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PubMed1997

Leukemia: A model for drug development.

Early attempts at preclinical model development for cancer drug development relied heavily on mouse leukemias and lymphomas to detect agents with antitumor activity. These models were applied clinically, and the concepts of combination chemotherapy, remission induction, and maintenance treatment all developed in leukemia. Subsequently, the predominant impact of cytogenetics on probability of response to treatment and survival was first illustrated in leukemia. The power of a single drug to change the natural history of a disease was noted in acute myelogenous leukemia, in which a previously incurable disease was rendered potentially curable with 1-beta-D-arabinofuranosylcytosine. Additional studies illustrated the exquisite relationship between karyotype and response to specific agents. The ability to achieve a high proportion of complete remissions and to control the complication of intravascular coagulation, acute promyelocytic was noted with all-trans retinoic acid. The concept that new drug activity would only be demonstrated in patients with minimal prior therapy has been challenged by the curative potential of a number of agents in far-advanced hairy cell leukemia. In addition, fludarabine monophosphate (Fludara) was sufficiently active in advanced refractory patients that approval for this agent in chronic lymphocytic leukemia was granted by the Food and Drug Administration without comparative clinical trials. Fludara was initially a drug with limited therapeutic range, active only in indolent lymphoproliferative disorders. However, understanding of the multiple biochemical actions of this agent has led to its use in combinations with 1-beta-D-arabinofuranosylcytosine in acute myelogenous leukemia and myelodysplastic syndrome and with DNA active agents such as novantrone and cyclophosphamide in other lymphoproliferative disorders. The understanding of the various actions of this drug gives rise to a wide range of possibilities for biochemical modulation with agents active in solid tumors. The evolution of this understanding of the new role of Fludara has occurred over a period of 10 years. A drug with similar potential in the next decade is compound 506U78, an analogue of arabinosyl guanosine. This agent has potent activity in acute T-cell leukemia. Because it shares many of the activities of Fludara in interfering with enzyme systems important in DNA and RNA synthesis and DNA repair, it is likely that this agent will also have a wider scope than is presently obvious. The unique accessibility of leukemia cells for study has allowed hematologists to understand more fully the range of activities of new agents and has led to important new concepts in the area of drug development.

Adult↗
PubMed1984

[Creatine phosphotransferase, B subunit, as a tumor marker. Preliminary results].

Creatine kinase B (CK-B) was evaluated as a tumor marker by radioimmunoassay determination of the isoenzyme in 518 persons (control group, malignant tumors, and several other diseases). Amounts higher than 8 ng/ml (upper normal limit) was observed in 12.6 per 100 of the digestive tumors, 6.1 per 100 of the mammary tumors, 37.7 per 100 of the respiratory tumors, and 22.2 per 100 of the prostatic tumors. A relation exists between CK-B and sigmoid flexure, liver, pancreas and esophagus tumors, between CK-B and acid phosphatase in prostate tumors, and between CK-B and evolution of digestive tumor. The determination of CK-B is useful in the case of tumors lacking known tumor markers, and also as a complementary sign in the diagnosis and evolution of sigmoid flexure and prostate neoplasms.

Adolescent↗
PubMed1980

Effects of prostaglandins on tumor transplantation.

Administration of prostaglandins F2 alpha (PGF2 alpha) and E2(PGE2) to syngeneic mice transplanted with chemically induced squamous cell carcinoma from the same species (allograft) markedly enhanced the transplantability and cellular atypicality of these tumors. Large and invasive tumors with an atypical cellular pattern, anaplastic squamous cell carcinoma, grade IV (or fibrosarcoma), occurred in approximately 87% of mice transplanted with squamous cell carcinoma, grade I, and treated with PGF2 alpha. Similar transplanted tumors in syngeneic nontreated mice grew to a much lesser extent and remained squamous cell carcinoma, grade I. Light microscopic autoradiography and radioactivity measurements revealed a significant increase of 3H-thymidine incorporation in tumor tissue of transplanted and PG-treated mice as compared to control epidermis or to that of tumor transplanted only. Electron microscopic examination revealed that the cellular evolution in transplanted tumors treated with PGF2 alpha is shifted towards atypical fibroblasts (fibrosarcomas) which originate from the squamous cells. These findings demonstrate that PGF2 alpha and PGE2 can play an important role in tumor transplantability and cellular evolution.

Animals↗
PubMed1982

Evolution of DNA polymerase alpha, beta and terminal deoxynucleotidyl transferase in hamster lymphoid populations during the development of different types of tumors.

We followed the evolution of DNA polymerase alpha, beta and terminal deoxynucleotidyl transferase (TdT) in the thymus, spleen and bone marrow of tumor bearing hamsters. Tumors were induced by spontaneously transformed fibroblasts (EHB), by SV40 (ZD) or by 20-methylcholanthrene (MCH2) transformed fibroblasts. We have shown that, in the thymus, the TdT activity of the various tumor bearing hamsters is generally inferior to the TdT activity of the control. In the spleen of animals bearing viral or spontaneously induced (ZD or EHB) tumors, the TdT activities were higher than in the controls. Moreover, DNA polymerase alpha and DNA polymerase beta activities in the spleen of the EHB tumor bearing hamsters were higher than in the controls. This fact, however, was not observed in the two other kinds of tumor, possibly because EHB tumors were growing much faster and led to earlier changes in DNA polymerases activities, as well as in spleen size and cellular populations. Finally, in the bone marrow, TdT, polymerase alpha and beta of ZD and EHB tumor bearers reached much higher activities than in the controls; for the MCH2 tumor bearing hamsters, no difference with the controls could be observed.

Animals↗
PubMed2006

Signs of positive selection of somatic mutations in human cancers detected by EST sequence analysis.

BACKGROUND: Carcinogenesis typically involves multiple somatic mutations in caretaker (DNA repair) and gatekeeper (tumor suppressors and oncogenes) genes. Analysis of mutation spectra of the tumor suppressor that is most commonly mutated in human cancers, p53, unexpectedly suggested that somatic evolution of the p53 gene during tumorigenesis is dominated by positive selection for gain of function. This conclusion is supported by accumulating experimental evidence of evolution of new functions of p53 in tumors. These findings prompted a genome-wide analysis of possible positive selection during tumor evolution. METHODS: A comprehensive analysis of probable somatic mutations in the sequences of Expressed Sequence Tags (ESTs) from malignant tumors and normal tissues was performed in order to access the prevalence of positive selection in cancer evolution. For each EST, the numbers of synonymous and non-synonymous substitutions were calculated. In order to identify genes with a signature of positive selection in cancers, these numbers were compared to: i) expected numbers and ii) the numbers for the respective genes in the ESTs from normal tissues. RESULTS: We identified 112 genes with a signature of positive selection in cancers, i.e., a significantly elevated ratio of non-synonymous to synonymous substitutions, in tumors as compared to 37 such genes in an approximately equal-sized EST collection from normal tissues. A substantial fraction of the tumor-specific positive-selection candidates have experimentally demonstrated or strongly predicted links to cancer. CONCLUSION: The results of EST analysis should be interpreted with extreme caution given the noise introduced by sequencing errors and undetected polymorphisms. Furthermore, an inherent limitation of EST analysis is that multiple mutations amenable to statistical analysis can be detected only in relatively highly expressed genes. Nevertheless, the present results suggest that positive selection might affect a substantial number of genes during tumorigenic somatic evolution.

Amino Acid Sequence↗
PubMed2001

Clonal evolution of a radon-induced rat lung tumor.

Radon gas may represent a source of pulmonary radio-contamination either in mine or in domestic conditions. Since epidemiological studies are controversial, as long as biological markers of the exposure to such agents will not be identified, the question will remain open. We have previously shown a direct dose-dependent relationship between lung cancer occurrence and radon inhalation of rats. In this study, we report a cytogenetic study of a radon-induced rat lung tumor. Chromosome banding and chromosome specific paintings were performed on cultures of both fresh and xenografted tumors. We found by analyzing 17 sub-clones that all karyotypes presented a translocation involving rat chromosomes (RNO) 8 and 20, and a terminal deletion of RNO 15p suggesting a monoclonal origin of this tumor. RNO 15 is homologous to numerous human chromosomes (HSA), in particular to HSA 3p14.2, 3p22-p24.1 and 3p24.2-p24.3, this human chromosome being frequently lost in human lung carcinomas. Besides sharing chromosome alteration involving common features with those found in human lung cancer, this rat lung carcinoma represents a useful model to study tumor progression with respect to clonal evolution.

Animals↗
PubMed2005

The evolution of antibodies into versatile tumor-targeting agents.

In recent years, monoclonal antibodies have become important weapons in the arsenal of anticancer drugs, and in select cases are now the drugs of choice due to their favorable toxicity profiles. Originally developed to confer passive immunity against tumor-specific antigens, clinical uses of monoclonal antibodies are expanding to include growth factor sequestration, signal transduction modulation, and tumor-specific drug delivery. In this review, we shall present the origins of antibody therapeutics within the field of immunotherapy and their evolution into effective anticancer agents, then discuss their multiple mechanisms of action, the basis of their tumor selectivity, and their therapeutic properties compared with traditional therapies. Antibodies are complex molecules whose efficacy and toxicity depend on the antigen, the antibody, any conjugated groups, and even the patient. Finally, we shall present new technologies being developed to increase the efficacy and selectivity of antibody-based therapeutics. Interestingly, many of the new approaches straddle the middle ground between immunotherapy and the traditional modalities of chemotherapy and radiotherapy, and can be seen as ways of combining the selectivity of the former with the efficacy of the latter.

Animals↗
PubMed1985

Role of heterochromatin variation in the instability of a marker chromosome during tumor progression.

Karyotypic evolution of the poorly metastasizing tumorigenic RSV-transformed B77-3T3 fibroblast line was investigated both in highly metastasizing clones (selected by growth in hard agar) and in spontaneous metastases. Analysis of structural chromosome aberrations associated with the transition from the nonmetastatic to the metastatic phenotype was focused on a readily identifiable marker chromosome (A), displaying an extracentromeric heterochromatic region as a main feature promoting genetic instability. Well-defined changes in the structure of this marker were observed, both in vitro and in vivo, and invariably involved C-heterochromatic variation. In the metastatic clones, a specific rearrangement of the A chromosome was selected. This structural variant (B) showed two extracentromeric C-positive regions and probably originated from duplication of the segment of A included between the centromere and the internal C-band. On the other hand, selection of a modified form of chromosome A, not displaying the interpolated C-heterochromatin, had occurred in the extremely rare B77-3T3 spontaneous metastases. The connection among heterochromatin variants, genetic instability, and chromosome aberrations is discussed.

Animals↗
PubMed1995

Low dose rate versus high dose rate intraluminal brachytherapy for malignant endobronchial tumors.

Although the evolution from low dose rate to high dose rate brachytherapy for malignant endobronchial malignancies was primarily based on economy, patient convenience, and radiation protection, the difference in therapeutic index, if any, between these two modalities must be kept in mind. Our experience with both methods permits assessment of the feasibility of replacing low dose rate brachytherapy with high dose rate brachytherapy. Results with our first 110 patients (group 1) treated with low dose rate brachytherapy (133 procedures) were compared with results with our initial 59 consecutive patients (group 2) treated with high dose rate brachytherapy (161 procedures). In group 1, patients were treated with one or two sessions of 30-60 Gy each calculated at a 1 cm radius. In patients in group 2, we aimed at three weekly sessions of 7 Gy each calculated at a 1 cm radius. External beam irradiation therapy had previously been given to 88% of patients in group 1 and to 85% of patients in group 2. Laser bronchoscopy was performed in 36% of patients in group 1 and in 24% of patients in group 2 before brachytherapy. Clinical or bronchoscopic improvement was noted in 72% of patients in group 1 and in 85% of patients in group 2 (p > 0.05). Complication rates were low and comparable. Survival was similar in both groups (median < 6 months). Although both low dose rate and high dose rate brachytherapy appear equally effective in palliation for malignant endobronchial obstruction, we are now practicing the latter exclusively.

Aged↗
PubMed2006

Mathematical modeling of tumor therapy with oncolytic viruses: effects of parametric heterogeneity on cell dynamics.

BACKGROUND: One of the mechanisms that ensure cancer robustness is tumor heterogeneity, and its effects on tumor cells dynamics have to be taken into account when studying cancer progression. There is no unifying theoretical framework in mathematical modeling of carcinogenesis that would account for parametric heterogeneity. RESULTS: Here we formulate a modeling approach that naturally takes stock of inherent cancer cell heterogeneity and illustrate it with a model of interaction between a tumor and an oncolytic virus. We show that several phenomena that are absent in homogeneous models, such as cancer recurrence, tumor dormancy, and others, appear in heterogeneous setting. We also demonstrate that, within the applied modeling framework, to overcome the adverse effect of tumor cell heterogeneity on the outcome of cancer treatment, a heterogeneous population of an oncolytic virus must be used. Heterogeneity in parameters of the model, such as tumor cell susceptibility to virus infection and the ability of an oncolytic virus to infect tumor cells, can lead to complex, irregular evolution of the tumor. Thus, quasi-chaotic behavior of the tumor-virus system can be caused not only by random perturbations but also by the heterogeneity of the tumor and the virus. CONCLUSION: The modeling approach described here reveals the importance of tumor cell and virus heterogeneity for the outcome of cancer therapy. It should be straightforward to apply these techniques to mathematical modeling of other types of anticancer therapy. REVIEWERS: Leonid Hanin (nominated by Arcady Mushegian), Natalia Komarova (nominated by Orly Alter), and David Krakauer.

Journal Article↗
PubMed1998

Chromosome band 1p36 contains a putative tumor suppressor gene important in the evolution of chronic myelocytic leukemia.

Chronic myelocytic leukemia (CML) is a common neoplasm of hematopoietic pluripotent stem cells. Although the evolution from chronic phase to blast crisis (BC) in CML patients is an inevitable clinical feature, little is understood about the mechanisms responsible for the transformation. We have previously performed allelotype analysis in CML BC and have detected frequent loss of heterozygosity (LOH) on the short arm of chromosome 1. To know the common region of LOH where a putative tumor suppressor gene may reside, deletional mapping was performed using 33 microsatellite markers spanning chromosome 1 in 30 patients with CML BC (21 myeloid and 9 lymphoid). DNA was extracted from slides of bone marrow smears or from bone marrow mononuclear cells. In each patient, DNA from chronic phase was analyzed alongside DNA from either their BC or accelerated phase. Allelic loss on 1p was observed in 14 of the 30 individuals (47%): 10 of the 21 myeloid and 4 of the 9 lymphoid BC cases. Serial cytogenetic information was available in 10 cases with LOH on 1p; interestingly, deletions in this region were not detected. Two samples showed LOH at all informative loci on 1p, whereas the other 12 samples showed LOH on at least one but not all loci on 1p. The common region of LOH resided proximal to D1S508 and distal to D1S507 (1p36). Our results suggest that a tumor suppressor gene that frequently plays an important role in the evolution to BC resides on 1p36 in CML.

Adult↗
PubMed2006

Mechanism of reoxygenation after antiangiogenic therapy using SU5416 and its importance for guiding combined antitumor therapy.

Emerging preclinical studies support the concept of a transient "normalization" of tumor vasculature during the early stage of antiangiogenic treatment, with possible beneficial effects on associated radiotherapy or chemotherapy. One key issue in this area of research is to determine whether this feature is common to all antiangiogenic drugs and whether the phenomenon occurs in all types of tumors. In the present study, we characterized the evolution of the tumor oxygenation (in transplantable liver tumor and FSAII tumor models) after administration of SU5416, an antagonist of the vascular endothelial growth factor receptor. SU5416 induced an early increase in tumor oxygenation [measured by electronic paramagnetic resonance (EPR)], which did not correlate with remodeling of the tumor vasculature (assessed by CD31 labeling using immunohistochemistry) or with tumor perfusion (measured by dynamic contrast enhanced-magnetic resonance imaging). Inhibition of mitochondrial respiration (measured by EPR) was responsible for this early reoxygenation. Consistent with these unique findings in the tumor microenvironment, we found that SU5416 potentiated tumor response to radiotherapy but not to chemotherapy. In addition to the fact that the characterization of the tumor oxygenation is essential to enable correct application of combined therapies, our results show that the long-term inhibition of oxygen consumption is a potential novel target in this class of compounds.

Angiogenesis Inhibitors↗
PubMed1984

Morphofunctional modifications associated with the inhibition by estradiol of MtTF4 rat pituitary tumor growth.

The MtTF4 pituitary tumor has been induced in Fischer rats by chronic estrogen administration. Recently, we reported that sustained pharmacological treatment of Fischer rats with 17 beta-estradiol inhibited the growth of the MtTF4 tumor transplanted s.c. The present work describes the associated morphofunctional changes occurring in the tumor during 17 beta-estradiol inhibition. It is shown that a 7-day 17 beta-estradiol treatment resulted in an increase of the surface area of cells, nuclei, nucleoli, Golgi complexes, and rough endoplasmic reticulum and an increase in the number of euchromatin-rich nuclei. Flow cytometry analysis of DNA distribution suggested that estradiol affects the cell progression through the early S phase. The ratio of RNA to DNA increased significantly, reflecting cell hypertrophy. Moreover, there was a significant increase in tumor prolactin concentration and a marked enhancement in the intensity of the immunocyto-chemical reaction with rat prolactin antiserum. On the other hand, cell mitoses were dramatically decreased. These morphofunctional changes indicate that the inhibition of the tumor growth by estradiol is accompanied by an evolution of the tumor cell population towards a more differentiated state. However, it cannot be decided whether 17 beta-estradiol induces a shift from a proliferative state to a differentiated state or whether 17 beta-estradiol treatment results in a selection of a subpopulation of tumor cells that are slow growing and more differentiated.

Animals↗
PubMed1993

[A brown tumor of the mandible and hyperparathyroidism secondary to chronic renal insufficiency. Review of the literature apropos of a case].

We report on a brown tumor of the mandible in a hemodialysed female patient with severe uncontrolled secondary hyperparathyroidism. Multiple other brown tumors were associated. The hyperparathyroidism was treated with a subtotal parathyroidectomy because only three parathyroids were found. Parathyroid removal led to normal C-terminal parathyroid hormone concentration (0 ng/ml). A review of the literature has shown that parathyroidectomy is usually curative. Our patient demonstrated, eleven days after the parathyroid surgery, rapid growth of the mandibular tumor. This unusual evolution has justified a local excision of the tumor. Histological preparations have confirmed the diagnostic of brown tumor with an important capillary proliferation.

Adult↗
PubMed1993

[Malignant transformation of juvenile-type laryngeal papillomatosis].

Juvenile laryngeal papillomatosis is characterized by benign budding tumors, developing from the endolaryngeal epithelium. Because the evolution of these tumors is unpredictable, choice of the best therapy is difficult. We report two cases where invasive juvenile laryngeal papillomatosis, progressively colonized the trachea and bronchi. Malignant transformation occurred without carcinoma predisposing factors. In both cases patients died after pulmonary dissemination. We discuss the role of the human papilloma virus and the high interest of viral typing, for an early diagnosis of possible degeneration. The choice of the best therapy, chemotherapy, CO2 laser, alpha interferon or auto-vaccination will depend on the type on the papilloma virus.

Adult↗
PubMed1996

[Myxoma of the upper jaw. Apropos of a case].

We report a patient with odontogenic myxoma of the upper maxillary. The authors underline for this particular case, that there are no clinical features specific of the tumor; the diagnosis can be only histological. The evolution of this tumor is always benign.

Adult↗