Enhanced tumor growth in chimeric mice.

Chimeras were produced by aggregation of B6D2F1 and SWA early embryos. Lewis lung tumor, syngeneic in B6D2F1, was used to study tumor growth and metastases in these chimeras. Enhanced tumor growth, low metastases rate and pronounced enlarged spleen could be observed in SWA equilibrium B6D2F1 chimeras 21 days after inoculation of tumor cells. Increased activity of suppressor T-cells which might be due to permanent allogeneic stimulation in chimeras is discussed as one of the possible mechanisms.     

Accelerated growth of syngeneic tumors in mice treated with methylcholanthrene

BALB/c and C3H- mice were given a single injection of methylcholanthrene (MCA) and were tested at various times thereafter for immunologic reactivity and resistance to syngeneic tumor challenge. MCA treatment did not affect the rejection of H-2-incompatible tumor allografts, the rejection of H-2-compatible skin allografts, or the induction of delayed hypersensitivity to DNCB as measured by footpad challenge. In contrast, mice treated with MCA exhibited an increase susceptibility to challenge with several syngeneic ultraviolet-induced and MCA-induced fibrosarcomas. These studies demonstrate that in the autochthonous host the measurement of host immune status by in vivo cell-mediated immune responses to exogenous antigens does not necessarily predict the host response to tumor growth.     

苦参碱对荷瘤小鼠抑瘤作用的实验研究

目的观察苦参碱的体内抗肿瘤活性,初步探讨其体内抑瘤作用机制。方法采用小鼠H22肝癌细胞实体瘤模型进行体内抑瘤实验,观察荷瘤动物的生长情况和肿瘤生长曲线,测定肿瘤生长抑制率;肿瘤组织病理学切片进行HE染色形态学观察,其超微结构行透射电镜观察。结果苦参碱对小鼠的H22实体瘤生长具有明显的抑制作用,抑瘤率达60％以上。苦参碱处理组小鼠的成瘤时间明显晚于生理盐水对照组,肿瘤生长也较对照组慢。组织学观察显示,肿瘤细胞大量变性坏死,电镜下可见凋亡细胞和凋亡小体。结论苦参碱具有较强的体内抗肿瘤作用,作用机制可能与其能够抑制肿瘤细胞的分裂和增殖、直接杀伤肿瘤细胞和(或)诱导肿瘤细胞凋亡、调节机体的抗肿瘤免疫应答效应有关。     

Growth of a methylcholanthrene-induced fibrosarcoma in mice with diabetes mellitus

Growth of a methylcholanthrene-induced fibrosarcoma was retarded in diabetic mice. Tumors maintained in diabetic mice grow faster after each subsequent transplantation into diabetic mice. The observed proliferation enhancement of fibrosarcoma maintained in diabetic mice is caused by insulin synthesis, apparently by the tumor cells themselves. Hypoglycemia accompanied intramuscular growth of fibrosarcoma. In diabetic hosts, the tumor decreased the blood glucose level almost to the level seen in non-diabetic mice.     

Secondary fibrosarcoma of the brain stem treated with cyclophosphamide and Imatinib

Radiation-induced midbrain fibrosarcoma is a rare, highly aggressive tumor, which is associated with poor prognosis. We present the case of a 48-year old man with brainstem fibrosarcoma 20 years following radiation therapy received for a pituitary tumor. We discuss this case in the context of the diagnostic criteria for these tumors, and previous reports of secondary and primary sarcomas of the central nervous system.     

Enhanced oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833.

Inhibition of intestinal P-glycoprotein might enhance the absorption of orally administered P-glycoprotein substrate drugs. We show here a 10-fold increased oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833. These results encourage further research on the development of a clinically useful oral formulation of paclitaxel.     

The effects of phytohemagglutinin in treated and untreated dog renal allografts

Dogs undergoing renal allografts were treated with phytohemagglutinin-M (PHA-M) with and without azathioprine before and after transplantation. PHA-M treatment was associated with histological evidence of decreased renal allograft rejection and minimal azotemia. PHA-M-treated animals had marked leukocytosis postoperatively and, unlike untreated control animals or azathioprine-treated dogs, had sustained elevations in total lymphocyte levels. However, PHA-M treatment did not decrease survival due to associated drug toxicity manifested by a distemper-like syndrome not observed in other concurrently evaluated animals.     

Effect of phytohemagglutinin on the growth of krebs-ii tumor-cells, body metabolism and internal organs of mice

Neoplastic proliferation requires the availability of polyamines. Phytohaemagglutinin (PHA) is a potent growth factor which induces polyamine-dependent growth of the gut. In the hope of directing polyamines and other nutrients away from the tumour to the growing gut, mice fed PHA-containing or lactalbumin diets were injected intraperitoneally with Krebs II ascites cells and the number of tumour cells and the weights of internal organs were followed. PHA-treatment significantly slowed down the proliferation of tumour cells. Changes in the weight and polyamine content of tissues indicated that inter-organ competition between the tumour and vital organs can be used to manipulate the metabolism of tumour-bearing mice.     

Enhanced cardiotoxicity in rabbits treated with verapamil and adriamycin

Verapamil, a calcium channel blocker, reduces resistance of some tumors to Adriamycin by inhibiting Adriamycin efflux from resistant cells. This study shows that rabbits given 7 mg/kg of Adriamycin and 0.8 mg/kg of verapamil died earlier with functional and morphological cardiac abnormalities than rabbits given Adriamycin alone. Rabbits that were given verapamil and died peracutely had higher concentrations of Adriamycin in the myocardium. The relatively high dose of Adriamycin was expected to produce cardiotoxicity in rabbits within a matter of days. However, peracute death (within hours) in rabbits given the same dose of Adriamycin but with verapamil treatment was unexpected. These results suggest that combining Adriamycin with verapamil increases early cardiac toxicity. Therefore, clinical use of this combination should be approached cautiously until the interactions, including the possibility for enhanced normal tissue damage, are fully understood.     

Glucocorticoid receptor-mediated effects on rat fibrosarcoma growth

Glucocorticoid receptors are present in most normal and malignant mammalian cells. To examine the hypothesis that the growth of methylcholanthrene-induced malignant sarcoma is glucocorticoid dependent, we evaluated the behavior of malignant fibrosarcoma (MCA) in adrenalectomized rats treated with either normal saline or deoxycorticosterone acetate and in intact rats treated with placebo or with the glucocorticoid receptor antagonist RU 486. Survival, tumor weight, and loss of body weight (an index of cachexia) were measured. In MCA-bearing rats, neither survival nor loss of body weight was affected by bilateral adrenalectomy or by treatment with RU 486. Tumor weight and time-integrated tumor volume, however, were significantly less in bilaterally adrenalectomized rats without deoxycorticosterone acetate replacement than in animals treated with deoxycorticosterone acetate. Similarly, tumor weight and time-integrated tumor volume were less in intact animals treated with RU 486 than in intact animals treated with placebo. The glucocorticoid receptors in the tumor cells had similar binding capacity (Ro) and equilibrium dissociation constant (Kd) as in control rat fibroblasts. These results suggest that the growth of MCA sarcoma cells is partially dependent upon glucocorticoids. This effect of glucocorticoids, however, was not of sufficient magnitude to improve survival and prevent cachexia. We conclude that glucocorticoids appear to influence MCA sarcoma growth in the rat, and that glucocorticoid receptor blockade, perhaps in combination with other antitumor agents, merits future study in the treatment of malignant tumors.     

Enhanced growth of an estrogen receptor-negative endometrial adenocarcinoma by estradiol in athymic mice

The aim of this study was to investigate the effects of estradiol and tamoxifen (TAM) on the growth of human endometrial carcinomas in athymic mice. Tissues from primary tumors were implanted into estradiol-treated mice. In passage 2, animals were treated with (a) placebo, (b) estradiol, (c) estradiol plus TAM, and (d) TAM alone. The size of the tumors was measured weekly. Estrogen receptors (ER) were determined with the dextran-coated charcoal method and/or ER enzyme-linked immunoassay. Progesterone receptors were measured with the dextran-coated charcoal technique. Of 16 primary tumors, 2 grew in the athymic mice and were studied further. Tumor EL was positive for ER (145 fmol/mg protein) and progesterone receptors (993 fmol/mg protein). Tumor EL in passage 2 was not significantly stimulated by estradiol, but was stimulated by a combination of estradiol and TAM. Treatments (estradiol, estradiol plus TAM, or TAM) all increased tumor growth in passage 3. Tumor BR and a metastasis BR-MET were ER and progesterone receptor negative, applying dextran-coated charcoal, ER enzyme-linked immunoassay, and immunocytochemistry. The BR and BR-MET cells contain the complete ER gene but do not express any measurable amounts of ER mRNA as quantitated by Northern blot analysis, using a complete ER complementary DNA probe. In all animal passages the growth rate was significantly higher in estradiol-treated mice compared with the control. TAM alone had some growth stimulatory effect, but much smaller than observed in the estradiol group. TAM inhibited estradiol-stimulated growth. These results suggest that estradiol and possibly TAM are capable of stimulating tumor growth in the athymic mice independently from ER, potentially through a host-mediated mechanism.     

Enhanced in vitro growth suppression of human glioblastoma cultures treated with the combination of recombinant fibroblast and immune interferons

In the present study we have evaluated the effect of recombinant human fibroblast, IFN-beta ser, and immune, IFN-gamma, interferon, alone and in combination, on the proliferation of fifteen early passage human glioblastoma cell cultures. Explant cultures were established from glioblastoma tumor tissue obtained at the time of surgery. After sufficient outgrowth, cultures were dispersed with trypsin/versene and maintained as independent cell lines. IFN-beta ser induced a greater than or equal to 50% reduction in the 7 day growth of 6 of the 15 cultures. The majority of cultures, 9 of 15, displayed less than or equal to 50% growth suppression in comparison with control cultures after 7 days exposure to 2000 Units/ml of IFN-beta ser. When treated with 2000 Units/ml of IFN-gamma, only 1 of the 15 glioblastoma cultures exhibited a greater than or equal to 50% reduction in growth. In contrast, when treated with the combination of IFN-beta ser plus IFN-gamma, 1000 Units/ml of each interferon preparation, 12 of 15 cultures were inhibited by greater than or equal to 50% after 7 days growth. The combination of interferons was effective in suppressing glioblastoma growth both in cultures displaying relative sensitivity and those exhibiting innate resistance to either or both types of interferon when employed alone. One glioblastoma culture, G-7, was studied through 45 passages and displayed the same sensitivity at different passages to growth inhibition when exposed to IFN-beta ser, IFN-gamma or both interferons. Based on previous clinical studies indicating that IFN-beta or IFN-gamma when administered alone to patients do not generally alter the clinical progression of malignant gliomas, the present results suggest that the combination of IFN-beta plus IFN-gamma may prove more effective than either agent alone in the clinical treatment of patients with glioblastoma multiforme.     

Enhanced photodynamic destruction of a transplantable fibrosarcoma using photochemical internalisation of gelonin

Photochemical internalisation (PCI) is a technique for releasing biologically active macromolecules from endocytic vesicles by light activation of a photosensitiser localised in the same vesicles of targeted cells. This study investigated the PCI of the toxin gelonin as a way of enhancing the effect of photodynamic therapy (PDT) on a human malignant fibrous histiocytoma transplanted into nude mice using the photosensitiser disulphonated aluminium phthalocyanine (AlPcS(2a)). Pharmacokinetic studies after intraperitoneal administration showed that the serum level of AlPcS(2a) fitted a biexponential model (half-lives of 1.8 and 26.7 h). The tumour concentration was roughly constant up to 48 h, although fluorescence microscopy showed that the drug location was initially mainly vascular, but became intracellular by 48 h. To compare PDT with PCI, 48 h after intraperitoneal injection of 10 mg kg(-1) AlPcS(2a), and 6 h after direct intratumour injection of 50 microg gelonin (PCI) or a similar volume of phosphate-buffered saline (PDT controls), tumour-bearing animals were exposed to red light (150 J cm(-2)). Complete response was observed for more than 100 days in 50% of the PCI tumours but only 10% of the PDT tumours (P<0.01). In tumours examined histologically 4 days after light delivery, the depth of necrosis was 3-4 mm after PDT, but 7 mm after PCI. The deeper effect after PCI demonstrates that the light fluence needed to kill tumour is less than with PDT. We conclude that PCI with gelonin can markedly enhance the effect of PDT on this type of tumour and may have a role clinically as an adjunct to surgery to control localised disease.     

Rapid growth of primary cerebral fibrosarcoma with conversion to glioblastoma at second recurrence

We present a case of de novo fibrosarcoma in a 43-year-old male, with MRI documented evolution from a 5 mm hyperintense area to 5 cm tumor mass in a 12-month period. The diagnosis of low-grade fibrosarcoma was established by three experienced neuropathologists. The patient underwent gross total resection with adjuvant fractionated conformal radiotherapy. Following first recurrence 3 months later, the patient was reoperated and stereotactic radiosurgery of a residual tumor was performed thereafter. The pathological diagnosis was similar, but with additional extensive radiation effects. Six months later the patient underwent aggressive surgical resection for second recurrence. The pathological diagnosis was WHO grade IV glioblastoma. The etiology of this highly unusual progression from primary mesenchymal neoplasm to high-grade glioma is discussed.     

Spontaneous lymphomas in mice genetically selected for high or low phytohemagglutinin responsiveness

Biozzi mice selected for high (Hi) or low (Lo) responsiveness to phytohemagglutinin (PHA) have been followed for their entire life-span to examine their pathology at death. Spontaneous lymphomas were found to exhibit higher incidence and faster development in Lo/PHA than in Hi/PHA females, whereas a similar difference between the two lines did not attain the level of statistical significance in male mice. The incidence of solid tumors was higher in Lo/PHA than in Hi/PHA males but the same in females of the two lines, yet the probability of dying from solid tumors was slightly increased in Lo/PHA mice of both sexes. All these results indicate that T-cell-mediated immunity influences mainly the spontaneous incidence of lymphomas and, to a lesser degree, the appearance of other solid tumors.     

Uterine carcinoma in mice treated neonatally with tamoxifen

The induction of preneoplastic and neoplastic lesions by the widely used antiestrogen Tamoxifen was studied in female mice. Outbred CD-1 mice were treated with Tamoxifen (1, 2, 5, 10, 25 or 50 microg/pup/day) for the first 5 days after birth. At 14-17 months, reproductive tract tissues were examined for pathological changes. In the ovary, corpora lutea were lacking while cysts were quite common in Tamoxifen-exposed mice at all doses; cystadenomas were seen in two mice. Structural malformations and epithelial hyperplasia of the oviduct were seen in 100% of the treated mice. Malformations of the uterus, cervix, and vagina were also seen. Excessive vaginal keratinization was not a common feature although vaginal adenosis was observed more often after Tamoxifen treatment than previously reported after similar treatment with diethylstilbestrol (DES). The most striking histological features, however, were seen in the uterus. One hundred percent of the Tamoxifen- treated mice at all doses exhibited uterine hypoplasia with focal areas of basal cell hyperplasia in the lining endometrium. Progressive cellular atypias were seen in the lining endometrium ranging from atypical hyperplasia to uterine adenocarcinoma; the highest incidence of uterine adenocarcinoma was 7/14 (50%) observed in the Tamoxifen 10 microg/pup/day dose group. No similar tumors were observed in corresponding control mice. The induction of atypical uterine hyperplasia and adenocarcinoma combined with other abnormalities observed in genital tract structure following neonatal treatment with Tamoxifen suggests the developing reproductive tract is exquisitely sensitive to perturbation by compounds with hormonal activity. These studies provide the basis for future investigation into the mechanisms of Tamoxifen's carcinogenic effects in experimental animals, and to the risk benefit analysis for the prophylactic use of Tamoxifen in healthy women who are at risk of developing breast cancer.