Therapeutic effect of cisplatin given with a lymphatic drug delivery system on false‐negative metastatic lymph nodes

Tada, Asuka; Horie, Seichi; Mori, Shiro; Kodama, Tetsuya

doi:10.1111/cas.13387

Cited by 21 publications

(37 citation statements)

References 25 publications

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“…False‐negative metastatic LNs are those that contain tumor cells but, due to the early stage of tumor development, have a size and shape similar to those of LNs not hosting tumor cells. The LDDS is a new approach to treat or prevent LN micrometastasis, and we have previously demonstrated this novel therapeutic concept . The LDDS operates by injecting drugs into sentinel (upstream) LNs in order to deliver them to downstream metastatic LNs in the lymphatic network and maintain high concentrations of drug within the targeted LNs.…”

Section: Introductionmentioning

confidence: 99%

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Treatment of false‐negative metastatic lymph nodes by a lymphatic drug delivery system with 5‐fluorouracil

et al. 2019

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Metastatic lymph nodes ( LN s) may be the origin of systemic metastases. It will be important to develop a strategy that prevents systemic metastasis by treating these LN s at an early stage. False‐negative metastatic LN s, which are found during the early stage of metastasis development, are those that contain tumor cells but have a size and shape similar to LN s that do not host tumor cells. Here, we show that 5‐fluorouracil (5‐ FU ), delivered by means of a novel lymphatic drug delivery system ( LDDS ), can treat LN s with false‐negative metastases in a mouse model. The effects of 5‐ FU on four cell lines were investigated using in vitro cytotoxicity and cell survival assays. The therapeutic effects of LDDS ‐administered 5‐ FU on false‐negative metastatic LN s were evaluated using bioluminescence imaging, high‐frequency ultrasound ( US ), and histology in MHX 10/Mo‐ lpr / lpr mice. These experimental animals develop LN s that are similar in size to human LN s. We found that all cell lines showed sensitivity to 5‐ FU in the in vitro assays. Furthermore, a concentration‐dependent effect of 5‐ FU to inhibit tumor growth was observed in tumor cells with low invasive growth characteristics, although a significant reduction in metastatic LN volume was not detected in MHX 10/Mo‐ lpr / lpr mice. Adverse effects of 5‐ FU were not detected. 5‐Fluorouracil administration with a LDDS is an effective treatment method for false‐negative metastatic LN s. We anticipate that the delivery of anticancer drugs by a LDDS will be of great benefit in the prevention and treatment of cancer metastasis via LN s.

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Section: Introductionmentioning

confidence: 99%

“…The LDDS is a new approach to treat or prevent LN micrometastasis, and we have previously demonstrated this novel therapeutic concept. 23 The LDDS operates by injecting drugs into sentinel (upstream) LNs in order to deliver them to downstream metastatic LNs in the lymphatic network and maintain high concentrations of drug within the targeted LNs.…”

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confidence: 99%

Treatment of false‐negative metastatic lymph nodes by a lymphatic drug delivery system with 5‐fluorouracil

et al. 2019

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“…Development of a minimally invasive treatment to prevent lymph nodemediated hematogenous metastasis is desirable, and we have previously reported (using the same animal model) that anticancer drugs can be injected into an upstream lymph node to treat micrometastasis in a downstream lymph node. [31][32][33] A lymphatic anticancer drug delivery system can remove the origin of lymph node-mediated hematogenous metastasis by targeting micrometastases in lymph nodes, avoiding surgical intervention and preventing the risk of activation of distant metastatic lesions by lymph node resection. Therefore, this novel cancer chemotherapy approach may be a promising technique that should be further investigated in future studies.…”

Section: Discussionmentioning

confidence: 99%

Lymph node resection induces the activation of tumor cells in the lungs

et al. 2019

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Lymph node (LN) dissection is a crucial procedure for cancer staging, diagnosis and treatment, and for predicting patient survival. Activation of lung metastatic lesions after LN dissection has been described for head and neck cancer and breast cancer. Preclinical studies have reported that dissection of a tumor‐bearing LN is involved in the activation and rapid growth of latent tumor metastases in distant organs, but it is also important to understand how normal (non‐tumor‐bearing) LN resection influences secondary cancer formation. Here, we describe how the resection of tumor‐bearing and non‐tumor‐bearing LN affects distant metastases in MXH10/Mo‐lpr/lpr mice. Tumor cells were administered intravenously and/or intranodally into the right subiliac lymph node (SiLN) to create a mouse model of lung metastasis. Luciferase imaging revealed that tumor cells in the lung were activated after resection of the SiLN, irrespective of whether it contained tumor cells. No luciferase activity was detected in the lungs of mice that did not undergo LN resection (excluding the intravenous inoculation group). Our results indicate that resection of an LN can activate distant metastases regardless of whether the LN contains tumor cells. Hence, lung metastatic lesions are suppressed while metastatic LN are present but activated after LN resection. If this phenomenon occurs in patients with cancer, it is likely that lung metastatic lesions may be activated by elective LN dissection in clinical N0 cases. The development of minimally invasive cancer therapy without surgery would help to minimize the risk of activation of distant metastatic lesions by LN resection.

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“…In other words, false-N0 metastatic LNs can be a source of hematogenous metastasis. The importance of false-N0 LNs in distant metastasis is supported by the results of clinical trials suggesting that LN dissection [25,26] and sentinel LN biopsy [27] do not always improve survival in patients with cancer.…”

Section: Discussionmentioning

confidence: 99%

“…The development of new methods to detect and treat metastasis in false-N0 LNs will be extremely important. In previous studies, we have shown that a lymphatic drug delivery system has great potential in the therapeutic and prophylactic treatment of false-N0 LNs [25,26] , and we expect this technique to be applied in the clinical setting in future.…”

Section: Discussionmentioning

confidence: 99%

Tumor cell invasion from the marginal sinus into extranodal veins during early-stage lymph node metastasis can be a starting point for hematogenous metastasis

Kodama¹,

Mori²,

Nose³

2018

JCMT

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Therapeutic effect of cisplatin given with a lymphatic drug delivery system on false‐negative metastatic lymph nodes

Cited by 21 publications

References 25 publications

Treatment of false‐negative metastatic lymph nodes by a lymphatic drug delivery system with 5‐fluorouracil

Treatment of false‐negative metastatic lymph nodes by a lymphatic drug delivery system with 5‐fluorouracil

Lymph node resection induces the activation of tumor cells in the lungs

Tumor cell invasion from the marginal sinus into extranodal veins during early-stage lymph node metastasis can be a starting point for hematogenous metastasis

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