Combined cytotoxicity effect of hyperthermia and anthracycline antibiotics on human tumor cells.

The effects of temperature on the anthracycline antibiotics-induced cell kill of DND-1A human malignant melanoma (MM) and DND-39A Burkitt's lymphoma (BL) cell lines were studied by means of a clonogenic assay. The two cell lines differed in sensitivity when exposed to heat: The MM cells were unaffected by hyperthermia (42 degrees C), whereas BL cells were sensitive to this temperature. With the MM cells, hyperthermia potentiated the cytotoxic effects of doxorubicin (ADM), daunorubicin, mitoxantrone (DHAD), and quelamycin but did not enhance that of aclacinomycin (ACM). Conversely, the exposure of cells to the anthracycline compounds at 0 degree C resulted in almost complete disappearance of cell kill effects except with ACM; ACM retained substantial cell kill effects even at the given low temperature. For BL cells, ADM- or DHAD-induced cell lethality was also potentiated by hyperthermia; ACM produced only additive cell kill. At 0 degree C, ACM's effects virtually disappeared. These data indicate that human tumor cell lines have a substantial variety in heat sensitivity and that not every anthracycline antitumor agent is potentiated by temperature. ACM's thermoresponse is unique among anthracycline antibiotics studied. Additionally, it was shown that normothermic cell kill by ADM was not affected by hyperthermic preheating; however, preheating of appropriate duration produced important influence on subsequent hyperthermic ADM-induced cell kill.

Transplantation of human malignant mesothelioma into nude mice.

Human pleural malignant mesothelioma was successfully transplanted into nude mice from 2 of 3 patients. The tumor implants of the first generation grew in 6 of 20 mice (30%), with a take of implants of 17 of 32 (53%). Overall, tumors grew from 52 of 80 mice (65%) in a total of 169 of 266 implants (64%) during the first four generations. The mean delay between transplantation and tumor growth was 46 days (range, 18 to 104 days). Pathological examination by light and electron microscopy confirmed the nature of the growing tumors in nude mice. Pathology of transplanted tumors was grossly similar to the human tumors in both first- and second-generation transplants. Up to eight generations have been presently carried out with presence of a human karyotype in transplanted tumors. The potential usefulness of this model with particular reference to chemosensitivity of these tumors will be investigated.

Unattainable homeostasis in healing leads to interstitial and vascular intimal fibroses: a unified hypothesis of their pathogenesis.

Homeostasis, or the maintenance of constant internal environment in the organism, is disrupted by injury. In this case, pathological defence reactions such as inflammation and healing take place in order to restore it. They succeed if etiological harmful factors are eliminated. In the opposite case, constant injury leads to continuous healing and fibrosis. Both interstitial and vascular intimal fibroses have similar pathogeneses and may be provoked by the same etiological factors. It may be concluded, therefore, that in spite of their apparent differences, both fibroses are only the different expressions of the same process by which injury should be healed and homeostasis restored. Fibrosis itself may become dangerous for the patient, depending on its extent and on the affected organ. In this case, the inhibition of healing reaction by antiangiogenesis may be envisaged as a life-saving measure.

Ingrowth of hyperplastic capillary sprouts into fibrin clots: further evidence in favor of the angiogenic hypothesis of repair and fibrosis.

According to the conventional hypothesis and its variants, wound granulation tissue is formed by the proliferation and the migration of two closely cooperating but separated cell systems: the endothelial and the fibroblastic (including pericytes). While the elaborated theory of angiogenesis explains the former, there is not a similar theory concerning the latter. The recently proposed angiogenic hypothesis of repair and fibrosis unifies both cell systems by proposing endothelial origin for fibroblastic cells. It was formed on the basis of hyperplastic capillaries and vascular endothelium derived fibroblastic cells in chronic fibrotic diseases. The recent description of hyperplastic capillary sprouts in experimental fibrin clots confirms the validity of this hypothesis also in healing by primary and secondary intentions.