A total of 429 g-ray-induced thymic lymphomas were obtained from F 1 and backcross mice between BALB/c and MSM strains, about a half of which carried a p53-de®cient allele. A genome-wide allelic loss analysis has revealed two loci exhibiting frequent allelic losses but no allelic preference, one is localized within a 2.9 cM region between D12Mit53 and D12Mit279 loci on chromosome 12, and the other is near the D16Mit122/D16Mit162 loci on chromosome 16. The frequency of allelic loss in the D12Mit279 region is 62% and does not dier in tumors between the presence and absence of the p53-de®cient allele. In contrast, the loss frequency of D16Mit122 is raised by the existence of p53-de®cient allele: 62% for p63(7/+) and 13% for p53(+/+), suggesting cooperative function of the two losses. The D12Mit279 and D16Mit122 regions probably harbor dierent types of tumor suppressor gene that play key roles in lymphoma development.
Our previous genome-wide analysis of allelic loss for thymic lymphomas that were induced by g-irradiation in F 1 hybrid mice between BALB/c and MSM strains suggested the centromeric region on chromosome 11 as a site harboring a tumor suppressor gene. Interestingly, to this region the mouse Ikaros gene was mapped which was postulated to participate in oncogenic process from the study of Ikaros knockout mice. Here we show ®ne allelic loss mapping in the vicinity of Ikaros in 191 lymphomas, indicating that the critical region of allelic loss was centered at the Ikaros locus. PCR analysis revealed that nine lymphomas failed to give PCR-ampli®cation for either of two exon primer pairs, indicative of homozygous deletion. Six and ®ve mutations were detected in the N-terminal zinc ®nger domain and the activation domain of Ikaros, respectively, and six of the eleven were frameshift or nonsense mutations that resulted in truncation of Ikaros protein. The results strongly suggest a direct role for Ikaros in development of mouse thymic lymphomas. This provides the experimental basis for further analysis of Ikaros mutations in human cancer.
1,2 Models of the development of cytotoxic drug resistance suggest that maximal initial treatment will reduce the risk of relapse.3,4 Although small cell lung cancer (SCLC) is the histologic type most sensitive to combination chemotherapy, the majority of SCLC patients relapse with chemoresistant tumors. Circumvention of this secondary chemoresistance has been addressed using different treatment modalities.In a recent study, patients with limited-disease SCLC were randomly assigned to receive higher-or lower-dose cyclophosphamide and cisplatin during the first course of a cisplatin, etoposide, doxorubicin and cyclophosphamide regimen followed by five additional cycles at standard doses.5 A moderate increase in the cisplatin and cyclophosphamide doses during the first course resulted in a 17% increase in 2-year survival. However, myelosuppression is the limiting toxicity for this chemotherapy regimen.For the majority of drugs, myelosuppression is the initial dose-limiting toxicity. While hematopoietic growth factors have been utilized to reduce the toxicity and improve delivery of the planned dose, only a modest increase in dose intensity can be achieved.Recently, peripheral blood stem cells (PBSCs) have been used as a source of stem cells and shown to restore hematopoietic functions rapidly after PBSC autografting. Highdose chemotherapy with PBSC rescue has been used for leukemia and lymphoma, but for most chemosensitive solid tumors, a single high-dose chemotherapy as late intensification does not appear to prolong survival. 6 Since adjustments of the dose of cytotoxic drugs, as well as shortening of the intervals between courses, can increase dose intensity, multicyclic chemotherapy may offer the opportunity to maximize dose intensity of the treatment.
F1 offspring of male MSM male mice with a p53-deficient (knockout) allele and normal female BALB/c mice were backcrossed with MSM mice to produce N2 mice. Female F1 and N2 mice were irradiated with gamma-radiation, and thymic lymphomas were obtained from 69 F1 and 82 N2 mice heterozygous for X chromosome markers. Of these 151 mice, 91 carried a p53-deficient allele. These lymphomas were analyzed for allelic loss by using four marker loci distributed on X chromosome to assess the stability of the inactive X chromosome, which contributes little to cellular functions. Twenty lymphomas showed allelic loss of all four loci, suggesting loss of a whole inactive X chromosome due to mitotic nondisjunction, whereas 24 lost only a part of an X chromosome, as a result of somatic recombination. The p53 status of the lymphomas was determined by genotyping and allelic loss analysis: 53 had retained two wild-type p53 alleles, suggesting normal function; 69 had lost both alleles, indicating loss of function; and the remaining 29 had at least one wild-type p53 allele, so their p53 status was unclear. Compilation of these two data revealed one nondisjunction-type change and five recombination-type mutations on X chromosome in 53 lymphomas retaining functional p53. In contrast, 14 and 16 of these alterations, respectively, were observed in 69 lymphomas lacking p53 function. These results suggest that p53 loss significantly increases the accumulation of recombinant chromosomes and decreases the fidelity of mitotic chromosome transmission of the X chromosome in gamma-ray-induced lymphomas.
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