Surgical Removal Of Primary Tumor Research Articles

Role of serum humoral factors in the development of metastases and relapses of Ehrlich's carcinoma in mice

Induction of metastases in a guest mouse in parabiotic pair of a mouse with removed tumor and a mouse with secondary transplant is demonstrated in male hybrids (CBA×C57B1/6) F1. The minimum dose of transplanted tumor cells inducing the growth of a secondary transplant in parabiont mice is decreased. Surgical removal of primary tumor is believed to lead to the appearance of humoral factors regulating the development of tumor process.

Dominance of metastatically competent cells in primary murine breast neoplasms is necessary for distant metastatic spread

We have previously shown, using tumor cell populations genetically tagged by random integrations of plasmid DNA, that metastatically-competent clonal cell variants have a strong growth advantage within primary tumors over their non-metastatic counterparts. As a result, primary tumors can become overgrown by the progeny of such cells, a process referred to as "clonal dominance" of primary tumors by metastatically-competent cells. Because of the well-known "metastatic inefficiency" of the multi-step cascade process of spread and growth, clonal dominance within primary tumors may be necessary for distant metastatic spread or increase the probability of its occurrence. To examine this hypothesis mice were inoculated s.c. with mixture of non-metastatic and genetically tagged, metastatically-competent mouse mammary carcinoma cells in defined ratios, but always containing an excess of the unmarked non-metastatic population. Progressive overgrowth of the metastatic subpopulation was monitored as a function of time by Southern analysis of DNA obtained from mixed primary tumors. This allowed us to evaluate the effects that surgical removal of the primary tumor had before, during and after effective clonal dominance, and what influence this had on the subsequent formation of distant metastases. Surgical removal of primary tumors before metastatic clonal dominance resulted in a low (0.25%) frequency of lung metastases, whereas removal just 1 or 2 weeks later during or after clonal dominance was achieved resulted in a high (75-100%) frequency of such metastases. Our results support the hypothesis that dominance of primary tumors by metastatically competent cells may be necessary for distant metastatic spread, and also suggest that clonal interactions play a significant role in modulating the metastatic ability of tumor cells in vivo.

Neoadjuvant immunotherapy with interferon of the spontaneously metastasizing murine B16F10L melanoma

We have previously demonstrated that administration of interferon a/b (IFN) for 4-5 days after challenge with a transplantable Moloney sarcoma virus-induced tumor completely inhibited tumor development. In the present study, we examined the therapeutic effects of IFN on mortality induced by metastatic dissemination of the B16F10L murine melanoma. IFN was administered at various times in relation to the surgical removal of primary tumor: days -5 to -1 prior to tumor excision (neo-adjuvant protocol), or for 5 days after tumor excision, beginning on days 1, 6 or 11 after excision of the primary tumor (adjuvant protocols). The neo-adjuvant protocol was superior to all other protocols, significantly increasing percentage survival (56% vs. 0%) and median survival time (greater than 84 days vs. 33 days) compared to untreated controls, as well as to all adjuvant protocols. In contrast, IFN treatment on days 1 to 5 after excision of the primary tumor decreased median survival time of cases compared to untreated controls (20 days vs. 33 days). Both IFN-induced inhibition and enhancement of metastatic dissemination were dose-dependent, with higher amounts of IFN producing greater inhibition or enhancement. The superior therapeutic efficacy of the neo-adjuvant IFN treatment was associated with increased spleen and lung-derived natural killer cell cytolytic activity (on days -4, 0 and 2) followed by a later (day 13) increase in lung-associated cytolytic T-cell responses.

Antimetastatic action of the prostacyclin analog Iloprost in the mouse

The antimetastatic activity of the prostacyclin analog Iloprost has been examined in mice bearing Lewis lung carcinoma. An inhibition of lung colony formation is observed when 100 or 200 micrograms/kg Iloprost are administered i.v. 1 h before i.v. injection of tumor cells, which is dependent on the size of tumor inoculum. The effects of 200 micrograms/kg Iloprost persist for 24 h, and are of the same magnitude as those obtained with 10 mg/kg prostacyclin, which last only for 30 min. When treatment with Iloprost is followed by surgical removal of primary tumor, spontaneous metastasis formation is reduced, and the survival time of the treated animals is significantly increased over controls treated with surgery only. The antimetastatic effects of Iloprost appear dissociated from drug's effects on the hemostatic system of the host as indicated by the clot retraction assay, performed after in vivo treatment, using ADP or tumor cells as platelet aggregating agents. Iloprost thus appears to reduce spontaneous metastasis formation and intraoperative tumor cell dissemination, with pharmacological properties more favourable to therapeutic use than those of prostacyclin.

The therapeutic effects of an immunopotentiator, PS-K, on 3-methylcholanthrene-induced autochthonous tumors in C57BL/6 mice in combination with the surgical removal of primary sites.

We investigated the therapeutic effects of an immunopotentiator PS-K on recurrent or metastatic tumors observed after the surgical removal of MCA-induced primary tumors in autochthonous C57BL/6 mice and on the survival time of treated mice. The MST of mice treated with PS-K at various times (59.8-63.4 days) was prolonged as compared with that of mice treated by surgery alone (48.6 days). Local recurrence of tumors was found in 36 of 66 mice (54.6%) treated by surgery alone, whereas it was inhibited significantly (P less than 0.05) when treatment with PS-K was started 1 day after the surgery and occurred in 22 of 64 mice (34.4%) when PS-K was given for 5 days in 1 week, or in 22 of 66 mice (33.3%) when PS-K was administered twice a week for 7 weeks. The MSTs of mice with local recurrence were also found to be prolonged as compared with those of mice treated by surgery alone (54.8-67.5 days vs 49.8 days). The MSTs of mice without tumor recurrence were also prolonged significantly (P less than 0.05-0.001) by combinations of PS-K at various times, although most of the mice died of metastatic tumors even in the groups of mice where a combined treatment with PS-K had been administered. The above findings suggest that the administration of PS-K inhibits the growth of recurrent or metastatic tumor cells in autochthonous mice after the surgical removal of the primary tumors.

Long-term treatment of tumor-operated mice with high doses of alpha-difluoromethylornithine.

Mice inoculated subcutaneously with a mammary adenocarcinoma M3cell suspension and submitted 10 to 15 days later to the surgical removal of primary tumors have been chosen in our laboratory as the experimental model to study the effect of several drugs on metastasis spreading. A 90-day treatment of tumor-operated mice with high doses of alpha-difluoromethylornithine showed, in addition to a marked decrease of lung metastases, several side effects including a loss of body weight, a delay of surgical wound healing and a reduced number of megakaryocytes in bone marrow. The measurement of ceruloplasmin in serum has indicated that treated animals contained increased levels of this oxidase activity in spite of the polyamine depletion caused by alpha-difluoromethylornithine. These results rule out a direct correlation between ceruloplasmin activity and polyamine concentration.

Prevention of Tumor Metastasis after Surgical Removal of Primary Tumor by Using In Vitro Activated Macrophages

In vitro activation of peritoneal macrophages by Propionibacterium acnes and its immunotherapeutic potential for inhibiting metastasis was investigated. C3H/HeN mouse adherent peritoneal exudate cells as a source of macrophages were treated in vitro with P. acnes. These P. acnes-activated macrophages were tested for tumoricidal activity in vitro and antimetastatic activity in vivo. In vitro cytotoxicity tests revealed that they had potent cytotoxicity. Surgical resection of X5563 tumors in syngeneic C3H/HeN mice 10 days after the tumor implantation failed to rescue the hosts from tumor metastasis despite successful removal of the primary tumor. When the activated macrophages were transferred intravenously into C3H/HeN mice following the surgical operation, an appreciable number of mice survived without exhibiting any sign of metastasis. Thus, these results demonstrate that macrophages can be activated in vitro by utilizing appropriate stimulating reagents, and that these activated macrophages have a potent antimetastatic effect.

Effect of alpha-difluoromethylornithine in lung metastases before and after surgery of primary adenocarcinoma tumors in mice.

The depletion of polyamines by alpha-difluoromethylornithine (DFMO) treatment of mice after subcutaneous inoculation of adenocarcinoma M3 cells caused a remarkable inhibition in the growth rate of primary tumors as well as in the occurrence and number of lung metastases with a concomitant increase in survival time. Tumor-bearing mice submitted to the surgical removal of primary tumors and then treated with alpha-difluoromethylornithine also showed a significant reduction of lung metastases. In addition, a lower number of lung metastatic nodules correlated with decreased levels of polyamines in the same tissue. The described approach provides a useful experimental model for studies in human cancer therapy.

Current Status of Adjuvant Therapy in the Treatment of Large Bowel Cancer

Large bowel cancer is a common malignant disease whose surgical treatment is comparatively successful. However, undetected systemic or local dissemination of disease frequently frustrates the surgeon’s well-executed local or regional attack. Thus, adjuvant radiotherapy and chemotherapy are being used more often to eradicate distal foci of malignant cells after surgical removal of primary tumor.

Therapy of spontaneous pulmonary metastases of a murine mammary carcinoma with anaerobic corynebacteria

Corynebacterium parvum given intravenously or into the tumor 7 or 2 days before surgical removal of primary tumors greatly reduced the number of spontaneous pulmonary metastases of a syngeneic mammary carcinoma of C3Hf/Bu mice. When a single dose of 6000 rads γ-rays was used to eliminate primary tumors the number of lung metastases significantly increased. Administration of C. parvum before irradiation not only prevented this metastasis — facilitating effect of radiation, but also reduced the number of lung nodules below that in amputated mice. Metastatic spread was not altered by postoperative treatment of mice with single doses of C. parvum or C. granulosum. However, significantly more mice had lung metastases if they were given 2 intraperitoneal injections of C. granulosum.