==================================BSR03================================== 3. Tumor and normal tissue blood flow in animals. Effect of hyperthermia and drugs on tumor and normal tissue blood flow. 1 UI - 87084960 AU - Reinhold HS ; Endrich B TI - Tumour microcirculation as a target for hyperthermia. AB - A great number of investigators have, independently, shown that tumour blood flow is affected by a hyperthermic treatment to a larger extent than normal tissue blood flow. While the majority of the studies on experimental tumours show a decrease and even a lapse in blood flow within the microcirculation during or after hyperthermia, the data on human tumours are less conclusive. Some of the investigators do not find a decrease in circulation, while others do. Obviously, this is an important field of investigation in the clinical application of hyperthermia because a shut down of the circulation would not only facilitate tumour heating (by reducing venous outflow, this reducing the 'heat clearance' from the tumour), but would also facilitate tumour cell destruction. The same holds for alterations that occur subsequently to the circulatory changes, like a heat-induced decrease of tissue pO2 and pH. If the frequently reported circulatory collapse of the tumour circulation could selectively be stimulated by, e.g. acidification or by vasoactive agents, hyperthermic treatment of patients would possibly be greatly facilitated and intensified. In hyperthermic tumour therapy a number of complex processes and interactions takes place, especially when the treatment is performed in combination with radiation therapy. One of them represents the group of processes related to the random probability of cell sterilization of individual tumour cells resulting in exponential survival curves which are typically evaluated with e.g. cell survival assays. This aspect has not been the issue of this paper. The other group of processes deals with the heat-induced changes in the micro-physiology of tumours and normal tissues which, as discussed before, may not only enhance the exponential cell kill, but which may also culminate in vascular collapse with the ensuing necrosis of the tumour tissue in the areas affected. If this takes place, a process of bulk killing of tumour cells results, rather than the random type of cell sterilization. At present it is not clear to what extent the various separate mechanisms contribute to the total effect of tumour control. With all these considerations in mind, one should be aware of the fact that effects, secondary to heat-induced vascular stasis alone will never be efficient enough to eliminate all tumour cells, even though a heat reservoir is created. This is so because some malignant cells will inevitably have already infiltrated normal, surrounding structures and will therefore not be affected by changes in the tumour vascular bed.(ABSTRACT TRUNCATED AT 400 WORDS) MH - Animal ; Human ; *Hyperthermia, Induced ; Microcirculation ; Neoplasms, Experimental/*BLOOD SUPPLY/THERAPY ; Review ; Support, Non-U.S. Gov't SO - Int J Hyperthermia 1986 Apr-Jun;2(2):111-37 2 UI - 87083036 AU - Mechling JA ; Strohbehn JW TI - A theoretical comparison of the temperature distributions produced by three interstitial hyperthermia systems. AB - Three interstitial hyperthermia systems were compared on the basis of their abilities to heat tumors: ferromagnetic seeds, microwave antennas, and rf electrode needles. The theoretical calculations were performed using two-dimensional tumor models containing static tissue and electrical properties and various blood flow patterns. Basic assumptions were kept the same to permit a meaningful comparison of the different systems. Power deposition patterns were calculated based on the appropriate theoretical expressions. The bioheat transfer equation was solved using a finite element method. Temperature distributions were calculated for four 1 or 2 mm diameter implants on the corners of 1, 2, and 3 cm squares. The tumor was assumed to be circular with a diameter 1 cm longer than the diagonal of each square. Three blood flow models were considered: homogeneous, nonhomogeneous, and concentric annulus perfusion models. The blood flow ranged from 0 to 100 ml/100 g/min with the ratio of tumor/normal tissue blood flow ranging from 0 to 40. A Hyperthermia Equipment Performance (HEP) rating was used as a criterion for comparing the temperature distributions from the various cases examined. As expected, the higher HEP ratings were generally produced by decreasing the spacing between the implants and/or lower blood perfusion rates. Under the conditions of this study, the microwave antennas were able to adequately heat a larger number of cases to therapeutic temperatures than either of the other two modalities. MH - Brachytherapy ; Comparative Study ; Computer Simulation ; Human ; Hyperthermia, Induced/*METHODS ; Microwaves ; Models, Biological ; Neoplasms/BLOOD SUPPLY/*THERAPY ; Support, U.S. Gov't, Non-P.H.S. ; Support, U.S. Gov't, P.H.S. ; Temperature SO - Int J Radiat Oncol Biol Phys 1986 Dec;12(12):2137-49 3 UI - 87059500 AU - Bastida E ; Escolar G ; Ordinas A ; Jamieson GA TI - Morphometric evaluation of thrombogenesis by microvesicles from human tumor cell lines with thrombin-dependent (U87MG) and adenosine diphosphate-dependent (SKNMC) platelet-activating mechanisms. AB - The Baumgartner perfusion apparatus has been used for quantitative comparison of the interaction of platelets with subendothelium in the presence of microvesicles derived from SKNMC (human neuroblastoma) cells, which aggregate platelets by an adenosine diphosphate (ADP)-dependent mechanism, and U87MG (human glioblastoma) cells, which function by a thrombin-dependent mechanism. The derived microvesicles from each line were as effective as the intact cells in inducing thrombogenesis on both undigested and alpha-chymotrypsin-digested subendothelium. Thrombus size on digested vessels was greater than on undigested vessels by fivefold for SKNMC cells and microvesicles and by 20-fold for U87MG cells and sevenfold for U87MG microvesicles. The results show that microvesicles from both cell lines initiate interactions between platelets and subendothelium identical to those caused by intact tumor cells. The results also demonstrate that intact tumor cells in the circulation may not be necessary for the thromboembolic complications of malignancy. MH - Adenosine Diphosphate/*PHARMACODYNAMICS ; Blood Platelets/*DRUG EFFECTS/ METABOLISM ; Cell Line ; Chymotrypsin/METABOLISM ; Human ; Microcirculation ; Neoplasms/*BLOOD SUPPLY ; Perfusion ; Platelet Aggregation ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; Thrombin/*PHARMACODYNAMICS ; Time Factors SO - J Lab Clin Med 1986 Dec;108(6):622-7 4 UI - 87051346 AU - DiPette DJ ; Ward-Hartley KA ; Jain RK TI - Effect of glucose on systemic hemodynamics and blood flow rate in normal and tumor tissues in rats. AB - The effect of hyperglycemia on systemic hemodynamics and blood flow rate of Walker 256 carcinoma and several normal tissues of unanesthetized, unrestrained female Sprague-Dawley rats was measured, using the radioactive microsphere technique prior to and at 30 and 60 min after glucose administration (6 g/kg body weight i.v.). Whereas the mean arterial pressure and heart rate remained unchanged following glucose injection, cardiac output (CO), cardiac index, and stroke volume decreased by approximately 25% (P less than 0.05), and the total peripheral resistance increased by more than 25% (P less than 0.05). Redistribution of blood flow, expressed as a percentage of CO, among normal tissues was traced to the brain, kidneys, spleen, and liver and away from the skin, pancreas, and stomach. Changes in percentage of CO to the jejunum, colon, peritumor muscle, hindlimb, and forelimb muscles were not significant. Reduction in blood flow in large tumors (greater than 0.6 g) was proportional to the reduction in CO, and in small tumors (less than 0.6 g) was more than the reduction in CO. These results suggest that the reduction in blood flow due to hyperglycemia in large tumors is primarily due to reduction in CO and in small tumors due to both systemic and local effect; and changes in the blood flow to normal tissues should not be disregarded when using hyperglycemia in combination with hyperthermia and/or chemotherapy for cancer treatment. MH - Animal ; Blood Glucose/ANALYSIS ; Cardiac Output/DRUG EFFECTS ; Female ; Glucose/*PHARMACODYNAMICS ; Hemodynamics/*DRUG EFFECTS ; Hyperthermia, Induced ; Microspheres ; Neoplasms, Experimental/BLOOD SUPPLY/ *PHYSIOPATHOLOGY ; Rats ; Rats, Inbred Strains ; Regional Blood Flow/DRUG EFFECTS ; Support, U.S. Gov't, P.H.S. SO - Cancer Res 1986 Dec;46(12 Pt 1):6299-304 5 UI - 87002186 AU - Creasey AA ; Reynolds MT ; Laird W TI - Cures and partial regression of murine and human tumors by recombinant human tumor necrosis factor. AB - We tested the effect of recombinant human tumor necrosis factor (TNF) on the growth of the murine methylcholanthrene induced fibrosarcoma and the human ovarian carcinoma (NIH:OVCAR-3) in mice. The mice received multiple doses (25-250 micrograms/kg) of TNF starting 7-10 days after s.c. transplantation of tumors when they were easily palpable. TNF was administered i.v. every other day for a total of 6 injections per mouse, or i.p. daily for 7 days. Complete tumor regression was observed in the methylcholanthrene induced tumor bearing mice in 90% of the mice treated with TNF (100 micrograms/kg), 67% treated with TNF (50 micrograms/kg), and 34% treated with TNF (25 micrograms/kg). Tumors which did not completely regress were growth retarded during the course of TNF treatment. All mice given the highest TNF dose are still alive and tumor free (currently over 400 days), whereas the median survival of control mice was 28-39 days. Partial regression was observed in 100% of mice bearing the ovarian carcinoma treated i.p. with 250 micrograms/kg. Injections of TNF i.v. resulted in higher percentage of cures than i.p. injections at similar dose levels. These results suggest that tumor necrosis factor represents a likely potent drug against solid tumors and that the method of administration is critical in optimizing its use in cancer. MH - Animal ; Cell Survival/DRUG EFFECTS ; Cells, Cultured ; Drug Administration Schedule ; Female ; Glycoproteins/*ADMINISTRATION & DOSAGE ; Human ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Transplantation ; Ovarian Neoplasms/*DRUG THERAPY ; Recombinant Proteins/ ADMINISTRATION & DOSAGE ; Sarcoma, Experimental/BLOOD SUPPLY/*DRUG THERAPY SO - Cancer Res 1986 Nov;46(11):5687-90 6 UI - 86277549 AU - Baba T ; Aoki K ; Kuroiwa T ; Taniguchi S TI - Some cardiotonics enhance the effectiveness of angiotensin II-induced hypertension cancer chemotherapy in mice. AB - Angiotensin II-induced hypertension chemotherapy proved to be more effective than conventional chemotherapy using cis-diamminedichloroplatinum (II) (DDP), when applied to an established mouse mammary carcinoma. In an attempt to improve the effectiveness, a cardiotonic such as aminophylline or trans-pi-oxocamphor was added to a solution containing angiotensin II and DDP. A remarkable improvement in therapeutic efficacy was apparent as compared to angiotensin II hypertension chemotherapy. A possible synergism between angiotensin II and the cardiotonic may result in selective delivery of the antitumor drug to the tumor tissue. MH - Aminophylline/THERAPEUTIC USE ; Angiotensin II/*THERAPEUTIC USE ; Animal ; Blood Pressure/*DRUG EFFECTS ; Cardiotonic Agents/*THERAPEUTIC USE ; Cisplatin/THERAPEUTIC USE ; Drug Synergism ; Female ; Mice ; Mice, Inbred Strains ; Neoplasms, Experimental/BLOOD SUPPLY/*DRUG THERAPY ; Support, Non-U.S. Gov't SO - Jpn J Cancer Res 1986 May;77(5):432-5 7 UI - 86274931 AU - de Vries EG ; Beekhuis H ; de Jong R ; Mulder NH ; Piers DA TI - Evidence for capillary leakage during chemotherapy in man. AB - The influence of intensive chemotherapy with high dose VP 16-213, cyclophosphamide and autologous bone marrow transplantation on transcapillary escape rate of albumin was evaluated. Transcapillary escape rate and plasma volume were measured with 131I-labelled albumin. Measurements were performed 1 day before (T0), 1 week after (T1) and 2 weeks after (T2) start of chemotherapy. Before therapy TER (n = 7, means = 7.1% h-1) was already raised in patients compared to controls (n = 5, means = 3.8% h-1, P less than 0.025). No difference was found for transcapillary escape rate on T1 (n = 9, means = 7.6% h-1) compared to T0. There was an increase of transcapillary escape rate from T0 to T2 (n = 8, means = 9.5% h-1, P less than 0.05). Plasma volume did not change during therapy. Serum albumin concentrations were reduced before chemotherapy (means = 38 g 1(-1] compared to controls (means = 44 g l(-1]. After 1 (means = 34 g 1(-1] and 2 weeks (means = 31 g 1(-1] these concentrations decreased further. The same was found for intravascular mass of albumin related to body weight. The intravascular mass of albumin/bodyweight and the transcapillary escape rate are related in the patients (r = -0.477, P less than 0.01) and the patients plus controls (r = -0.585, P less than 0.001). This means the higher the transcapillary escape rate the lower the intravascular mass of albumin. No correlation between transcapillary escape rate and presence of fever was found. It can be concluded that intensive chemotherapy leads to further increase of an already elevated transcapillary escape rate for albumin. MH - Adult ; Antineoplastic Agents, Combined/*ADVERSE EFFECTS ; Capillary Permeability/*DRUG EFFECTS ; Cyclophosphamide/ADMINISTRATION & DOSAGE/ ADVERSE EFFECTS ; Etoposide/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS ; Female ; Human ; Male ; Middle Age ; Neoplasms/BLOOD SUPPLY/DRUG THERAPY/ METABOLISM ; Serum Albumin/METABOLISM SO - Eur J Clin Invest 1986 Jun;16(3):243-7 8 UI - 86271742 AU - Boddie AW Jr ; Wright K ; Frazer JW ; Stephens LC ; Montgomery L ; McBride CM ; Wallace S ; Martin RG TI - Mechanisms of synergism between arteriolar embolization and hyperthermia in a rabbit V-2 model of solitary hepatic metastasis. AB - In a V-2 model of solitary hepatic metastasis, residual tumor was histologically identified in the treatment field in only three of 14 (21%) animals subjected to microsphere embolization of tumor arterioles plus focal (43 degrees C, 40 min) hyperthermia compared with seven of ten (70%) subjected to focal (43 degrees C, 40 min) hyperthermia alone (P less than or equal to 0.05), five of seven (71%) (P less than or equal to 0.05) treated by occlusion plus sham heating, and five of five (100%) (P less than or equal to 0.01) sham-treated controls. Prior occlusion tended to reduce the radiofrequency power required for heat up and steady-state temperature maintenance of tumors (P less than or equal to 0.09 and P less than or equal to 0.06, respectively) and reduced the cooling rate after heating compared to unoccluded tumors (P less than or equal to 0.02) but did not affect mean time to temperature, maximum and minimum temperature measured at the tumor-normal tissue interface, and animal core temperature compared with that of the hyperthermia alone treatment group. In ten other animals with hepatic V-2 tumors of comparable size subjected to focal hyperthermia plus or minus arteriolar embolization, temperatures were continuously monitored at four additional intratumor sites in a fixed geometric orientation around the heating probe. No significant differences were noted in maximum and minimum temperatures in comparably oriented probes over a 40-min heating period between the hyperthermia and the occlusion-hyperthermia treatment groups. In five other animals with solitary V-2 hepatic implants, comparable microembolization plus or minus focal tumor heating to 43 degrees C, 40 min, did not significantly reduce tumor interstitial pH compared with pretreatment values. This study reproduces previously observed synergism between arteriolar embolization and hyperthermia but suggests the mechanism may be unrelated to observable differences in intratumor pH and thermal profile and may result from other mechanisms, perhaps by mimicking the angioocclusive effects of hyperthermia itself. MH - Animal ; Embolization, Therapeutic ; Hydrogen-Ion Concentration ; Hyperthermia, Induced ; Liver Neoplasms/BLOOD SUPPLY/*SECONDARY ; Neoplasms, Experimental/*THERAPY ; Rabbits ; Support, U.S. Gov't, P.H.S. SO - Cancer Res 1986 Sep;46(9):4576-81 9 UI - 86263070 AU - Daehlin L ; Damber JE TI - Blood flow in the Dunning R3327H rat prostatic adenocarcinoma; effects of oestradiol and testosterone. AB - Copenhagen X Fischer F1 rats were implanted with Dunning R3327H prostatic adenocarcinoma and studied over a period of three weeks. The tumour volumes in intact and testosterone supplemented castrated rats showed parallel increases. After castration alone the tumour volumes decreased. Treatment of castrates with oestradiol and testosterone combined produced an arrest of tumour growth, suggesting that oestradiol had a direct inhibitory effect on tumour growth. Blood flow in tumours was measured using the microsphere technique. In intact rats, tumour blood flow per unit of weight decreased with increasing weight of tumours and blood flow in peripheral parts was higher than in central parts of large tumours. Oestradiol in combination with testosterone increased tumour blood flow. MH - Adenocarcinoma/BLOOD/*BLOOD SUPPLY/PATHOLOGY ; Animal ; Estradiol/ *PHARMACODYNAMICS ; Male ; Muscles/BLOOD SUPPLY ; Orchiectomy ; Organ Weight/DRUG EFFECTS ; Prostate/ANATOMY & HISTOLOGY/BLOOD SUPPLY ; Prostatic Neoplasms/BLOOD/*BLOOD SUPPLY/PATHOLOGY ; Rats ; Regional Blood Flow/DRUG EFFECTS ; Renal Circulation/DRUG EFFECTS ; Seminal Vesicles/ BLOOD SUPPLY ; Support, Non-U.S. Gov't ; Testosterone/BLOOD/ *PHARMACODYNAMICS SO - Urol Res 1986;14(2):113-7 10 UI - 86252679 AU - Nussbaum GH ; Babbs CF ; Mintun MA TI - Results of a preliminary study of the potential of vasodilators for improving thermotherapy of deep-seated tumours. AB - Administration of the vasodilator hydralazine to a single mongrel dog with a transplanted, superficial transmissible venereal tumour in the abdomen permitted tumour-adjacent normal tissue temperature differences produced in local hyperthermia to be enhanced by nearly 2 degrees C. A preliminary study of tumour and normal tissue perfusion rate in the dog, employing the 15O-labelled water-positron emission tomography technique, suggested that administration of the vasodilator led to a significant reduction in the tumour perfusion rate, consistent with the observed tumour temperature enhancement. Computational studies with a multi-layer, one-dimensional cylindrical model of deep-tumour heating suggest that vasodilator-induced reductions of tumour perfusion rates could significantly increase deep tumour-superficial normal tissue temperature differences produced in deep-tumour thermotherapy. MH - Animal ; Dog Diseases/THERAPY ; Dogs ; Evaluation Studies ; Hydralazine/ PHARMACODYNAMICS ; *Hyperthermia, Induced ; Neoplasm Transplantation ; Neoplasms, Experimental/BLOOD SUPPLY/*THERAPY ; Vasodilator Agents/ *THERAPEUTIC USE ; Venereal Tumors, Veterinary/BLOOD SUPPLY/*THERAPY SO - Int J Hyperthermia 1986 Jan-Mar;2(1):61-4 11 UI - 86252676 AU - Knudsen M ; Heinzl L TI - Two-point control of temperature profile in tissue. AB - A strategy for controlling the temperature profile in the tissue with a single applicator hyperthermia system is described. By manipulating the cooling water temperature as well as the heating power, the tissue temperatures in two selected locations can be controlled. By proper choice of these two locations and the corresponding temperature set-points, a temperature maximum can be obtained in a fairly superficial tumour. If the tissue composition and consequently the temperature distribution is fairly regular, a temperature profile above 43 degrees C in the tumour and below that in normal tissue can be obtained along an axis perpendicular to the surface. The controller is self-tuning and provides dynamic decoupling, bumpless transfer and anti-reset windup. Test of the controller by simulation and on a phantom indicates it is superior to the single point controller currently used. MH - Adipose Tissue/BLOOD SUPPLY ; *Body Temperature ; Human ; Hyperthermia, Induced/INSTRUMENTATION/*METHODS ; Microcomputers ; Models, Biological ; Muscles/BLOOD SUPPLY ; Neoplasms/BLOOD SUPPLY ; Regional Blood Flow ; Skin/BLOOD SUPPLY SO - Int J Hyperthermia 1986 Jan-Mar;2(1):21-38 12 UI - 86249944 AU - Paskins-Hurlburt AJ ; McCracken S ; Hollenberg NK TI - Autonomy extends to the arterial supply of rapidly growing tumors. Studies on the feeder vessel to carcinoma in rat testis. AB - There has been longstanding interest in the characteristics of "feeder vessels: to tumors. To develop a convenient model for assessing the determinants of the responsiveness of the arterial blood supply to tumors, we assessed by arteriography the response of the spermatic artery to norepinephrine, vasopressin, and ergonovine after implantation of Walker carcinoma in the testis of the rat. Loss of response to norepinephrine of the spermatic artery supply to the tumor occurred by the fourth day of tumor growth in this model, along the entire length of the spermatic artery. As expected, there was sustained vasoconstriction of the contralateral spermatic artery to the normal testis in response to norepinephrine. Vasopressin and ergonovine exerted no effect, so that the specificity of the loss of response to norepinephrine remains unclear. The spermatic artery provides an accessible and convenient model for studying the blood supply to tumors. MH - Animal ; Arteries/DRUG EFFECTS/*PHYSIOPATHOLOGY ; Carcinoma 256, Walker/ *BLOOD SUPPLY/PHYSIOPATHOLOGY ; Ergonovine/PHARMACODYNAMICS ; Male ; Neoplasm Transplantation ; Norepinephrine/PHARMACODYNAMICS ; Rats ; Rats, Inbred Strains ; Support, U.S. Gov't, P.H.S. ; Testicular Neoplasms/ *BLOOD SUPPLY/PHYSIOPATHOLOGY ; Testis/*BLOOD SUPPLY ; Vasopressins/ PHARMACODYNAMICS SO - Invest Radiol 1986 Jun;21(6):455-8 13 UI - 86247989 AU - Katsuragi M ; Obara T ; Makino T ; Ito S ; Ura H ; Yoshiya K ; Ohishi G ; Uchida H ; Konishi Y TI - Vascular changes associated with growth of primary and transplantable pancreatic adenocarcinomas induced in Syrian golden hamsters by N-nitrosobis(2-oxopropyl)amine (BOP) and N-nitrosobis(2-hydroxypropyl)amine (BHP). AB - Microangiographic and histological methods were used to characterize vascular structure of primary and transplantable pancreatic adenocarcinomas induced by propylnitrosamines in Syrian golden hamsters. Originally of well-differentiated tubular morphology, serial transplantation subcutaneously to the back region was not associated with change in histopathological pattern or increase in invasive or metastatic potential. In contrast, pancreatic subserosal grafts displayed prominent invasion of surrounding tissues. Whereas primary tumors induced by N-nitrosobis(2-oxopropyl)amine (BOP) and those transplanted subserosally were characterized by hypovascularity, subcutaneous transplantation resulted in hypervascular tumors. Encasement, which is defined as invasion of normal arteries by the tumor, showing uneven caliber, irregular outline, appeared on earlier microangiographic findings rather than luminal irregularity, which is change of tumor vessels in neovascularization and occurs in tumor blood vessels subsequent to transplantation. The vascular component of subcutaneously transplanted tumors had a total vessel length ranging from 9.2 +/- 0.7 mm to 18.1 +/- 1.1 mm, a total vessel surface from 2.5 +/- 0.4 mm2 to 9.3 +/- 0.6 mm2 and a total vessel volume from 0.07 +/- 0.02 mm3 to 0.49 +/- 0.04 mm3, indicating that the vessels were of relatively large diameter and short length. MH - Adenocarcinoma/ANALYSIS/*BLOOD SUPPLY/CHEMICALLY INDUCED ; Angiography/ METHODS ; Animal ; Blood Vessels/ANALYSIS/*PATHOLOGY ; Injections, Subcutaneous ; Male ; Mathematics ; Mesocricetus ; Neoplasm Transplantation ; Neoplasms, Experimental/ANALYSIS/*BLOOD SUPPLY ; Nitrosamines/ADMINISTRATION & DOSAGE/*PHARMACODYNAMICS ; Pancreatic Neoplasms/ANALYSIS/*BLOOD SUPPLY/CHEMICALLY INDUCED ; Support, Non-U.S. Gov't SO - Exp Pathol 1986;29(3):129-42 14 UI - 86243009 AU - Robinson BA ; Clutterbuck RD ; Millar JL ; McElwain TJ TI - Effects of verapamil and alcohol on blood flow, melphalan uptake and cytotoxicity, in murine fibrosarcomas and human melanoma xenografts. AB - Verapamil had previously been shown to increase cellular melphalan uptake and cytotoxicity in fibrosarcomas, and increased the area under the blood concentration versus time curve (AUC) for melphalan in CBA mice. Verapamil (10 mg kg-1 i.p.) had no effect on the fractional distribution of cardiac output (FDCO), measured with 86Rb-rubidium chloride, to subcutaneous fibrosarcomas. 14C-Melphalan uptake by FS13 fibrosarcomas was increased 60 min after verapamil (10 mg kg-1 i.p.), but not after lower doses which did not affect the AUC. Flunarizine (5 mg kg-1 i.p.) also had no effect on FDCO to FS13 fibrosarcomas, and tended to increase 14C-melphalan content of blood and the fibrosarcomas and to promote growth delay by melphalan. Alcohol increased FDCO to FS13 fibrosarcomas, maximally at a 1:20 dilution in saline, but had no effect on 14C-melphalan uptake or growth delay. Thus, melphalan cytotoxicity correlated with tumour melphalan uptake, and both followed changes in the AUC for melphalan but not changes in FDCO. In these murine fibrosarcomas melphalan uptake and cytotoxicity were not limited by blood flow. In subcutaneous human melanoma HX46 xenografts, verapamil had no effect on the FDCO, nor on 14C-melphalan uptake, and did not affect blood 14C-melphalan levels, suggesting absence of effects on the AUC and on cellular uptake. Alcohol did not increase the FDCO to HX46 xenografts, providing evidence for a different vascular supply. MH - Alcohol, Ethyl/*PHARMACODYNAMICS ; Animal ; Cinnarizine/ANALOGS & DERIVATIVES/PHARMACODYNAMICS ; Drug Synergism ; Female ; Fibrosarcoma/ *BLOOD SUPPLY/DRUG THERAPY/METABOLISM ; Human ; Male ; Melanoma/*BLOOD SUPPLY/DRUG THERAPY/METABOLISM ; Melphalan/*METABOLISM/THERAPEUTIC USE ; Mice ; Mice, Inbred CBA ; Regional Blood Flow/DRUG EFFECTS ; Support, Non-U.S. Gov't ; Verapamil/*PHARMACODYNAMICS SO - Br J Cancer 1986 May;53(5):607-14 15 UI - 86242299 AU - Lazo JS TI - Endothelial injury caused by antineoplastic agents. AB - The vascular lining of the blood vessels to normal organs and malignant tissues would be expected to reflect the functional demands placed upon it. These functional requirements may be accomplished by specific biochemical macromolecules, some of which are localized on the plasma membrane of the endothelium. Considerable evidence exists that toxicity to at least some normal organs caused by antineoplastic agents is heralded by endothelial damage. This endothelial damage may reflect a specific drug-endothelium interaction, the mechanism and basis of which are not yet understood. The possibility also exists that destruction of solid tumors by currently employed antitumor agents is mediated in part by local loss of essential vasculature. Selective destruction of the tumor endothelium could be a rational and novel target to which drugs could be designed. MH - Animal ; Antineoplastic Agents ; Bleomycins ; Blood Vessels/*DRUG EFFECTS/ RADIATION EFFECTS ; Cyclophosphamide ; Endothelium/DRUG EFFECTS/ PHYSIOLOGY/ULTRASTRUCTURE ; Human ; Intercellular Junctions ; Neoplasms/ BLOOD SUPPLY ; Nitrosourea Compounds ; Review ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. SO - Biochem Pharmacol 1986 Jun 15;35(12):1919-23 16 UI - 86227803 AU - Selman SH ; Kreimer-Birnbaum M ; Chaudhuri K ; Garbo GM ; Seaman DA ; Keck RW ; Ben-Hur E ; Rosenthal I TI - Photodynamic treatment of transplantable bladder tumors in rodents after pretreatment with chloroaluminum tetrasulfophthalocyanine. AB - Chloroaluminum tetrasulfophthalocyanine (AlPCS) was used as a photosensitizer for the photodynamic treatment of transplantable N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) induced urothelial tumors. Two groups of six rats each were injected with AlPCS (three micrograms./gm. body weight) and 24 hours after injection underwent photodynamic treatment with red light (greater than 590 nm., 360 joules/cm.2). Tumors examined four hours (Group I) and 24 hours (Group II) after the completion of phototreatment showed extensive hemorrhagic necrosis. Tumors treated with AlPCS alone showed no changes. In two other groups of six rats each, blood flow to tumors treated with AlPCS alone (Group III) and AlPCS plus light (Group IV) was measured using the radioactive microsphere technique. AlPCS plus light resulted in a significant decrease (p less than .05) in tumor blood flow within 10 minutes of completion of phototreatment while AlPCS alone had no effect on tumor blood flow. These findings are similar to those observed when higher doses (10 micrograms./gm. to 20 micrograms./gm. body weight) of hematophorphyrin derivative (HpD) and light were used for phototreatment of FANFT induced tumors. AlPCS is a stable sulfonated derivative of tetraazotetrabenzoporphyrin which absorbs maximally in the red portion of the visible spectrum, a region with good tissue penetration properties. These studies suggest the AlPCS may be a useful new agent for photodynamic therapy of cancer. MH - Animal ; Bladder Neoplasms/BLOOD SUPPLY/*DRUG THERAPY/PATHOLOGY ; Indoles/ PHARMACODYNAMICS/*THERAPEUTIC USE ; Male ; Neoplasm Transplantation ; Rats ; Rats, Inbred F344 ; Regional Blood Flow/DRUG EFFECTS ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. SO - J Urol 1986 Jul;136(1):141-5 17 UI - 86226580 AU - Bomber P ; McCready R ; Hammersley P TI - Propranolol hydrochloride enhancement of tumor perfusion and uptake of gallium-67 in a mouse sarcoma. AB - The effect of propranolol hydrochloride on the blood perfusion of a mouse sarcoma and other tissues has been studied using 86Rb. The maximum increase in relative tumor perfusion (2x controls) occurred 15 min after an i.v. administration of 10 mg per kg propranolol hydrochloride. To study the effect of this drug on the uptake of 67Ga, it was injected at a concentration of 10 mg/kg 10 min before administering 3 microCi (110 kBq) [67Ga]citrate. Tissue uptakes were measured 4 hr later. The tumor: blood ratio increased from 1.16 +/- 0.17 to 3.41 +/- 2.27 (s.d.) and tumor: liver ratio increased from 2.39 +/- 0.30 to 7.13 +/- 3.52 (s.d.). The results showed that propranolol hydrochloride can improve the relative tumor blood flow and radiopharmaceutical concentration in an animal model. It is hoped that this and other agents will yield similar results in the human situation. MH - Animal ; Cardiac Output ; Gallium Radioisotopes/*DIAGNOSTIC USE/ METABOLISM ; Mice ; Mice, Inbred BALB C ; Propranolol/*PHARMACODYNAMICS ; Regional Blood Flow/DRUG EFFECTS ; Sarcoma, Experimental/BLOOD SUPPLY/ METABOLISM/*RADIONUCLIDE IMAGING ; Tissue Distribution SO - J Nucl Med 1986 Feb;27(2):243-5 18 UI - 86217734 AU - Braunschweiger PG ; Schiffer LM TI - Effect of dexamethasone on vascular function in RIF-1 tumors. AB - The present series of experiments was conducted to determine the effect of dexamethasone on vascular function and cell proliferation in s.c. RIF-1 tumors. 125I-BSA, 51Cr-EDTA dilution techniques were used to evaluate dexamethasone induced changes in tumor plasma water, capillary permeability, and extracellular water volumes, while 59Fe and 51Cr labeled erythrocyte techniques were used to assess changes in tumor exchangeable erythrocyte volumes. 86RbCl distribution studies were also conducted to evaluate vascular perfusion in RIF-1 tumors after dexamethasone treatment. In this corticosteroid receptor containing tumor model, dexamethasone had profound effects on all of the measured parameters of vascular function. Reduced tumor cell proliferation after dexamethasone treatments was accompanied by reduced capillary permeability, reduced interstitial water volumes, increased plasma volumes, and reduced vascular perfusion. Serial studies after dexamethasone treatments indicated that increases in vascular perfusion preceded proliferative recovery. Intervals of maximal [3H]thymidine labeling after dexamethasone were characterized by transient increases in capillary permeability, interstitial water volumes, and tumor erythrocyte exchange with the general circulation. At intervals of maximal cell proliferation (36-48 h after dex) 86RbCl distribution in tumors was about 3 times that seen in untreated controls. The results seem to indicate that, as in edematous normal tissues, dexamethasone can have profound effects on vascular function and water compartmentalization in RIF-1 tumors. MH - Animal ; Capillary Permeability/DRUG EFFECTS ; Dexamethasone/ *PHARMACODYNAMICS ; Extracellular Space/PHYSIOLOGY ; Female ; Mice ; Neoplasms, Experimental/*BLOOD SUPPLY ; Regional Blood Flow/DRUG EFFECTS ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; Water-Electrolyte Balance/DRUG EFFECTS SO - Cancer Res 1986 Jul;46(7):3299-303 19 UI - 86217725 AU - Weiss L ; Tveit E ; Jansson I ; Hultborn R TI - Vascular reactivity to norepinephrine of 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors and normal tissue as studied in vitro. AB - Vascular reactivity to norepinephrine has been studied in dimethyl-benz(a)anthracene-induced rat mammary neoplasia and compared with that of skeletal muscle, salivary gland, kidney, and uterus by means of an artificial perfusion technique. Perfusion of tissues and organs was measured with the microsphere tracer technique during smooth muscle relaxation and infusion of norepinephrine at two different dose levels. This procedure makes possible a dose-response analysis of several tissues under controlled conditions without confounding endogenous vasoregulation. The tumor vascular bed has a low perfusion capacity during smooth muscle relaxation and responds rapidly with an increased resistance to norepinephrine infusion. The results indicate a hypersensitivity, although the relative maximal constrictor response is equal to or less than that of other vascular beds studied. MH - Animal ; Female ; Mammae/*BLOOD SUPPLY ; Mammary Neoplasms, Experimental/ *BLOOD SUPPLY ; Norepinephrine/*PHARMACODYNAMICS ; Perfusion ; Rats ; Regional Blood Flow/DRUG EFFECTS ; Support, Non-U.S. Gov't ; Vascular Resistance/DRUG EFFECTS ; Vasomotor System/DRUG EFFECTS ; 9,10-Dimethyl-1,2-Benzanthracene SO - Cancer Res 1986 Jul;46(7):3254-7 20 UI - 86213779 AU - Peterson HI TI - Tumor angiogenesis inhibition by prostaglandin synthetase inhibitors. AB - The release of prostaglandins from tumor cells seems to play an important role in tumor angiogenesis, in which platelet-derived factors may be also included. Administration of prostaglandin synthetase inhibitors reduces the growth of both experimental and human malignant tumors. One explanation may be reduced tumor vascularization, as observed in microangiographic studies of experimental transplantable tumors. A similar effect was observed after induced thrombocytopenia. A number of angiogenesis stimulating factors have been isolated from tumors during recent years. Factors released from host cells in the tumor area (e.g., mast cells, macrophages) with similar properties may also contribute to tumor vascularization. This seems to make stimulation of tumor angiogenesis to a rather complicated cascade of events, about which more must be learned before efficient inhibition of tumor vascularization can be attained. The target cell for angiogenesis stimulation, the endothelial cell, seems increasingly important as an object for future studies. MH - Animal ; Blood Platelets/PHYSIOLOGY ; Endothelium/PHYSIOLOGY ; Human ; Indomethacin/PHARMACODYNAMICS ; Neoplasms, Experimental/*BLOOD SUPPLY ; *Neovascularization ; Prostaglandin Synthase/*ANTAGONISTS & INHIBITORS ; Prostaglandins/PHYSIOLOGY ; Rabbits ; Thrombocytopenia/PHYSIOPATHOLOGY SO - Anticancer Res 1986 Mar-Apr;6(2):251-3 21 UI - 86206681 AU - Wallen CA ; Colby TV ; Stewart JR TI - Cell kill and tumor control after heat treatment with and without vascular occlusion in RIF-1 tumors. AB - RIF-1 tumors (100-300 mg) were exposed in vivo to heat treatment (41-48 degrees C) for 30 min and then assayed for either cell survival or tumor control. The tumors were heated either with normal perfusion or with temporary vascular occlusion (clamped for 30 min prior to and during the 30-min treatment). The physical technique of water bath heating ensured temperature uniformity in both the perfused and vascularly occluded tumors. Survival curves for tumor cells heated under both conditions had a shoulder and exponential regions. While the T0's were not statistically different in the two cases, cells from the tumors whose blood flow had been occluded showed an enhanced sensitivity to heat as evidenced by a reduction of the shoulder by 2.5 degrees C. A similar increase in sensitivity was measured with the tumor cure assay with the TCT50 decreasing from 47 degrees C for unclamped tumors to 45 degrees C for clamped tumors. The two assays are therefore in excellent agreement in assessing the effectiveness of heat treatment and the influence of vascular occlusion on the heat sensitivity of this tumor. Since the clonogenic assay was performed immediately after treatment, this agreement between assays indicates that direct cell kill by heat is the major factor in determining cure in this tumor. MH - Animal ; Cell Survival ; Constriction ; Female ; *Hyperthermia, Induced ; Male ; Mice ; Mice, Inbred C3H ; Neoplasms, Experimental/BLOOD SUPPLY/ *THERAPY ; Support, U.S. Gov't, P.H.S. ; Time Factors ; Tumor Stem Cell Assay SO - Radiat Res 1986 May;106(2):215-23 22 UI - 86189755 AU - MacPherson GG ; North RJ TI - Endotoxin-mediated necrosis and regression of established tumours in the mouse. A correlative study of quantitative changes in blood flow and ultrastructural morphology. AB - The fractional distribution of cardia output was measured in tumour-bearing mice treated with 50 micrograms intravenous endotoxin, and correlated with ultrastructural changes in tumour morphology. The proportion of the cardiac output going to the tumour decreased to less than 50% of its original value by 2 h and to 10%-30% by 6 h after giving endotoxin. Because endotoxin decreases absolute cardiac output, the actual perfusion of the tumour will be considerably less than these figures suggest. The decrease in perfusion correlated closely with changes in vascular morphology. Venous congestion on the tumour edge started within 1 h of giving endotoxin and by 3 h, endothelial damage and platelet aggregates were visible. At this time, all cells, tumour, connective tissue and infiltrate in the tumour centre were dead or damaged. By 24-48 h a conspicuous infiltrate of neutrophils and macrophages was present on the edge of the tumour and many of these cells were closely related to tumour cells. We suggest that the haemorrhagic necrosis may be caused by vascular obstruction leading to hypoxia and that the subsequent regression is mediated by activated macrophages and perhaps by neutrophils. MH - Animal ; Cardiac Output ; Endotoxins/*PHARMACODYNAMICS ; Glycoproteins/ PHYSIOLOGY ; Macrophage Activation ; Mice ; Mice, Inbred C57BL ; Necrosis ; Neoplasms, Experimental/BLOOD SUPPLY/DRUG THERAPY/*ULTRASTRUCTURE ; Neutrophils/PATHOLOGY/PHYSIOLOGY ; Phagocytes/PATHOLOGY ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; T Lymphocytes/IMMUNOLOGY SO - Cancer Immunol Immunother 1986;21(3):209-16 23 UI - 86189571 AU - Star WM ; Marijnissen HP ; van den Berg-Blok AE ; Versteeg JA ; Franken KA ; Reinhold HS TI - Destruction of rat mammary tumor and normal tissue microcirculation by hematoporphyrin derivative photoradiation observed in vivo in sandwich observation chambers. AB - The effect of hematoporphyrin derivative photoradiation on tumor and normal tissue microcirculation was studied microscopically in vivo on rats with mammary carcinomas transplanted into subcutis in transparent observation chambers. One day after i.p. injection of hematoporphyrin derivative (15 mg/kg), chambers were exposed to red light (632 +/- 2 nm, eight light dose values, 0 to 270 J/cm2). After an initial blanching (ischemia) of the tumor accompanied by apparent vasoconstriction, reperfusion was observed with a slowing down of the tumor circulation, vasodilatation, and eventually a complete stasis, together with diffuse hemorrhages and subsequent necrosis. Besides, in large normal tissue vessels, platelet aggregates were observed, but no hemorrhage. Tumor regrowth occurred unless the tumor circulation and the adjacent normal tissue circulation were both destroyed. Tumor cell viability after treatment was assessed by transplanting the tumor from the chamber into the flank of the same animal. Even after a combined porphyrin and light dose 4 times the lethal dose for all tissues in the chamber, five of five transplanted tumors did regrow. This leads to the conclusion that, in our model system, tumor cell death after photoradiation occurs secondary to destruction of the microcirculation. In order to obtain additional information on normal tissue damage, rat ears were also irradiated. For the same light dose, the biological effect was only slightly larger than that of the normal tissue in the observation chambers, even though the measured ratio of porphyrin concentrations in ears and normal tissue in the chambers (subcutis) was about six. MH - Animal ; Dose-Response Relationship, Drug ; Ear/BLOOD SUPPLY ; Female ; *Hematoporphyrin Photoradiation ; Hematoporphyrins/THERAPEUTIC USE ; Mammary Neoplasms, Experimental/BLOOD SUPPLY/*DRUG THERAPY ; Microcirculation/*DRUG EFFECTS ; Neoplasm Transplantation ; *Photochemotherapy ; Rats ; Support, Non-U.S. Gov't SO - Cancer Res 1986 May;46(5):2532-40 24 UI - 86182734 AU - Luthert PJ ; Greenwood J ; Lantos PL ; Pratt OE TI - The effect of dexamethasone on vascular permeability of experimental brain tumours. AB - The vessels of experimental gliomas show an abnormally high permeability to small polar molecules, such as mannitol. To establish whether this change in vessel permeability is modified by treatment with the corticosteroid dexamethasone, the kinetics of [14C]mannitol transfer into rat astrocytomas were estimated in both steroid-and saline-treated, tumour-bearing animals. This was achieved by injecting [14C]-mannitol i.v., using a specially devised technique, so as to maintain a constant concentration of tracer in the blood plasma. In separate experiments steady levels of the tracer were maintained in the circulation from 1 to 30 min. Mean plasma and tumour radioactivity were measured, and the apparent transfer constant of mannitol across the vascular endothelium and the size of the extravascular extracellular mannitol space in the tumours were calculated. Despite a significant clinical improvement in the treated animals and adequate circulating levels of dexamethasone at the time of the permeability studies, no difference in either the apparent transfer constant for the movement of mannitol into the tumours or the fractional extracellular mannitol space was detected between these animals and the controls. With steroid treatment both tumour-bearing and non-tumour bearing animals lost weight, and in the latter there was no consistent change in routine biochemical or haematological parameters. It was concluded that under these conditions it is unlikely that clinical improvement with dexamethasone therapy was due to a non-specific reduction in tumour vessel permeability to polar substances. MH - Animal ; Brain Neoplasms/*BLOOD SUPPLY/CHEMICALLY INDUCED/DRUG THERAPY/ METABOLISM ; Capillary Permeability/*DRUG EFFECTS ; Carbon Radioisotopes/ DIAGNOSTIC USE ; Dexamethasone/BLOOD/*THERAPEUTIC USE ; Ethylnitrosourea ; Female ; Glioma/*BLOOD SUPPLY/CHEMICALLY INDUCED/DRUG THERAPY/ METABOLISM ; Kinetics ; Male ; Mannitol/METABOLISM ; Neoplasm Transplantation ; Rats ; Rats, Inbred Strains ; Support, Non-U.S. Gov't SO - Acta Neuropathol (Berl) 1986;69(3-4):288-94 25 UI - 86129136 AU - Hiesiger EM ; Voorhies RM ; Basler GA ; Lipschutz LE ; Posner JB ; Shapiro WR TI - Opening the blood-brain and blood-tumor barriers in experimental rat brain tumors: the effect of intracarotid hyperosmolar mannitol on capillary permeability and blood flow. AB - Using quantitative autoradiography, we investigated the effect of intracarotid infusions of hyperosmolar mannitol solutions on capillary permeability and blood flow. Capillary permeability, expressed in terms of a blood-to-tissue transfer constant (K), was determined in two rat brain tumor models by measuring the entry of 14C-alpha aminoisobutyric acid into brain tumor, into brain tissue adjacent to tumor, and into cortex. Cerebral blood flow was determined by measuring the uptake of 14C-iodoantipyrine in one rat brain tumor model. Blood flow was examined in the same regions as K, as well as in the corpus callosum. Before mannitol administration, K values in both Walker 256 (W256) carcinosarcoma and C6 gliomas were much higher than those in cortex. C6 gliomas were about three times more permeable than were W256 tumors. There was a direct correlation between tumor size and increased capillary permeability. Mannitol at a concentration of 1.37 M did not increase the K values for either tumor or adjacent tissue. At 1.6 M, mannitol increased the K values for both tumors (1.7-fold in C6 glioma and 13-fold in W256) as well as for adjacent tissue. At both concentrations, mannitol markedly increased cortical K values in all groups: by 48- to 72-fold at 1.37 M and by 90- to 105-fold at 1.6 M. The net effect of the mannitol was to reverse the tumor-to-cortex permeability relationship. Cortical blood flow increased modestly after intracarotid mannitol administration on both sides of the brain. These data provide little justification for using intracarotid mannitol during chemotherapy of human brain tumors. MH - Animal ; Blood-Brain Barrier/*DRUG EFFECTS ; Brain Neoplasms/*BLOOD SUPPLY/SECONDARY ; Capillary Permeability/*DRUG EFFECTS ; Carcinosarcoma/ *BLOOD SUPPLY/SECONDARY ; Carotid Arteries ; Cerebral Cortex/BLOOD SUPPLY ; Cerebrovascular Circulation/*DRUG EFFECTS ; Glioma/*BLOOD SUPPLY ; Injections, Intra-Arterial ; Male ; Mannitol/*PHARMACODYNAMICS ; Osmolar Concentration ; Rats ; Rats, Inbred Strains ; Regional Blood Flow/DRUG EFFECTS ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. SO - Ann Neurol 1986 Jan;19(1):50-9 26 UI - 86105655 AU - Rong GH ; Alessandri G ; Sindelar WF TI - Inhibition of tumor angiogenesis by hexuronyl hexosaminoglycan sulfate. AB - The efficacy of heparin (HEP), the heparin analogue hexuronyl hexosaminoglycan sulfate (HHS), and hydrocortisone (HC) was studied in inhibiting the growth of four morphologically distinct pancreatic adenocarcinoma lines (CBP, LHP2, LSP3, and Pour-LVG) in hamsters. Animals were inoculated with LD100 doses of one of the four tumor lines and were randomly allocated to groups of five animals, which received in their drinking water either: HEP (1000 U/ml) alone, HHS (10 mg/ml) alone, HC (0.5 mg/ml) alone, HEP plus HC, HHS plus HC, or no additives (control). Tumors were measured, growth rates calculated, and nonparametric statistical comparisons made among the median growth rates of all of the treatment groups. All four tumors were tested in the rabbit cornea assay for their ability to induce angiogenesis. Extracts of tumors from control animals as well as from animals treated with HHS plus HC were prepared for quantitative testing in vitro by endothelial cell migration assay. All four tumor lines caused angiogenesis as measured in the rabbit cornea assay. A reduction in median tumor growth rates was observed in animals treated with HHS plus HC bearing the CBP, Pour-LVG, and LSP3 tumors. Similarly, in vitro capillary endothelial cell migration was decreased by HHS plus HC treatment in animals bearing CBP, Pour-LVG, and LSP3 tumors. Animals bearing the LHP2 tumor showed no effect of HHS plus HC treatment on tumor growth rate and no effect on endothelial cell migration. HEP alone, HHS alone, HC alone, and HEP plus HC showed no effect on tumor growth rate in any of the four tumors tested. MH - Animal ; Anticoagulants/*PHARMACODYNAMICS ; Cell Movement ; Female ; Glycosaminoglycans/*PHARMACODYNAMICS ; Hamsters ; Heparin/ PHARMACODYNAMICS ; Hydrocortisone/PHARMACODYNAMICS ; Neoplasms, Experimental/*BLOOD SUPPLY/PATHOLOGY ; *Neovascularization ; Rabbits SO - Cancer 1986 Feb 1;57(3):586-90 27 UI - 86053243 AU - Rofstad EK ; Brustad T TI - Primary and secondary cell death in human melanoma xenografts following hyperthermic treatment. AB - The response to hyperthermic treatment (42.5 degrees C for 60 min) of 5 human malignant melanomas grown in athymic mice (BALB/c/nu/nu/BOM) was studied. Local hyperthermia was given by immersing the tumor-bearing leg of the mice into a thermostatically regulated water bath. Growth delay studies indicated that the melanomas were different in heat responsiveness. The differences were confirmed by measuring the fraction of clonogenic cells in the melanomas as a function of time after treatment. The latter experiment showed that some tumor cells were inactivated during the treatment, while others lost clonogenicity first after completion of the treatment. Examinations of histological sections from tumors fixed 1 h after treatment revealed considerable vascular occlusion in all 5 melanomas. This indicates that the observed delayed cell death might be due to a number of factors, e.g., insufficient supply of oxygen and nutrients, increased tumor acidity, and accumulation of toxic metabolic products. It is concluded that at least two different mechanisms govern the overall heat response of the melanoma xenografts: the primary cell death, induced during treatment, is due to direct cytotoxic effects of the heat; the secondary cell death, induced after completion of treatment, is due to heat-induced vascular damage. The differences among the melanomas in overall heat responsiveness appeared mainly to be a consequence of differences in secondary cell death. The secondary cell death was shown to be least pronounced for those melanomas in which most of the larger vessels were embedded in broad bands of connective tissue. MH - Animal ; Cell Division ; Cell Survival ; Female ; Human ; *Hyperthermia, Induced ; Male ; Melanoma/BLOOD SUPPLY/PATHOLOGY/*THERAPY ; Mice ; Microcirculation/PATHOLOGY ; Support, Non-U.S. Gov't ; Tumor Stem Cells/ PATHOLOGY SO - Cancer Res 1986 Jan;46(1):355-61