In vitro antitumor effect of lymphoid cells from Corynebacterium parvum-treated mice: effect of route of C. parvum administration.

Corynebacterium parvum administration in CBA mice resulted in the stimulation in the peritoneal exudate and other lymphoid organs of cells which nonspecifically inhibited the tumor growth in vitro. The distribution of the antitumor activity in different organs was dependent on the route of C. parvum injection. Both ip and iv treatments stimulated antitumor activity in the peritoneal exudate, whereas the sc route was ineffective. Only iv treatment stimulated the antitumor activity in the blood, and only the sc route produced the antitumor activity in the lymph node. The antitumor activity following the sc treatment was confined mainly to nodes draining the site of C. parvum injection. All routes of treatment provoked some antitumor activity in the spleen, although the degree of the activity varied with the route in the order of ip, iv, and sc. The antitumor activity in all organs peaked between 4 and 14 days after C. parvum injection. This activity in all organs, except the spleen, disappeared by day 42 post treatment. The results are discussed in the light of the in vivo observations on the antitumor effects of C. parvum.     

Plasma and tumor concentrations of cisplatin following intraperitoneal infusion or bolus injection with or without continuous low-dose-rate irradiation

Our purpose of this study was to determine whether whole-body, continuous low-dose-rate irradiation (CLDRI) alters the plasma and/or tumor platinum pharmacokinetics after ip bolus injection or ip infusion as a possible mechanism of interaction between CLDRI and cisplatin. The C3Hf/Sed mice bearing SCCVII/SF tumors were given 6 mg cisplatin/kg ip by bolus injection or an ip infusion of 0.25 mg cisplatin.kg-1.hour-1 for 48 hours with and without CLDRI at 0.56 Gy/hr for 24 or 48 hours. Plasma and tumor platinum concentrations were determined with an atomic absorption spectrophotometer at appropriate intervals during infusion and up to 48 hours after drug administration. Both total and ultrafilterable plasma platinum followed a biphasic elimination after ip bolus injection, whereas only a prolonged single-phase elimination was seen after ip infusion. Tumor uptake of platinum appeared to follow a passive diffusion pattern with a prolonged cellular retention of platinum. Whole-body CLDRI had no apparent effect on the pharmacokinetics of plasma and tumor platinum administered by ip bolus injection or prolonged continuous infusion.     

Anti-tumorigenic Effects of Emodin and Its’ Homologue BTB14431 on Vascularized Colonic Cancer in a Rat Model

Objective: New drugs for cancer treatment are being sought worldwide. Therapeutic agents derived from natural substances can provide cost-efficient options. We evaluated the effect of emodin, an active natural anthraquinone derivate, and it’s in-silico homologue the novel substance BTB14431 in vivo. Method: CC-531 colon cancer cells were implanted intraperitoneal (ip) and subcutaneous (sc) in 100 WAG/Rij rats. 28 days after tumor cell implantation, solid cancers were treated for 7 days by varying doses of BTB14431 (0.3 mg/kg body weight; 1.7 mg/kg) or emodin (2.5 mg/kg; 5 mg/kg). Treatment was applied either via an intravenous (iv) port catheter or by ip injection. Saline solution served as control. 21 days after final dose all animals were euthanized and ip tumor weight, sc tumor weight and animal body weight (bw) were determined by autopsy. Significant lower total tumor weight occurred after iv treatment with low dose BTB14431 (6.8 g; 90% confidence interval (CI) 5.3 - 8.2 g; p ≤ 0.01) and also low and high concentrations of emodin (9.4 g; CI 7.9 - 10.7 g; p ≤ 0.01 and 8.3 g; CI 7.6 - 9.3; p ≤ 0.01). Iv treatment by high dose BTB14431 did not lead to a decline in tumor weight. High dose ip treatment by emodin led to a lower overall (11.1 g; CI 10.1 – 13.8 g; p ≤ 0.01) and ip tumor weight (8.6 g; CI 6 – 10.4 g; p ≤ 0.01). Sc tumor weight was not affected. All other ip treatments did not result in changes of combined, ip or sc tumor weight. Bw decreased during iv treatment in all animals and increased after treatment was completed. Regain of bw was stronger in animals receiving low dose emodin. Conclusion: Our study shows promising anti-cancer properties of BTB14431 and supports the evidence regarding emodin as a natural antitumorigenic agent. Optimal dosing of iv emodin and especially BTB 14431 for maximal efficacy remains unclear and should be a subject of further research.     

Transforming growth factor beta 1 induces cachexia and systemic fibrosis without an antitumor effect in nude mice

While stimulating the growth of fibroblasts, transforming growth factor beta 1 (TGF-beta 1) inhibits the growth of various normal and malignant cell lines in vitro. We studied the effects of TGF-beta 1 in vivo. The level of TGF-beta 1 in serum was maximally elevated 2 h after injecting 1 muCi of 125I-TGF-beta 1 into the peritoneal cavity of nude mice. Five h after the i.p. administration of 10 micrograms of unlabeled TGF-beta 1, 20 ng/ml of TGF-beta-like material in serum were detected by a radioreceptor assay on A549 lung carcinoma cells. Trichloracetic acid-precipitable 125I-TGF-beta 1 was taken up by liver, spleen, lungs, kidneys, and tumor tissue but not by the brain. At doses exceeding 2 micrograms/day, TGF-beta 1 induced a generalized interstitial fibrosis and a cachexia, which was not mediated by elevated serum levels of tumor necrosis factor alpha as determined by Western blot analysis and enzyme-linked immunosorbent assay. A total of 200,000 cells of the estrogen receptor-negative human breast cancer line MDA-MB-231, which had been shown to be maximally growth inhibited in vitro by 40 pM TGF-beta 1 and to have high-affinity receptors (9, 11, 12), were injected into the mammary fat pad of each nude mouse. The duration of treatment was 16 days with ten animals in the control group and five animals in the treated groups. The dose ranged from 1 to 4 micrograms per animal daily. The treatment was started 24 h after the injection of the tumor cells. Tumor growth was not significantly affected at either nontoxic or toxic doses of TGF-beta 1. Thus, we have demonstrated that TGF-beta 1, apart from being a local growth factor, has systemic effects, such as cachexia and multiple fibrosis. Its role as an antitumor agent may be limited.     

Preclinical antitumor activity and pharmacological properties of deoxyspergualin

A new antibiotic, deoxyspergualin (DSG), demonstrated antitumor activity against L1210 leukemia in mice. The life span of mice bearing either i.p. or s.c.-implanted L1210 increased greater than 150% following i.p. administration of 25 mg/kg DSG on days 1-9. Activity obtained with i.p. bolus treatments was schedule dependent. The tumor burden in mice bearing the s.c. implanted L1210 was reduced by 4-6 log10 units at the end of treatment when DSG was administered every 3 h for 8 injections on days 1, 5, and 9. By contrast, single injections of DSG on days 1, 5, and 9 allowed the tumor burden to increase at least 100-fold during treatment and daily single injections for 9 days reduced the tumor burden by 2 log10 units. The therapeutic advantage for i.p.-implanted L1210 of maintaining plasma concentrations of DSG was indicated further by infusion studies using s.c.-implanted Alzet osmotic pumps. Tumor burden was reduced by 3.5 and 6 log10 units following s.c. bolus treatments every 3 h on day 1 and a 24 h-infusion, respectively. The optimal infusion time for an infusion rate in mice of 179 mg/kg/day appeared to be 72 h. Pharmacokinetic studies following bolus i.v. injection revealed a rapid plasma clearance of parent drug (20.8 ml/min/kg) and a beta half-life of approximately 12 min. The bolus dose kinetics was used to predict the steady state plasma concentrations resulting from s.c. infusion; good agreement was observed between predicted values and experimental results. Based on these preclinical data, DSG has been developed to clinical trial. Initial Phase I protocols involve a 120-h infusion schedule.     

Antitumor activity of the DNA fraction from Mycobacterium bovis BCG. II. Effects on various syngeneic mouse tumors

MY-1, a fraction extracted from BCG and composed of 70.0% DNA and 28.0% RNA, was examined for its antitumor activity against 9 different syngeneic mouse tumors. Tumor regression was induced in almost all of the mice bearing any of five kinds of solid tumors by repeated intralesional injections of 100 micrograms MY-1. When cells of some tumors were inoculated intradermally together with MY-1, tumor growth was suppressed, lung metastases were inhibited, and the survival times of mice bearing 1 of 3 leukemic tumors were prolonged. Repeated sc injections with MY-1 in sites remote from tumor cell inoculation or repeated iv injections were more or less effective against three kinds of solid tumors. Mice inoculated with Lewis lung carcinoma cells in a hind footpad and whose legs were amputated 9 days later were given iv or sc injections of MY-1 every other day (8 times in total), resulting in substantial prolongation of survival. No direct cytotoxicity of MY-1 for these tumors could be shown in three kinds of experiments, which indicates that the antitumor mechanism of MY-1 is host mediated. MY-1 was equally effective in mice with or without presensitization with BCG, whereas BCG was much more effective in BCG-sensitized mice. This finding suggests that a delayed-type hypersensitivity reaction elicited by BCG protein is not required for the antitumor activity of MY-1.     

Improvement of differential toxicity between tumor and normal tissues using intratumoral injection with or without a slow-drug-release matrix system

The therapeutic effects of cisplatin on tumor and normal tissues were assessed when the drug was given by different administration routes either as free drug or associated with a collagen-based matrix. Tumor response was assessed by growth delay of the murine RIF1 tumor, grown subcutaneously in female C3H/km mice. Normal tissue responses were assessed by plasma clearance of [51Cr]EDTA (giving an estimate of kidney damage), by the drop in peripheral white blood cells, and by a loss in mouse body weight. Intraperitoneal injections of cisplatin were the most toxic to the normal tissues for a given drug dose. Intratumoral injections of matrix-associated drug were the least toxic. Comparison of tumor growth delays for a given normal tissue damage demonstrated the superiority of all intratumoral schedules over the ip route.     

Response of murine tumors to matrix-associated cisplatin intratumoral implants

The response to collagen matrix-associated cisplatin (cis-DDP-CM) implanted intratumorally into KHT and RIF-1 fibrosarcomas grown sc in C3H mice was studied. The effects on tumor growth as well as body weight and animal survival were assessed. The effect of cis-DDP-CM (8 mg/kg) on the growth of KHT tumor was assessed by determining the number of days required for tumors to grow to three times the pretreatment volume of 100-150 mm3. When cisplatin (cis-DDP) was administered ip, the number of days required for threefold growth was 11.1 +/- 2.5 SE. Administration of cis-DDP-CM intratumorally resulted in a value of 17.2 +/- 1.7 days. Epinephrine (0.1-5.0 mg/kg) was also added to the matrix as a vasoconstrictor to further localize the activity of cis-DDP. This resulted in enhanced antitumor activity and, presumably, lower systemic exposure to cis-DDP. For cis-DDP administered ip, the dose required to kill 50% of the test group at 10 days after injection was approximately 14 mg/kg. When cis-DDP-CM was administered intratumorally in doses less than or equal to 30 mg/kg, no mice died. Loss in mouse body weight (greater than 3 g) was detected with ip doses of cis-DDP at 8 mg/kg, but no weight loss was detected for mice treated with matrix implant delivering cis-DDP doses less than or equal to 25 mg/kg.     

Control of solid tumor metastases with a high-molecular-weight derivative of methotrexate.

Methotrexate (MTX) covalently bound to bovine serum albumin (MTX-BSA), injected ip (10 mg/kg) once every 4 days for a total of 4 doses, was more effective than an equivalent dose of free MTX in reducing the number of metastases observed in female (C57BL/6 X DBA/2)F1 mice bearing the sc implanted Lewis lung carcinoma. Treatment with the high-molecular-weight derivative of MTX in addition caused a decreased rate of growth of the primary tumor and a modest increase in the life-span of the tumor-bearing animal. When tumor-bearing mice were killed after receiving injections of [3H]MTX or [3H]MTX-BSA, no difference in the amount of drug was found at the tumor site after 1 hour; however, after 8 or 24 hours, twice as much radioactivity was found in the tumors of mice treated with carrier-bound drug. Analysis of this radioactivity indicated a ratio of 60--80% carrier-bound to 20--40% free MTX.     

Effect of a rice-rich diet on the therapeutic efficacy of cyclophosphamide with special reference to the enhancement of transplantation immunity

The present study investigated the problem of whether the therapeutic efficacy of cyclophosphamide in the in vivo Ehrlich ascites tumor system can be improved by adjuvant use of hydrocortisone or of dietary hydrocortisone mobilizers. In the chemotherapy experiment, female ICR mice each received an inoculum of 1 x 10(6) cells of Ehrlich ascites tumor ip followed by 2 ip injections of cyclophosphamide 36 and 37 hr later (2.4 mg/mouse for the 1st injection, and 1.0 mg/mouse for the 2nd injection). The effects of both cyclophosphamide and adjuvant treatments were assessed in terms of either survival rate or cure rate in the 1-month experiment. The results obtained were as follows. 1) Prolonged use of hydrocortisone as an adjuvant can improve the survival of cyclophosphamide-treated mice. 2) Adjuvant use of a rice-rich diet for maintenance increased the rates of both survival and cure in the cyclophosphamide-treated mice. 3) The same maintenance of mice on a rice-rich diet increased transplantation immunity on the one hand, and induced a set of steroidal changes including hydrocortisone excess on the other hand. 4) Evidence is presented to indicate that the beneficial influence of a rice-rich diet on the drug effect is related to an increase of transplantation immunity in the host, and that there could be a causal relationship between hormonal and immunological changes in rice-saturated mice.     

Synergy of Nocardia rubra cell wall skeleton and interleukin 2 in the in vivo induction of murine lymphokine-activated killer cell activity

Combination of an ip injection of Nocardia rubra cell wall skeleton (N-CWS) and 3 daily sc injections of human recombinant interleukin 2 (rIL 2) into C3H/HeN mice resulted not only in a significant increase in the number of peritoneal cells (PC) but also in a potent induction of their lymphokine-activated killer (LAK) activity, compared with results obtained with N-CWS or rIL 2 alone. The augmented LAK activity of PC was mediated by nonadherent, nonphagocytic, Thy-1.2+(-)- and asialo GM1+ cells. Nonadherent PC induced by an ip injection of N-CWS bound more 125I-labeled rIL 2 than did normal, nonadherent PC, and generated high LAK activity when cultured overnight with rIL 2. In contrast, normal, nonadherent PC responded only weakly to the overnight stimulation with rIL 2. The phenotype of N-CWS-induced PC with an elevated IL 2 responsiveness was Thy-1.2+(-)-, Lyt-1.1-, Lyt-2.1- and asialo GM1+, suggesting that the N-CWS-stimulated LAK precursors were derived mainly from the NK cell lineage. However, mature T cells may also be involved in this mechanism, because N-CWS failed to augment the IL 2 responsiveness of nonadherent PC in BALB/c nu/nu mice. Treatment of C57BL/6N mice bearing solid Lewis lung carcinoma (3LL) tumors with an intratumoral injection of N-CWS followed by 6 daily sc injections of rIL 2 resulted in the apparent suppression of tumor growth, while N-CWS or rIL 2 alone produced no such suppression. These results suggest that N-CWS augments the antitumor effect of rIL 2 by accumulating LAK precursors and elevating their responsiveness to rIL 2 at the injection site.     

Enhancement of the effectiveness of daunorubicin (NSC-82151) or adriamycin (NSC-123127) against early mouse L1210 leukemia with ICRF-159 (NSC-129943).

The LD50 of intraperitoneally (ip) injected daunorubicin in nonleukemic mice (1.8 mg/kg, q4d times 3) can be increased several fold by the concomitant ip injection of ICRF-159. In addition, the survival of leukemic mice treated with daunorubicin and ICRF-159 on Days 1, 5, and 9 after ip inoculation of L1210 tumor cells was substantially greater than after treatment with either drug alone. This potentiation of survival with combination treatment usually occurred with doses of daunorubicin greater than the LD50 of daunorubicin alone. The LD50 of subcutaneously (sc) injected daunorubicin alone (14.0 mg/kg, q4d times 3) was not increased by concomitant ip treatment with ICRF-159. However, when leukemic mice were treated sc with daunorubicin and ip with ICRF-159 on Days 1, 5, and 9 after ip injection of L1210 leukemia cells, survival was greater than with treatment with either drug alone. The toxicity of ip injected adriamycin was not reduced by ICRF-159, but treatment of leukemic mice with this combination was more effective in prolonging survival than treatment with either drug alone. Combination treatment with daunorubicin plus ICRF-159 showed much less therapeutic enhancement against sc implanted L1210 leukemia than against the ip implanted tumor.     

Effect of a Rice-rich Diet on the Therapeutic Efficacy of Cyclophosphamide with Special Reference to the Enhancement of Transplantation Immunity

The present study investigated the problem of whether the therapeutic efficacy of cyclophosphamide in the in vivo Ehrlich ascites tumor system can be improved by adjuvant use of hydrocortisone or of dietary hydrocortisone mobilizers. In the chemotherapy experiment, female ICR mice each received an inoculum of 1 × 10⁶ cells of Ehrlich ascites tumor ip followed by 2 ip injections of cyclophosphamide 36 and 37 hr later (2.4 mg/mouse for the 1st injection, and 1.0 mg/mouse for the 2nd injection). The effects of both cyclophosphamide and adjuvant treatments were assessed in terms of either survival rate or cure rate in the 1-month experiment. The results obtained were as follows. 1) Prolonged use of hydrocortisone as an adjuvant can improve the survival of cyclophosphamide-treated mice. 2) Adjuvant use of a rice-rich diet for maintenance increased the rates of both survival and cure in the cyclophosphamide-treated mice. 3) The same maintenance of mice on a rice-rich diet increased transplantation immunity on the one hand, and induced a set of steroidal changes including hydrocortisone excess on the other hand. 4) Evidence is presented to indicate that the beneficial influence of a rice-rich diet on the drug effect is related to an increase of transplantation immunity in the host, and that there could be a causal relationship between hormonal and immunological changes in rice-saturated mice.     

Potentiation of chemotherapeutic activity by a Chinese herb medicine juzen-taiho-toh

Antitumor activity of Juzen-Taiho-Toh (JTX) and combination effect of JTX with antitumor agents were studied using murine tumors. In order to determine the antitumor activity of JTX, mice inoculated ip with IMC carcinoma (1 X 10(6) cells/CDF1 mouse), sarcoma-180(1 X 10(6) cells/ICR mouse) or Meth-A fibrosarcoma (1 X 10(6) cells/BALB/c mouse) were treated with JTX (12.5-50 mg/kg/day) ip on day 1 through day 10, and the survival days of mice were examined. Treatment with 25 mg/kg/day produced 38.7% increase of life span against IMC carcinoma. However, no antitumor effect was observed on solid form of these tumors by the daily treatment with JTX. Combination effect of JTX and antitumor agents was also examined. ICR mice inoculated sc with 1 X 10(6) cells of sarcoma-180 on day 0 were treated with JTX (2,000 mg/kg/day) po on day-7 through day 30. In addition, some of these groups received mitomycin C (5 mg/kg), cytoxan (67 mg/kg) or adriamycin (2.5 mg/kg) iv on days 3, 8 and 11, and the size of tumor grown in sc site was measured by a caliper. In combination with JTX, mitomycin C resulted in a significantly greater tumor growth inhibition than could be obtained with mitomycin C alone. Secondly, BALB/c or C57BL/6 mice inoculated sc with 1 X 10(4) cells of Meth-A fibrosarcoma or 1 X 10(5) cells of B16 melanoma on day 0 were treated with JTX (2,000 mg/kg/day) po on day 1 through day 30. Some of these group received ip with mitomycin C (3 mg/kg), adriamycin (2 mg/kg), 5-FU (33 mg/kg) or cytoxan (67 mg/kg) on days 3, 6, 9, 12, 15 and 18. From this result, the group treated with JTX and mitomycin C also showed a higher tumor-growth inhibition. Thus, a combination of a high dose of mitomycin C with JTX was more effective than mitomycin C alone.     

Promotion of tumor growth in vivo by antimacrophage agents.

Various attempts were made to assess the role of the mononuclear phagocyte system in tumor resistance of rats in vivo. The growth of sc inoculated, weakly immunogenic, carcinogen-induced, syngeneic tumor cells was modestly reduced by ip injection and, more impressively, by local injection of peptone-induced, activated, nonimmune macrophages. A single iv injection of silica particles or carrageenan on the day of sc tumor cell inoculation greatly enhanced tumor growth. When these agents had been given a few days before or after tumor cell inoculation, the tumor-promoting efficiency was distintly diminished or even cancelled. The enhancing effects of silica and carrageenan on tumor growth were nulified by the macrophage-stabilizing agent, poly-2-vinylpyridine N-oxide, To assess the in vivo consequences of silica administration, various cellular, biochemical, and functional macrophage parameters were determined at different intervals. Results indicated the complexity of events elicited after the mononuclear phagoycte system was damaged, which made the interpretation of such results difficult.     

Changes of anticancer activity and pulmonary toxicity of bleomycins in differences of administration schedules and routes in mice

Anticancer activity and pulmonary toxicity of bleomycin and peplomycin in mice were found to be dependent on administration schedules and routes. That is, at the same total dose of 50 mg/kg, the anticancer activity against Lewis lung carcinoma was most strongly exhibited by continuous infusion of peplomycin for 7 days among all schedules tested and decreased in the order of the continuous infusion greater than 4 times injections per day for 10 days greater than daily injection for 10 days greater than daily injection for 2 days. In contrast, the pulmonary toxicity occurred lowest in the continuous infusion and strongest in daily injection for 10 days among the schedules. With respect to administration routes, the anticancer activity and the pulmonary toxicity of them were strongly exhibited in the order of i.v. much greater than i.m. greater than s.c. greater than i.p., except that no route dependency was observed in the continuous infusion. The pulmonary toxicity of peplomycin was lower than that of bleomycin in every administration schedules and routes. From these results, the continuous infusion was concluded to be the best schedule to increase the anticancer activity and to reduce the pulmonary toxicity.     

IL-6 signaling contributes to cisplatin resistance in non-small cell lung cancer via the up-regulation of anti-apoptotic and dna repair associated molecules

Cisplatin-based chemotherapy is currently the most effective treatment regimen for non-small cell lung cancer (NSCLC), but eventually tumor resistance develops which limits its success. The potential implication of IL-6 signaling in the cisplatin resistance of NSCLC was explored by testing whether NSCLC cells with different levels of intracellular IL-6 show different responses to the cytotoxic treatment of cisplatin. When the cisplatin cytotoxicity of the IL-6 knocked down human NSCLC cells (A549IL-6si and H157IL-6si) were compared with their corresponding scramble control cells (A549sc and H157sc), higher cisplatin cytotoxicity was found in IL-6 si cells than sc cells. Subcutaneous xenograft mouse models were developed using a pair of A549sc and A549IL-6si cells. When the tumor grew to about 400 mm², mice were treated with cisplatin and tumor regression was monitored. Higher tumor regression was detected in the A549IL-6si xenografts compared to A549sc xenografts following cisplatin treatment. Immunostaining study results from tumor tissues also supported this finding. Expression of anti-apoptotic proteins Bcl-2 and Mcl-1 and DNA repair associated molecules ATM, CHK1, TP73, p53, and ERCC1 were significantly up regulated in cisplatin-treated A549sc and H157sc cells, but no increase was detected in A549IL-6si and H157IL-6si cells. Further inhibitor studies revealed that up regulation of these molecules by IL-6 may be through activation of IL-6 downstream signaling pathways like Akt, MAPK, Stat3, and Erk. These results provide potential for combining cisplatin and inhibitors of IL-6 signaling or its downstream signaling pathway as a future therapeutic approach in preventing development of cisplatin resistant NSCLC tumors.     

Combined treatments with vitamin A and 5-fluorouracil and the growth of allotransplantable and syngeneic tumors in mice

The combined effect of retinol palmitate (RP) and 5-fluorouracil (FUra) was examined with the use of allotransplantable and syngeneic murine tumor systems. The ip combined administration of RP (5,000 IU/kg/day) and FUra (5 mg/kg/day, 20 mg/kg/day, or 20 mg/kg/every 3d day) suppressed the tumor growth in ICR/JCL mice given sc inoculations of 5 X 10(6) allotransplantable sarcoma 180 cells and prolonged the survival time of mice inoculated ip with 10(7) tumor cells, as compared with the survival time of mice given the single administration of either RP or FUra. Similar results were obtained when BALB/c mice were inoculated sc with a syngeneic BALB/c Meth A fibrosarcoma and treated with RP (5,000 IU/kg/day) and FUra (20 mg/kg/every 3d day). The growth of Meth A implanted on day 10, as a rechallenge, was significantly suppressed in the group pretreated with RP alone or both RP and FUra for 9 days from day 1. The growth of Meth 1, another syngeneic tumor of BALB/c origin, inoculated on day 10 as a rechallenge tumor was unaffected by the treatment with RP and/or FUra. An immune response to tumor-specific antigens seemed to be involved in the combined effects of these two drugs.     

Protective effects of amphotericin B against spontaneous and transplantable murine tumors.

Two tumor systems were used to test prophylactic effects of amphotericin B (AmB). When 0.5 mg AmB was given ip every 2 weeks to AKR mice beginning at 8 weeks of age, the 50% tumor incidence for spontaneous lymphoma development was delayed 2-3 months. In the second tumor system, BALB/c mice received injections of either 20 or 50 mug AmB before receiving MOPC-315-C cells sc. The mice given the low dose of AmB demonstrated a decreased tumor incidence and a reduced tumor growth rate, when compared with controls. Opposite effects were found for the group administered the high dose; tumor incidence and rate of growth were increased.     

Antibody-dependent lysis of tumor cells in vivo. II. Elimination of chromium-51 as a measurement of cytolysis.

The effect of antibody on tumor cells was studied in vivo by measurement of the rate of elimination of 51Cr in A/J mice inoculated with labeled Ehrlich tumor cells. Mice receiving ip injections of tumor cells and normal serum eliminated 51Cr rapidly during the first 24 hours and at a much slower rate thereafter. This biphasic pattern of elimination was due to the fact that 51Cr predominantly labels small (less than 13,000 mol wt) intracellular molecules, which the mouse rapidly eliminates, whereas larger labeled molecules are eliminated slowly. Antibody to tumor cells significantly accelerated the elimination of 51Cr at concentrations that regularly suppressed tumor growth. Antibody also induced a faster elimination rate in mice treated with cobra venom factor but not in mice treated with silica or inoculated sc with the tumor cells. Unlabeled tumor cells inhibited antibody-induced 51Cr clearance in normal mice but not in proteose peptone-treated mice. These results suggested that peritoneal cells are required in the induction of antibody-dependent cytolysis in vivo. In addition, actively or passively alloimmunized mice exhibited a similar accelerated 51Cr elimination rate when inoculated with the appropriate labeled target cells.