Studies in mice treated with ICRF-159 combined with daunorubicin or doxorubicin

We have investigated the effect of ICRF-159 on the toxicity of daunorubicin (DR) and doxorubicin (DX) given iv, and the effectiveness of ICRF-159 combined with DR or DX on the growth of transplantable MLV-M (murine leukemia virus-Moloney) leukemia, MS-2 solid sarcoma, and pulmonary MS-2 metastases in mice. The injection of ICRF-159 concurrently with the administration of DR resulted in a marked decrease in the toxicity of the antibiotic. However, when DX was injected concurrently with ICRF-159 an increase in antibiotic toxicity was observed, except when ICRF-159 was employed at a very low dosage. ICRF-159 administered alone did not influence the tumor growth in the systems tested and did not result in antimetastatic activity. In mice bearing transplanted MLV-M leukemia, the effects of the combination of ICRF-159 with DR or DX were not superior to those of DR or DX treatment on either tumor growth or lifespan. The treatment of MS-2 tumor with the ICRF-159 and DX combination neither produced a therapeutic synergism (therapeutic response superior to the maximum response obtainable by either agent independently) nor antagonized the antineoplastic action of DX. A marked inhibition of tumor growth and increase in lifespan were observed in the mice treated with a high dose of DR (10 mg/kg/injection) plus ICRF-159 (50 mg/kg/injection). We have also examined, on MS-2 lung metastases, the effectiveness of surgical-adjuvant combination chemotherapy with DR or DX plus ICRF-159 injected at different times with respect to surgery. A synergistic effect of DX or DR with ICRF-159 was observed when the drug treatment was performed before the surgery, or both before and after the surgery. No synergistic effect of DX or DR with ICRF-159 on MS-2 lung metastases was found when the MS-2 lung metastases were treated after the surgery. A higher antimetastatic activity was observed in the groups treated with a combination of toxic doses of DR and ICRF-150 than in the groups treated with a combination of toxic doses of DR and ICRF-159 than in the groups treated with tolerated doses of the antibiotic.     

Improved therapeutic index of bleomycin when administered by continuous infusion in mice.

The effects of three different dosage schedules on both therapeutic effect and pulmonary toxicity of bleomycin were studied in mice. Therapy was assessed by both survival and decreased tumor size in mice bearing Lewis lung carcinoma. Lung toxicity was estimated in nontumored mice as increases in lung collagen content by measuring lung hydroxyproline concentrations. In the first set of experiments, bleomycin injections twice daily (low-dose, high-frequency) produced a significant (34%) increase in lifespan over controls, whereas the same total dose given twice weekly did not result in increased survival. Both schedules produced pulmonary toxicity. Continuous sc infusion of bleomycin via an osmotic minipump was compared to these two schedules of intermittent injection. Identical total doses of drug were administered in all three schedules. Continuous infusion for 7 days produced marked inhibition of tumor growth (T/C = 16%), which was significantly better than twice weekly or ten-times weekly injection of the same total dose. Furthermore, at a total dose of 40 mg/kg of bleomycin, continuous infusion did not result in measurable pulmonary toxicity, whereas both schedules of bolus injection produced significant increases in lung collagen content. Thus, continuous infusion of bleomycin improved its therapeutic effect against Lewis lung carcinoma and also reduced its pulmonary toxicity.     

Prophylactic naked DNA vaccination with the human vascular endothelial growth factor induces an anti-tumor response in C57Bl/6 mice

Passive immunotherapy against soluble pro-angiogenic factors and/or their receptors in endothelial cells has become a promising approach in cancer therapeutics. There is also experimental evidence indicating that an active immunotherapy strategy directed towards these target molecules could also be effective. In this paper we show that it is possible to reduce tumor growth or increase the survival of tumor-bearing C57Bl/6 mice when animals are vaccinated with the human vascular endothelial growth factor (VEGF) isoform 121 gene (hVEGF₁₂₁), and later challenged with melanoma or lung carcinoma tumor cells. Immunization was done with 10 μg DNA doses of the hVEGF121 gene, which is highly homologous to its mouse counterpart, administered on a weekly basis using a plasmid bearing 5 CpG bacterial motifs. Histopathology analyses of tumors of hVEGF₁₂₁ immunized animals showed a decrease in tumor cell density around vessels and in mitotic figures, as well as an increase in apoptotic tumor cells. A statistically significant cell cytotoxic response was found when spleen cells of immunized mice were co-cultured in vitro with mouse tumor VEGF-producing cells. Vaccination with an hVEGF121 gene mutated to make it deficient for VEGF receptor binding, produced similar in vitro and in vivo results, and significantly reduced the number of spontaneous metastases produced by the mouse Lewis lung carcinoma. Our results indicate that human VEGF DNA can be employed for anti-angiogenic active immunotherapy in mice, and that direct cell cytotoxicity is a contributor mechanism to the overall anti-tumor effects seen in immunized animals.     

Treatment of mouse tumors with 7-con-O-methylnogarol and other analogs of the anthracycline antibiotic, nogalamycin

The chemotherapeutic activity of analogs of the anthracycline antibiotic, nogalamycin, was investigated in the P388 and L1210 leukemias and the B16 melanoma in mice. Among the compounds tested, 7-con-O-methylnogarol was found to have superior activity. Depending on the route and schedule of administration, increases in lifespan (ILS) in excess of 100% were observed in all three tumor systems. Additional testing of 7-con-O-methylnogarol demonstrated significant activity in the murine colon 26 and colon 38 tumors and the CD8F1 mammary tumor. 7-Con-O-methylnogarol was not significantly effective against murine Lewis lung carcinoma, although ILSs of 38% and 29% were achieved in two experiments. Activity was observed against ip inoculated P388 leukemia after ip, sc, oral, and iv drug administration. 7-Con-O-methylnogarol was also highly active (ILS greater than or equal to 120%) after ip drug administration to mice with iv inoculated P388 leukemia. Significant ILS values resulted from a variety of schedules of administration against ip inoculated P388 leukemia and B16 melanoma. Experiments in which the time of single-dose administration was varied prior to the time of ip P388 leukemia inoculation showed that residual drug or bioactive drug-related materials remained in mice for 8 hours after 50 mg/kg administered ip and for 48 hours after 200 mg/kg administered sc.     

Humoral leukocyte adherence inhibition (H-LAI) follow-up trials on malignant process in mice

Humoral antitumor response of Lewis lung tumor-bearing mice was measured by humoral leukocyte adherence inhibition (H-LAI) test. The reactivity of serum against tumor antigens prepared from primary tumor and lung metastases could be revealed at the first day after injection of tumor cells. On the other hand, the macroscopical appearance of the primary tumors and lung metastases was observed after 5 and 11 days, respectively. These findings suggest that the immune reaction of the host could be detected by H-LAI test earlier than the tumor can manifest itself. The antigens prepared from primary tumors and metastases seemed to be very similar, however, the metastasis antigen had additional determinants as detected by the H-LAI technique. Comparison of two tumor lines, the original Lewis lung tumor (LLT) and its variant with high metastatic capacity (LLT-HH), showed high similarity between their antigens as tested in H-LAI system by cross-reaction probes.     

Treatment with monoclonal antibody to a Lewis lung carcinoma-associated antigen: different effects on primary tumor and its metastases

The growth and dissemination of Lewis lung carcinoma have been analyzed following treatment of isolated tumor cells or of tumor-bearing animals with monoclonal antibody (MoAb) 135-13C, which recognizes a cell surface tumor-associated protein of 180,000 daltons. The results of this study indicate that MoAb 135-13C binds with high affinity to Lewis lung tumor cells and induces different effects on the primary tumor (20%-25% reduction of tumor weight) and its metastasis (twofold increase of lung nodule formation). Different schedules of MoAb 135-13C administration have shown that these effects are dose- and time-dependent. In particular, the maximum increase in metastasis formation is observed when the MoAb 135-13C is administered at time of systemic tumor dissemination. In vitro preincubation of tumor cells with MoAb prior to their iv injection into normal animals results in a significant increase of pulmonary metastatic nodules.     

吉西他滨对Lewis肺癌放射增敏的实验研究

目的　吉西他滨是一种核苷类似物,能够掺入到肿瘤细胞的DNA分子中,有效抑制DNA合 成。本实验观察联合应用吉西他滨和放疗治疗荷Lewis肺癌实体瘤C57BL小鼠的疗效,以明确吉西他滨 对Lewis瘤的放射增敏作用。方法　建立小鼠Lewis肺癌实体瘤模型后,分对照组、单纯放疗组、吉西他滨 组及吉西他滨联合放疗组。对照组给予腹腔注射生理盐水0.1ml,单纯放疗组荷瘤鼠右下肢肿瘤局部以 34Gy射线照射,吉西他滨组分两个亚组,分别以25mg/kg、50mg/kg吉西他滨腹腔注射,联合放疗组则以 25mg/kg吉西他滨腹腔注射加荷瘤鼠右下肢肿瘤局部34Gy射线照射。然后每两天测量肿瘤的长、短径, 比较各组瘤体积、肿瘤生长延缓天数、荷瘤鼠存活数和肺转移率等。结果　与对照组比较,25mg/kg和 50mg/kg的单剂量吉西他滨都对Lewis实体瘤生长有抑制作用(P<0.05);联合放疗组局部肿瘤生长受 到明显抑制,抑瘤率为86.6%,明显高于单纯放疗组(64.7%,P<0.05)和吉西他滨组(47.3%,P< 0.05);联合放疗组肿瘤生长延缓天数(瘤体积0.3～1.0cm3)超过9天,高于单纯放疗组(5天,P<0.05) 和吉西他滨组(3天,P<0.05);联合放疗组60天内存活的鼠最多(4个),单纯放疗组为2个,其他两组鼠 全部死亡。联合放疗组平均肺转移为0.5个/叶肺,单纯放疗组为1.5个/叶肺,吉西他滨组     

Therapy for mouse tumors and human tumor xenografts with the antitumor antibiotic AT-125.

The antimetabolite antibiotic L-(alphaS,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125) showed significant antitumor activity against L1210 and P388 mouse leukemias and the M5076 mouse ovarian tumor. Depending on the schedule of administration, increases in lifespan of greater than 100% were observed. Activity was observed after ip, oral, or sc inoculation of AT-125 in mice inoculated with L1210 by the ip route. Lewis lung carcinoma and B16 melanoma were not affected by AT-125. The compound was used to treat human tumor xenografts in athymic (nude) mice. The MX-1 mammary tumor regressed when treated with either 8 or 16 mg/kg/day for 10 days, while a dose of 32 mg/kg was toxic. On an every-4-days x 3 schedule there was a marked slowing of MX-1 tumor growth at 50, 100, and 200 mg/kg. The LX-1 lung tumor xenograft growth was slowed significantly by a dose of 32 mg/kg. Growth of colon tumors, CX-1, CX-2, and CX-3, was not affected by AT-125.     

NMU-1, a new transplantable mouse lung tumor: biological and chemosensitivity properties in vivo

NMU-1 is a lung adenocarcinoma induced by N-nitroso-N-methyl-urea in a BALB/c Lac Dp mouse and maintained in vivo by sc passages of tumor fragments. No spontaneous regressions have been observed. After sc implantation, NMU-1 metastasizes to the lung as shown by a bioassay. Seven established antitumoral drugs were used to evaluate the chemosensitivity of this neoplasm. Mitomycin, cyclophosphamide, and cisplatin statistically affected tumor growth, as evaluated by three end points (ie, tumor weight, increase in lifespan, and tumor growth delay). 5-FU, doxorubicin, and vincristine showed significant activity on two end points. Carmustine did not affect any end points.     

UFT inhibits lung metastases in spontaneous metastasis model of lung cancer

BACKGROUND: UFT, an oral 5-fluorouracil derivative, is the only drug that is effective as a postoperative adjuvant therapy for non-small cell lung cancer (NSCLC) [ ], but the mechanism of the action remains unclear. We examined whether UFT and/or its metabolite, gamma-hydroxybutyric acid (GHB) inhibits lung metastases in a mouse model. METHODS: Lewis lung carcinoma cells were implanted into the foot pads of C57 BL/6 mice, and mice were treated with UFT or GHB. RESULTS: Both the mean number of metastatic nodules and the mean lung weight for UFT-treated mice (11.4 and 192.1 mg, respectively) were significantly lower than those for saline-treated mice (41.5 and 415.0 mg, respectively) (p < 0.001 for both). UFT did not inhibit tumor growth at the primary sites (foot pads). No significant body weight loss was documented in UFT-treated mice. GHB did not inhibit development of lung metastases even when a higher dose was used. CONCLUSIONS: UFT inhibits development of lung metastases without any toxicity in mouse model, which may explain the efficacy of postoperative administration of UFT for resected NSCLC.     

Vascular endothelial growth inhibitor (VEGI; TNFSF15) inhibits bone marrow-derived endothelial progenitor cell incorporation into Lewis lung carcinoma tumors

Bone marrow (BM)-derived endothelial progenitor cells (EPC) have a critical role in tumor neovascularization. Vascular endothelial growth inhibitor (VEGI) is a member of the TNF superfamily (TNFSF15). We have shown that recombinant VEGI suppresses tumor angiogenesis by specifically eliminating proliferating endothelial cells (EC). We report here that treatment of tumor bearing mice with recombinant VEGI leads to a significantly decreased population of BM-derived EPC in the tumors. We transplanted whole bone marrow from green fluorescent protein (GFP) transgenic mice into C57BL/6 recipient mice, which were then inoculated with Lewis lung carcinoma (LLC) cells. Intraperitoneal injection of recombinant VEGI led to significant inhibition of tumor growth and decrease of vasculature density compared to vehicle-treated mice. Tumor implantation yielded a decrease of BM-derived EPC in the peripheral blood, while VEGI-treatment resulted in an initial delay of such decrease. Analysis of the whole bone marrow showed a decrease of Lin⁻-c-Kit⁺-Sca-1⁺ hematopoietic stem cell (HSC) population in tumor bearing mice; however, VEGI-treatment caused a significant increase of this cell population. In addition, the number of BM-derived EPC in VEGI-treated tumors was notably less than that in the vehicle-treated group, and most of the apoptotic cells in the VEGI-treated tumors were of bone marrow origin. These findings indicate that VEGI inhibits BM-derived EPC mobilization and prevents their incorporation into LLC tumors by inducing apoptosis specifically of BM-derived cells, resulting in the inhibition of EPC-supported tumor vasculogenesis and tumor growth.     

Suppression of human myelosarcoma growth in athymic mice by a primate antiserum.

A primate (Macaca speciosa) antiserum prepared against the human chronic myelogenous leukemia cell line K-562 suppressed the growth of the human myelosarcomas in nude mice. The ip administration of 0.5 ml of immune serum plus 0.5 ml of guinea pig complement, starting 7 days after sc tumor transplantation, resulted in a fourfold to fivefold decrease in tumor weight at 15 days when compared to nude mice given pre-immune serum plus complement or complement alone. Whereas the other two groups experienced an exponential increase in tumor volume at 7-9 days after tumor transplantation, the immune serum-treated mice remained in a "lag" phase of tumor growth during which the tumor volume neither increased nor decreased substantially. Histopathologic studies revealed various degrees of tumor alterations ranging form focal hydropic cellular degeneration to massive coagulation necrosis. The incorporation of tritiated thymidine into the tumors was also markedly diminished in the mice given immune serum.     

Activity and pharmacokinetics of teniposide in Lewis lung carcinoma-bearing mice

The antitumor activity of teniposide (VM26) was investigated in Lewis lung carcinoma (3LL) of the mouse after a single dose of 20 mg/kg iv (given 8 or 14 days after tumor transplant) or after three doses of 6.5 mg/kg iv (given on Days 8, 11, and 14 after tumor transplant) (total dose, 19.5 mg/kg). The single dose resulted in only 25% primary tumor reduction but had marked antimetastatic activity. The repeated doses (6.5 mg/kg x 3) were much more effective, with 85% primary tumor reduction and the apparent disappearance of all metastatic deposits. The pharmacokinetics of VM26 was investigated in 3LL-bearing mice by a high-performance liquid chromatographic assay. At both of the above doses VM26 disappeared from mouse plasma biphasically, with an elimination half-life of about 70 mins. The concentrations in metastases were higher than in primary tumor, where very low levels were found. The highest VM26 levels were found in liver, small intestine, and kidney, and the lowest levels were found in the brain. Excretion of VM26 in urine amounted to less than 5% of the dose.     

Treatment of malignant pleural effusion

Two hundred consecutive patients with malignant pleural effusion were reviewed. The pathologic etiology of malignant pleurisy was: primary lung cancer in 123 cases; five, mesothelioma; and 72 cases secondary to metastatic tumors. Adenocarcinoma of the lung and mammary cancer were the most frequent tumors causing malignant pleural effusion. The modalities employed in local treatment consisted of thoracocentesis in 62 patients, tube thoracotomy in 111 cases with local instillation of adriamycin, MMC, CQ, 5FU, OK432 or talc. Surgical procedures including pleuropneumonectomy or reduction surgery of the tumor with decortication were performed in ten patients. Tube drainage with local instillation of drugs was more effective than thoracocentesis with or without local therapy. Excellent initial results were obtained in patients who received reduction surgery with decortication and pleurodesis. Results of cytologic investigation were positive in 157 cases (78.5 percent). The tumor cells disappeared in 79.4 percent of primary cancer pleurisy cases and 81.1 percent of patients with metastases while disappearance or significant decrease in pleural effusion following treatment was obtained in 75.2 and 77.8 percent respectively. The median survival was 11.3 months in primary cases, and 11.7 months in patients with metastases.     

Therapeutic efficacy of glucan in a murine model of hepatic metastatic disease

Glucan, a particulate beta-1,3-polyglucose immunomodulator, was evaluated for its ability to modify hepatic metastases and survival in mice with reticulum cell sarcoma. Sarcoma M5076 cells were injected subcutaneously (1 X 10(5) cells) into syngeneic C57BL/6J male mice. On Day 20, histopathological studies indicated the presence of hepatic micrometastases. At this time, glucan (0.45 mg per mouse) or dextrose was administered intravenously. Therapy was continued at 3-day intervals up to Day 50. By Day 36 postchallenge, the glucan-treated group, when compared to the control group, showed a marked decrease in hepatic metastases, both grossly and histopathologically. A significant inhibition in the growth of the primary tumor also occurred. Plasma clearance of bromosulfophthalein measured on Day 36, denoted that glucan therapy maintained hepatic parenchymal cell functional integrity, while a 4-fold impairment in bromosulfopthalein removal was observed in control mice. Glucan-treated mice showed a 28% (p less than 0.05) long-term survival. In contrast, control mice showed a 100% mortality by Day 42 postchallenge. Studies to evaluate the mechanism of the anti-metastatic action of glucan indicated that 8 days after glucan administration, isolated hepatic macrophages were significantly more cytotoxic to sarcoma cells in vitro than were normal Kupffer cells. At this time, the cytotoxic activity of peritoneal and splenic macrophages from glucan-treated mice were unaltered. Additionally, co-incubation of particulate glucan with diverse populations of normal or tumor cells in vitro indicated that glucan exerted a direct cytostatic effect on sarcoma and melanoma cells and, in contrast, had a proliferative effect on normal spleen and bone marrow cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

弓形虫排泄分泌抗原对Lewis肺癌小鼠瘤体生长的抑制作用

目的　探讨弓形虫排泄分泌抗原（ESA）对Lewis肺癌小鼠CD4+CD25+ Foxp3+ T（Treg）细胞亚群的影响,观察弓形虫ESA对肿瘤生长的抑制作用。方法　将C57BL/6小鼠随机分成PBS组（14只）和Lewis组（34只）。Lewis组小鼠右腋窝皮下接种Lewis肺癌细胞2 × 105个,PBS组注射等量无菌PBS。接种后第7 天（D7）,将PBS组小鼠分成PBS2组、PBS2 + ESA组,每组7只;将Lewis组分成Lewis2组和Lewis2 + ESA组,每组17只; PBS2 + ESA组及Lewis2 + ESA组小鼠腹腔注射100 μL弓形虫 ESA。ESA干预后7 d计算各组小鼠脾脏系数,检测Treg细胞数量变化,同时观察荷瘤鼠长期瘤体生长情况。结果　ESA干预后7 d,PBS2 + ESA组[（0.66 ± 0.09）%]和Lewis2 + ESA组[（0.69 ± 0.07）%]脾脏明显增大,脾脏系数与PBS2组[（0.30 ± 0.02）%]和Lewis2组[（0.33 ± 0.03）%]比较,差异均有统计学意义（P 均 < 0.05）。PBS2 + ESA组[（1.28 ± 0.14）%]和Lewis2 + ESA组[（1.58 ± 0.14）%]脾脏Treg细胞占脾细胞的比例均下降,与PBS2组[（2.06 ± 0.07）%]和Lewis2组[（2.44 ± 0.23）%]比较差异均有统计学意义（P 均< 0.05）。ESA干预后,瘤体生长延缓,在实验终点时,Lewis2 + ESA组小鼠瘤体明显小于Lewis2组（P < 0.05）。结论　ESA可下调荷瘤鼠脾脏Treg细胞占脾细胞的比例,抑制瘤体生长。     

弓形虫排泄分泌抗原对Lewis肺癌小鼠瘤体生长的抑制作用

目的　探讨弓形虫排泄分泌抗原（ESA）对Lewis肺癌小鼠CD4+CD25+ Foxp3+ T（Treg）细胞亚群的影响，观察弓形虫ESA对肿瘤生长的抑制作用。方法　将C57BL/6小鼠随机分成PBS组（14只）和Lewis组（34只）。Lewis组小鼠右腋窝皮下接种Lewis肺癌细胞2 × 105个，PBS组注射等量无菌PBS。接种后第7 天（D7），将PBS组小鼠分成PBS2组、PBS2 + ESA组，每组7只；将Lewis组分成Lewis2组和Lewis2 + ESA组，每组17只； PBS2 + ESA组及Lewis2 + ESA组小鼠腹腔注射100 μL弓形虫 ESA。ESA干预后7 d计算各组小鼠脾脏系数，检测Treg细胞数量变化，同时观察荷瘤鼠长期瘤体生长情况。结果　ESA干预后7 d，PBS2 + ESA组[（0.66 ± 0.09）%]和Lewis2 + ESA组[（0.69 ± 0.07）%]脾脏明显增大，脾脏系数与PBS2组[（0.30 ± 0.02）%]和Lewis2组[（0.33 ± 0.03）%]比较，差异均有统计学意义（P 均 < 0.05）。PBS2 + ESA组[（1.28 ± 0.14）%]和Lewis2 + ESA组[（1.58 ± 0.14）%]脾脏Treg细胞占脾细胞的比例均下降，与PBS2组[（2.06 ± 0.07）%]和Lewis2组[（2.44 ± 0.23）%]比较差异均有统计学意义（P 均< 0.05）。ESA干预后，瘤体生长延缓，在实验终点时，Lewis2 + ESA组小鼠瘤体明显小于Lewis2组（P < 0.05）。结论　ESA可下调荷瘤鼠脾脏Treg细胞占脾细胞的比例，抑制瘤体生长。     

Activity of 1-p-(3,3-dimethyl-1-triazeno) benzoic acid potassium salt in M 5076/73A ovarian reticular cell sarcoma of the mouse

1-p-(3,3-dimethyl-1-triazeno) benzoic acid potassium salt (DM-COOK) was tested on M 5076/73A (M5) mouse sarcoma at a dose of 40 or 50 mg/kg/day (Days 6--14) after im transplant of 7 x 10(5) cells, with or without surgical removal of the primary tumor on Day 14. Treatment at either dose level resulted in reduction of the primary tumor weight to around 50% of that in the controls, and striking antimetastatic effects were observed. When a dose of 40 or 50 mg/kg of DM-COOK was followed by surgery, there were 14% and 40% long-term survivors, respectively, but the higher dose caused about 30% toxic deaths. After iv injection of 10(3) or 10(5) M5 tumor cells, no artificial metastases appeared in DM-COOK-treated mice, whereas all control animals had metastatic involvement in the liver, spleen, ovaries, and kidneys.     

Differential distribution of antitumor agents in primary and secondary tumors

The differential distribution of a series of antineoplastic agents in metastatic tissues compared to their respective primary tumors has been investigated in one rat and two mouse experimental tumor systems, ie, the intramuscular Lewis lung carcinoma (3LL) of C57BL/6 mice, which gives rise to spontaneous lung metastases, the intratibial Sarcoma 180 (S180) of CD1 mice, which induces macroscopic metastases to the lymph nodes, and the Walker 256 carcinosarcoma of CD rats, which also metastasizes to the lymph nodes. The results described in this paper show that the concentrations of adriamycin, daunorubicin, cyclophosphamide and its alkylating metabolites, hydroxyurea, 1-methyl-1-nitrosourea, and 6-mercaptopurine are much higher in the pulmonary metastases of 3LL and/or in the lymph node metastases of S180 than the concentrations measured in the primary tumor. In the Walker 256 tumor system the distribution of adriamycin appears to follow the same pattern observed for the mouse tumors. Only for methotrexate (in the 3LL tumor) is the difference in the concentrations at the two sites not so evident. These findings are discussed in relation to the comparatively greater sensitivity of metastases to chemotherapy.     

Increased tumor cell multiplication after radiofrequency lesions in median hypothalamus in the mouse and rat

A significant increase of cell multiplication in inoculated ascitic and solid tumors was demonstrated in both DBA/2 and C57BL/6 mice as well as in Wistar rats after radiofrequency lesions in the median hypothalamus (ventromedial and dorsomedial nuclei; part of arcuate nucleus). The following tests were performed: mitotic and metaphasic index, doubling time of tumor, incorporation of tritiated thymidine into DNA, cell cycle parameters and growth fraction. The increased rate of cell proliferation measured was predominantly due to the higher speed of DNA biosynthesis with a minor contribution by an increase of the growth fraction. In the animals with hypothalamic lesions we demonstrated a slight decrease in the secretory activity of the adenohypophysis. Because it is generally stated that failure of hypophysis function hinders cell multiplication in normal and neoplastic tissues, we think that heightened cell proliferation after hypothalamic lesions is due to suppression of an inhibitory mechanism located in the hypothalamus and which is independent of the hypophysis.