its cell cycle in G2. In this phase chromosomes are in duplicate and significantly favor mitotic recombination (27).

Genotoxic effects of some herbicides and antiparasitic drugs in Aspergillus nidulans have been studied by means of Induced Mitotic Segregation Index (IMSI). The Index evaluates somatic segregation of genes for conidia yA2 and wA3 coloration induced by chemical substances in heterozygous diploids (6, 19).

Previous research showed a class of chemical compounds that are active in Aspergillus nidulans as powerful recombinagenic agents. However, they do not induce mutation in Salmonella typhimurium assays (18, 19).

Since the antineoplastic effect of vincristine is related to its ability to bind itself to tubuline and damage the mitotic apparatus, and since aneuploidy and somatic recombination may be prerequisites in the process of malign transformation, the aim of our current research is to evaluate the vincristine's ability to induce somatic segregation mediated by mitotic crossing-over (recombinagenic effect) in Aspergillus nidulans.


Strains. The genotypes and origin of A. nidulans strains are provided in Table I. Diploid strains (UT448//A757 and B211//A837) were prepared according to Roper (30).

Genotype and origin strains


A837 pabaA1, uvsH77, piroA4, choA1, chaA1 FGSC
B211 yA2, biA1, AcrA1, wA2, methA17, uvsH77, piroA4, chaA1 Busso et al. 2001 (4)
UT448 riboA1, pabaA124, biA1, AcrA1, wA2 Utrech (Holland)
A757 yA2, methA17, piroA4 FGSC

Mutant alleles give the following phenotypes: riboA1, pabaA124, methA17, piroA4, choA1; requirements for riboflavin, p-aminobenzoic acid, biotin, methionine, pyridoxine and choline respectively; y, w and cha: yellow, white and chartreuse coloring of conidia, respectively; AcrA1, resistant to Acriflavine. FGSC: Fungal Genetic Stock Center (University of Kansas Medical Center, Kansas, USA.


Culture media. Complete (CM) and minimum medium (MM) were prepared according to Van de Vate and Jansen (39). Selective medium was prepared with MM and nutritional requirements of each strain. Solid medium was prepared with 1.5% agar; incubation for strain growth was done at 37°C.

Vincristine treatment. Filter-sterilized aqueous solutions of vincristine (Sigma) were added to molten minimal medium. The vincristine concentration that induces micronucleated human lymphocytes (0.1 µg/ml) (11) and a higher concentration (2.0 µg/ml) were used in the present study, and the final ones were in agar medium.

Evaluation of drug toxicity. Conidia of diploid strains UT448//A757 and B211//A837 were inoculated in the plate center with CM (control) and CM + vincristine (treatment). Ten plates incubated at 37°C were used for each dose and for control. Diameters of colonies were measured after 24, 48, 72 and 96 hours of incubation. The Student's t test was used to compare values of colony diameters with and without the drug.

Evaluation of recombinagenic potential. Conidia of diploid strain (UT448//A757 and B211//A837) were inoculated in plates with MM and vincristine in 0.1 and 2.0 µg/ml concentrations. Plates were incubated for 5 days at 37°C. Treatment produced visible diploid sectors, D1-D16, identified by differentiated morphology of the original diploid. Sectors are mitotic segregants, homozygous (+/+) or heterozygous (+/- or -/+) prototrophic diploids. They are never recessive homozygous (-/-), since they do not grow in MM. Diploid sectors were haploidized spontaneously in CM after purification in MM.

After haploidization the haploid mitotic segregants from diploid D1 to D16 were purified in CM. Only mitotic stable segregants were selected for the recombinagenic test (10).

Conidia of each haploid sector were transferred one-by-one to 25 positions in CM plates (master plates). After being incubated for 48 hours at 37°C, colonies were transferred to the proper selective media for phenotypic analysis of haploid segregants.

Genes that are heterozygous at first in the original diploid (UT448//A837 and B211//A837) may be homozygous in diploid segregants (D1 to D16). Nutrition markers will segregate among the haploids after haploidization of treated diploids (D1-D16) in the proportion (i) 4+:4-, if drug fails to induce recombinagenesis or (ii) 4+: 2-, if drug induces crossing-over. Thus Homozygotization Indexes (HI), or the ratio between prototrophic segregants and auxotrophic segregants, equal to or greater than 2.0 show the recombinagenic effect of the compound under analysis (1, 28). Results were compared using the Yates correct Chi-square test.

Calculation of frequency of aneuploid segregants. Conidia of diploid UT448//A757 was inoculated in CM (control) and in CM with vincristine. Plates were incubated for 5 days at 37°C. Sectors were then purified in CM and their mitotic stability evaluated. Mitotic segregants with a mutant phenotype for one of the recessive markers of conidia coloration (y; w and cha) producing mitotic sectors at high frequency were labeled aneuploid.

The frequency of aneuploids was calculated as the ratio between the number of aneuploid segregants and the total number of mitotic segregants from diploid UT448//A757 in the presence or absence of the drug. Results were compared using the Yates correct Chi-square test.

Cytological analysis. Colonies of diploid UT448//A757 were cultivated in dialysis membranes placed aseptically on the surface of petri dishes with CM and CM + vincristine. Samples were collected after 8, 12, 18 and 24 hours of incubation at 37°C. Membranes were stained with lactophenol-blue-cotton and analyzed under an optic microscope. Changes in the morphology of conidiophores were reported.


The authors first analyzed the effects of 0.1 and 2.0 µg/ml vincristine concentrations on mycelial growth. Colonies of UT448//A757 and B211//A837 diploid strains obtained in a drug-containing medium failed to show macroscopic morphological alterations when compared to controls (untreated cultures). Vincristine did not interfere with the growth rate of the diploid strains at the above-mentioned concentrations (Figs. 1 and 2). On the other hand, morphological changes of conidiophores were reported from UT448//A757 diploid strain colonies growing in 0.1 and 2.0 µg/ml vincristine. Conidiophore is a multicellular reproductive structure that characterizes asexual reproduction in A. nidulans. It consists of an aerial hypha, a multinucleate vesicle and two tiers of uninucleate sterigmata, the metulae and phialides (3, 36). Bifurcated conidiophores and abnormal conidiophore vesicles were recorded from UT448//A757 diploid strain colonies growing over a dialysis membrane supported by MC with vincristine. Colonies produced shortened conidiophore stalks and malformed sterigmata too (Fig. 3).

Figure 1. Growth of diploid UT448//A757 in CM (control) and in CM + 0.1 and 2.0 µg/ml vincristine.


Figure 2. Growth of diploid B211//A837 with 0.1 and 2.0 mg/ml vincristine. Control: growth of diploid in CM

Vincristine's recombinagenic potential was evaluated by analysis of Homozygotization Indexes for the nutritional markers paba, bi and meth. Treatment of diploids UT448//A837 and B211//A837 in MM with vincristine produced only prototrophic heterozygous (+/- and -/+) or homozygous (+/+) diploids. Although auxotrophic diploids (-/-) are not selected in MM, recessive homozygous diploids may be obtained for conidia color markers (y, w and cha). Only prototrophic diploids with chartreuse conidia (cha//cha) were isolated from vincristine-treated diploid B211//A837. On the other hand, prototrophic diploids with green (y+//y) and yellow (y//y) conidia were isolated from vincristine-treated diploid colonies UT448//A757. Phenotypic analyses of diploids D4 and D7 (yellow) showed that they were recombinants for paba-y and centromere-paba intervals respectively. Both diploids showed HI>2.0 for markers paba and meth respectively (Tables II and III).

Figure 3. Cytological alterations of UT448//A757 conidiophores in CM + vincristine. A) normal conidiophore; B) bifurcated conidiophore (0.1µg/ml vincristine); C) malformend conidiophore vesicle (2.0µg/ml vincristine); D) vesicle with reduced number of metullae (2.0µg/ml vincristine); E) vesicle with aberrant sterigmata (2.0µg/ml vincristine); F) vacoules in vesicle and in the shortened stalk of the conidiophore (2.0µg/ml vincristine); V: vesicle; M: metullae; P: phialides; C: conidium; S: conidiophore stalk. Vesicle diameter: 10µM.

Diploid B211//A837 was more sensitive to vincristine treatment than diploid UT448//A757 in the recombinagenic test. A greater number of segregants was obtained in MC Figure 2. Growth of diploid B211//A837 with 0.1 and 2.0 µg/ml vincristine. Control: growth of diploid in CM after spontaneous haploidization of diploids D9-D16 (from strain B211//A837 after treatment with vincristine) when compared with D1-D8 diploids (from strain UT448//A757 after treatment with vincristine) (Tables II and III).


Homozygosity Index (HI) of the nutritional markers of diploids obtained from UT448//A757
diploid strain exposed to vincristine 0.1µg/ml (D1 - D4) and 2 µg/ml (D5 - D8)., number of haploid mitotic segregants


D1 D2 D3 D4 D5 D6 D7 D8


* Significantly different from control at p<0.05 (Yates correct Chi-square test, Statistic for Windows Program)


HI values obtained in this study reveal the occurrence of mitotic crossing-over between markers of chromosomes I and II of A. nidulans, thus demonstrating vincristine's recombinagenic potential.

The induction of aneuploidy by the antineoplastic agent under analysis was evaluated by culture of diploid strain UT448//A757 in CM with vincristine.


Homozygosity Index (HI) of the nutritional markers of diploids obtained from B211//A837
diploid strain exposed to vincristine 0.1µg/ml (D9 - D12) and 2 µg/ml (D13 - D16)., number of haploid mitotic segregants


  paba+ 86 *3.90 70 1.75 75 1.87 90 *3.91 89 *4.05 90 *3.50 78 1.95 89 *4.24 73 1.97
  paba- 22 40 40 23 22 20 40 21 37  
  bio+ 72 2.00 85 *3.44 76 1.94 75 1.97 73 1.92 85 *3.44 92 *3.53 80 *2.66 70 1.75
  bio- 36 25 39 38 38 25 26 30 40  
  meth+ 70 1.84 70 1.75 60 1.20 70 1.62 72 1.84 70 1.75 75 1.74 72 1.89 72 1.89
  meth- 38 40 50 43 39 40 43 38 38  

* Significantly different from control at p<0.05 (Yates correct Chi-square test, Statistic for Windows Program)


Aneuploid segregants obtained from treatments were identified by phenotype and by their pronounced mitotic instability. In the absence of vincristine most sectors were haploid. The latter were probably the result of a primary mitotic non-disjunction event that gave rise to final haploid segregants after some mitotic divisions. On the other hand, many aneuploid segregants were obtained from vincristine-induced sectors. This fact shows the involvement of the drug in the abnormal segregation of chromosomes during mitosis (Table IV).


Frequencies of aneuloid segregants formed by UT488//A757 diploid strain after treatment
with vincristine at 0.1 and 0.2µg/ml concentrations. n.seg., number of segregants

Concentration of
vincristine (µg/ml)
Frequencies of
aneuploids (%)


* Significantly different from control at p<0.1 (Yates correct Chi-square test, Statistic for Windows Program)



Vincristine is a chemotherapeutic drug widely used in the treatment of cancer, particularly in leukemia, lymphomas and breast cancer (23, 38).

Mutations in cell protooncogenes and the loss of heterozygosity at tumor-suppressor loci are two important oncogenic mechanisms. Heterozygous cells bearing a normal and a defective tumor-suppressor allele may lose the heterozygous state by inactivation of the remaining wild-type allele. This may occur either by a second point mutation or by somatic chromosomal non-disjunction or exchange at mitosis (5, 13, 33).

Since induced recombination may result in homozygosity of tumorigenic mutations, vincristine's potential to induce somatic aberrant segregation and recombination has been investigated in current research. Its capacity to produce sister chromatid exchange has been explored in a number of test systems, including studies with human lymphocytes treated with low doses of vincristine (20).

Current research shows that vincristine is effective in inducing mitotic crossing-over in diploid cells of A. nidulans. The HIs for vincristine at 0.1 and 2.0 µg/ml were greater than 2.0 indicating a significant increasing in the frequency of mitotic recombination (Tables II and III).

The B211//A837 diploid strain was more sensitive than the UT448//A757 strain in the vincristine recombinagenic-test (Tables II and III). This was expected since a previous report demonstrated the higher sensitivity of uvsH//uvsH diploid strain in the monitoring of A. nidulans mitotic recombination events. It was shown by the highest indexes of the uvsH//uvsH diploid's spontaneous mitotic recombination when compared with diploid uvsH+//uvsH+ (4). uvsH mutants are highly sensitive to UV light in non-dividing cells and increasing frequencies of spontaneous mitotic crossing-over in homozygous diploid strains (16, 26).

Data in Table IV show that vincristine in 0.1 and 2.0 µg/ml concentrations produced the highest percentage of unstable segregants when compared to controls. These segregants are probably aneuploid and originate from an irregular distribution of diploid chromosomes during mitosis. Diploid cells of A. nidulans seem fairly stable and produce two main types of mitotic segregants: mitotic recombinants from crossing-over and aneuploid segregants from mitotic chromosomal non-disjunction. Aneuploids are extremely unstable even though they may produce stable end-products after a secondary segregation process (15, 17). Since vincristine interferes with tubulin polymerization, it may impair normal chromosome segregation at mitosis, producing aneuploid segregants.

Antineoplastic agents interfering with cell division, such as vincristine, may be inductors of secondary malignancies (38). Alterations in the cell cycle and arrest in the G2/M phase are among the first modifications in cancerous cells after chemotherapy (22).

Since vincristine causes a transient arrest in G2 cells and interferes in normal chromosome segregation during cell division (22, 25, 37), results show that the carcinogenic potential of this alkaloid may be conducted not only by induction of numerical chromosome alterations, but also by the loss of mitotic crossing-over-induced heterozygosity.


We would like to thank Ms. Luzia A. S. Regasse and Ms. Sônia A. de Carvalho for their technical assistance. S.J.R. Chiuchetta is the holder of a CAPES fellowship.


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