Annette Siegal

Efficacy of anti-angiogenic treatment of tumors in old versus young mice.

Cancer treatment in the older population, the most afflicted by the disease, is as yet, inefficient. A reduced aggressiveness of tumors is often observed in the elderly, implying the necessity for therapeutic modalities adjusted to age. A rational design of age-related cancer therapy could be based on the mechanisms of this phenomenon. It is suggested that, in addition to the patients old age-specific health problems (which prohibit the use of the aggressive cancer treatments now in use), the age-related differential tumor biology (apparently beneficial to the old) should also be considered for the design of treatment modalities suitable for the aged. Based on one mechanism of the reduced aggressiveness of tumors in the old (age-dependent decreased angiogenesis), we compared the effect of an anti-angiogenic treatment in young and old mice. TNP-470 treatment resulted in an inhibitory effect on B16 melanoma in both young and old mice but the effect was more pronounced in old animals. Moreover, a high percentage of long-term surviving animals was observed only in the old-treated mice. Treatment with TNP-470 of the AKR lymphoma produced similar results. We thus found a differential age-dependent therapeutic efficiency of an anti-angiogenic agent on two tumors. Importantly, the anti-angiogenic drug was more efficient against tumors of old animals.

Designing ageing conditions in tumour microenvironment-a new possible modality for cancer treatment.

While tumour incidence is known to augment with age, paradoxically tumour growth and metastasis were often found to proceed at a slower rate at late ages. This age-related biological behaviour of tumours actually imposes a differential therapeutic approach to the old cancer patient. Several mechanisms of the age-related reduced tumour progression have been demonstrated: decreased tumour cell proliferation, increased apoptotic cell death, decreased angiogenesis and anti-tumoural immune response changes. We postulated that it might be possible to design age-adjusted treatment modalities based on the mechanisms responsible for the reduced tumour progression rate in the aged. Based on these mechanisms, we compared the effect of different treatments (apoptosis-inducing agents, Hydrocortisone and Adriamycin, anti-angiogenic agent, TNP-470, and immunomodulators-Levamisole and BCG) on two experimental tumours (B16 melanoma and AKR lymphoma) growing in young and old mice. Most treatments showed, in both tumours, a higher inhibitory effect on tumours growing in old mice than on those developing in young ones, to our knowledge, a feature not described before for anti-tumoural agents. We suggest that designing ageing conditions in tumours of young patients might possibly alleviate neoplastic aggressiveness in these patients as well.

Direct in‐vivo detection of atypical hormonal expression of a Sertoli‐Leydig cell tumour following stimulation with human chorionic gonadotrophin

A 60‐year‐old woman presented with progressive hirsutism and elevated serum testosterone levels. Selective bilateral ovarian and adrenal vein catheterization demonstrated mild elevated testosterone and androstenedione levels in the right ovarian vein, which increased considerably 15 minutes following intravenous injection of 5000 IU human chorionic gonadotrophin. Androgen levels decreased remarkably after administration of gonadotrophin hormone releasing hormone‐agonist (GnRH‐a). On histological examination, diffuse stromal hyperplasia of both ovaries was noted, with a small Sertoli‐Leydig cell tumour in the right ovary. This is the first report of preoperative, direct selective diagnosis of a small Sertoli‐Leydig cell tumour with such a hormonal expression.

Lack of correlation between hormonal blood levels and endometrial maturation in agonadal women with repeat implantation failure following embryo transfer from donated eggs.

Five women with ovarian failure who repeatedly failed to conceive following embryo transfer from donated eggs underwent endometrial development investigation. One endometrial biopsy was obtained on cycle days 19, 21, and 23 during three consecutive artificially induced cycles. All five patients had only early secretory changes on days 19 and 21. Histological evaluation on cycle day 23 revealed various developmental stages: two women had “in-phase” endometrium, two patients had adequately developed stroma but significantly retarded glandular maturation, and one women showed no progress. The histological findings were conclusive for a significant maturation delay and an impaired endometrial receptivity. There was a lack of correlation between the peripheral hormonal blood levels and the endometrial maturation.

Decreased DNA ploidy may constitute a mechanism of the reduced malignant behavior of B16 melanoma in aged mice

Numerous data demonstrate a lower aggressiveness of tumors in aged as compared to young patients. The mechanisms underlying this phenomenon have not yet been completely elucidated. Several mechanisms have been shown, such as reduced tumor cell proliferation, increased apoptosis, immune response modifications and reduced angiogenesis in aged organism tumors. In the present study we report an incidentally found, not yet described mechanism, of the age-related reduced tumor progression, namely a decreased ploidy in B16 melanoma growing in old (near diploidy) as compared to young mice (tetraploidy). We surprisingly observed that tumor cells from aged mice were of smaller cell and nuclear size than those of young animals. Flow cytometry forward scatter data also showed a smaller cell size of melanoma cells from old mice. DNA flow cytometry profile comparison demonstrated that while B16 melanoma cells from young animals contained a high percentage of tetraploid cells, those derived from old animals were mostly close to diploid. A high importance has recently been attributed to aneuploidy as being at the origin of the genetic instability of neoplasia. Our results may support this notion. The transit from tetraploidy to near euploidy in melanoma cells growing in aged mice might avoid the genetic instability inherent to tumor progression.

Combined Effect in vitro of Chemotherapy with Agents Acting on the Cell Membrane of Lewis Lung Carcinoma

The treatment of cancer is often impeded by the emergence of drug-resistant clones. Drug resistance is in many cases due to a decreased drug accumulation in the tumor cell. Membrane-acting agents, by increasing cell permeability, might counteract the loss of sensitivity to drugs. In the present study, the effect of two membrane-acting agents, hyperthermia and the calcium channel blocker verapamil, on the action of adriamycin (ADR) on Lewis lung carcinoma (3LL) was examined. Hyperthermia increased drastically the antitumoral effect of ADR. The effectiveness of the combined ADR-hyperthermia treatment was proportional to the ADR dose and to the degree of hyperthermia. Verapamil had a similar effect but at higher ADR doses. Treatment modalities designed for the circumvention of drug resistance could be one approach in the attempt to find a way to control cancer.

Decreased Ratio of Total Progesterone to Total Estradiol Receptor Levels in Endometria of Women with Adult Dysfunctional Uterine Bleeding

Total estradiol and progesterone receptor levels (TRE2, TRP) were measured in endometria of women with adult dysfunctional uterine bleeding (n = 2) and compared to those of controls. The women in both groups were comparable with respect to age, history, light and electron microscopic endometrial morphology and dating; plasma levels of LH, FSH, estradiol and progesterone were similar in both groups. A wide range of TRE2 and TRP levels was measured in both groups; however, the levels of the ratio of TRP/TRE2 for each case were significantly lower in 18 of the 22 women with adult dysfunctional uterine bleeding and were in the range of the controls in the remaining 4. Possible explanations for these findings are presented.

Apoptosis and Cell Proliferation Capacity in AKR Lymphoma Malignancy Variants

Abstract Dysregulation in apoptotic cell death has recently emerged as a factor in tumorigenesis, but its effect in tumor progression is not yet established. In the present study we evaluated the levels of proliferative and apoptotic cell fractions in a T-cell lymphoma tumor progression model. We compared these features and the expression of apoptosis-related genes in primary tumors of several AKR lymphoma malignancy variants. According to DNA flow cytometry, a considerable proportion of cells (35–40%) was in the proliferative (S + G2/M) phase in all variants, but a slight augmentation with increasing malignancy was noted. Apoptotic cell content was, unexpectedly, the lowest in the less malignant variant. This might be due to the higher content in macrophages observed in this variant, which possibly partly eliminated apoptotic bodies. We found an increase in bcl-2 level with increasing malignancy that was probably counterbalanced by the simultaneous increase observed in the Fas receptor

Acute rupture of an ovarian pregnancy associated with a negative serum B-HCG

A case of acute rupture of an ovarian pregnancy in which Beta Subunit of human chorionic gonadotropin was negative is presented. This is the first case known in the literature. Clinical and laboratory aspects of ovarian pregnancy are reviewed.

Cervico-isthmic pregnancy ending with the delivery of a live-born infant in late second trimester

A very rare case of cervico-isthmic pregnancy, terminated by cesarean section in late second trimester with the delivery of a live-born infant who subsequently remained alive, is described. The authors suggest that this is the first case of neonatal survival in late second trimester of a cervico-isthmic pregnancy.