Anesthetic drugs accelerate the progression of postoperative metastases of mouse tumors.

Shapiro, Joan Rankin; Jersky, J; Katzav, Shulamit; Feldman, Michaël; Segal, Shraga

doi:10.1172/jci110303

Cited by 128 publications

(62 citation statements)

References 21 publications

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“…Antineoplastic efficacy of doxorubicin is known to be schedule-dependent (15,16). In fact, bolus administration of free doxorubicin proved to be far more effective for L1210 tumor growth inhibition than continuous daily treatment with the same cumulative dose: thus, 8.4 mg/kg administered on day 1 (splenectomy) produced a 70% and 30% inhibition of tLD1o and LD50 values were derived from log-probit dose-mortality plots.…”

mentioning

confidence: 99%

Encapsulation of doxorubicin in liver-targeted erythrocytes increases the therapeutic index of the drug in a murine metastatic model.

Zocchi

Tonetti

Polvani

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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Doxorubicin-loaded, glutaraldehyde-treated murine erythrocytes, once reinjected into circulation, are rapidly taken up by liver and lungs and behave as an organtargeted, slow delivery system for the encapsulated drug. The antitumor activity ofencapsulated doxorubicin (former generic name, adriamycin) was compared with that of the free drug in a murine hepatic and pulmonary tumor model. This was obtained by intrasplenic i jection of L1210 lymphoma cells followed by splenectomy. Different schedules of treatment of tumor-bearing mice with erythrocyte-encapsulated or free doxorubicin were investigated. The optimal schedule of treatment for free doxorubicin proved to be i.v. bolus administration on the day of splenectomy. Under these conditions, the dose producing 50% inhibition of metastatic growth in the liver, as measured by inhibition of 5-[125'Iiodo-2'-deoxyuridine uptake 9 days after tumor induction, was 6.3 mg/kg for free doxorubicin and 0.48 mg/kg for the encapsulated drug. In these conditions pulmonary tumor development was even more efficiently prevented by encapsulated doxorubicin as compared with the free drug. The values of the therapeutic index (TI), dermed as the ratio between the maximal tolerated dose (LDIo) and the minimal effective dose (EDw, producing 90% inhibition of liver metastatic growth), were 4.2 and 1.8 for encapsulated and free doxorubicin, respectively. Doxorubicin (former generic name, adriamycin), an anthracycline antibiotic active against a wide range of tumors, is a very effective antineoplastic drug; however, its use is primarily limited by its remarkable delayed cardiotoxicity (9). Liver targeting of the drug should optimize antimetastatic effects and reduce cardiotoxicity, thus improving its therapeutic index (TI).Previous experiments (3) demonstrated that treatment of murine doxorubicin-loaded RBCs with diluted glutaraldehyde solutions dramatically increases liver uptake of the i.v. injected encapsulated drug (70% of the injected dose). Liver targeting is also accompanied by a reduced cardiac uptake of the RBC-encapsulated doxorubicin.In this report, we present evidence that encapsulation of doxorubicin within liver-targeted autologous RBCs enhances the antitumor activity of this drug towards hepatic metastases of L1210 lymphoma cells in a murine (B6D2F1) liver metastatic tumor model. The TI, defined as the ratio between the maximal tolerated dose (LD10) and the minimal effective dose (producing 90% inhibition of hepatic tumor growth) was found to be 4.2 for encapsulated doxorubicin and 1.8 for the free drug. The increase in the TI is apparently the result of a shift from heart to liver as the main toxicity target of doxorubicin.Selective targeting of drugs to tumors is the objective of new strategies for cancer treatment that pursue optimization of antineoplastic effects and reduction of toxicity: conjugation of antineoplastic drugs to tumor-specific monoclonal antibodies (1) and encapsulation of drugs within "targeted" liposomes (2)

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mentioning

confidence: 99%

Encapsulation of doxorubicin in liver-targeted erythrocytes increases the therapeutic index of the drug in a murine metastatic model.

Zocchi

Tonetti

Polvani

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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“…This effect on the immune system could plausibly be thought to reduce the cancer immunosurveillance and hence increase the risk of metastasis. In keeping with this, melanoma and lung cancer mouse model experimentation revealed a dramatic increase in the rate of metastasis when nitrous oxide was included in the anesthetic [19]. These findings do not appear to translate well for human colorectal cancer.…”

Section: Volatile Anesthetic Agentsmentioning

confidence: 95%

“…Almost forty years ago it was shown that anesthetics such as halothane and nitrous oxide accelerate metastasis in murine models of melanoma and lung cancer [19]. More recent studies indicate that volatile anesthetics may upregulate cellular signaling pathways including the hypoxia inducible factor 1-a (HIF-1a) pathway [20].…”

Section: Volatile Anesthetic Agentsmentioning

confidence: 99%

Perioperative Interventions During Cancer Surgery: Can Anesthetic and Analgesic Techniques Influence Outcome?

Levins

Buggy

2015

Curr Anesthesiol Rep

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Cancer is the second most significant cause of morbidity and mortality worldwide. While surgery is the primary treatment form most cancers, the perioperative period and surgical stress may cause an increased propensity for loco-regional or distant metastasis. There is perhaps a signal, from in vitro, animal model laboratory studies, and retrospective clinical studies, which collectively suggest a possible effect of various anesthetic agents and techniques on tumor metastasis and survival of minimal residual cancer. Prospective randomized control trials are needed in order to truly evaluate any effect anesthesia may have on the metastatic tendency of various tumors.

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“…Fifteen days after tumor inoculation, the animals were tested for metastases. The results were that in animals anesthesized via pentothal sodium, cells of the nonmetastatic clone IC9 did produce metastases (22). Cells of the IE7 clone produced in mice anesthesized via pentothal sodium a higher metastatic load than when injected to unanesthesized recipients.…”

Section: Acceleration Of Metastasis When Tumor Excision Is Performed mentioning

confidence: 96%

Interactions between the local tumor and its metastases

et al. 1982

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Anesthetic drugs accelerate the progression of postoperative metastases of mouse tumors.

Cited by 128 publications

References 21 publications

Encapsulation of doxorubicin in liver-targeted erythrocytes increases the therapeutic index of the drug in a murine metastatic model.

Encapsulation of doxorubicin in liver-targeted erythrocytes increases the therapeutic index of the drug in a murine metastatic model.

Perioperative Interventions During Cancer Surgery: Can Anesthetic and Analgesic Techniques Influence Outcome?

Interactions between the local tumor and its metastases

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