Proposal for Classifying the Emetogenicity of Oral Anticancer Agents with a Focus on PARP Inhibitors: A Prospective, Observational, Multicenter Study (JASCC-CINV 2002).

Background: Olaparib and niraparib (poly adenosine diphosphate [ADP]-ribose polymerase [PARP] inhibitors) have significant antitumor action in patients with ovarian cancer. However, the incidence of nausea and vomiting among patients on these drugs in clinical trials is rather high. There are no guidelines on antiemetic treatment for nausea caused by oral anticancer agents. This study aimed to investigate the incidence of nausea and vomiting caused by PARP inhibitors and the actual situation of antiemetic therapy in patients with gynecologic cancer. Methods: Patients with gynecologic cancer who were scheduled to receive PARP inhibitors were enrolled. Data on PARP inhibitor-induced nausea and vomiting were collected from patient diaries for 21 days. The primary endpoint was the incidence of vomiting during the 21 days after starting olaparib and niraparib. Results: Overall, between January 2020 and March 2023, 134 patients were enrolled. Of the 129 patients who were evaluated, 28 (21.7%) received prophylactic antiemetics for 21 days, and 101 (78.3%) did not. The overall incidence of PARP inhibitor-induced vomiting was 16.3%. The incidence of vomiting in the group that did not receive antiemetic prophylaxis was 13.9%. On dividing the group that did not receive antiemetic prophylaxis into the olaparib and niraparib subgroups, the incidence of vomiting was found to be 18.6% for the olaparib group and 10.3% for the niraparib group. Conclusion: The incidence of emesis without antiemetic prophylaxis among patients on olaparib and niraparib ranged from 10% to 30%. Therefore, olaparib and niraparib can be classified in the low emetogenic risk and prophylactic antiemetic therapy at the time of treatment initiation may be unnecessary.

A Nationwide Survey Aimed at Establishing an Appropriate Long-Term Storage and Management System for Fertility Preserving Specimens in Japan.

Purpose: The demand for fertility preservation continues to grow as cancer treatment outcomes improve. The specimen storage period is longer for fertility preservation than for conventional fertility treatment; therefore, a robust management system for stored specimens is required. We conducted the first national survey in Japan on the management of cryopreserved specimens in fertility preservation facilities. Methods: Questionnaires were mailed to 130 fertility preservation facilities. Primary outcomes included the official position of the storage manager, support system in case of facility closure, disaster countermeasures, management and operating system for liquid nitrogen storage containers, preservation costs, and method to confirm the intention to continue storage. Results: The response rate was 63.8%. The facility director most commonly functioned as the storage manager (59.0%). In case of facility closure, 20.5% had an approved transfer site; 59.0% had not made any decisions. In the management of liquid nitrogen containers, 83.1% regularly replenished the liquid nitrogen, 65.1% regularly checked the amount, and 16.9% had alarm monitoring systems. Regarding disaster countermeasures, 70.9% had taken measures to protect specimens. Conclusion: This survey revealed issues such as disparities among facilities regarding long-term specimen storage systems. Accordingly, management standards for fertility preservation facilities should be established.

[Qualitative Equalization and Sustainability of Decision Support Functions for AYA Patients in Oncofertility Networks- Initiatives of the Oncofertility Consortium Japan].

Starting from 2021, public subsidies for fertility preservation for CAYA cancer patients have been initiated, and from 2022, there is also public support for assisted reproductive technology(ART)after cancer treatment. On the other hand, regarding fertility preservation therapy, it's not universally beneficial for all cancer patients, and evidence regarding its outcomes and safety from both reproductive medicine and the perspective of the primary condition's treatment is still insufficient. As a result, the"public subsidy system"is being implemented as being coupling with to build evidence through close collaboration between the primary disease treatment and reproductive medical care, focusing on providing information and decision- making support. In response to these developments, the 4th Basic Plan for Promoting Cancer Control and the criteria for designating cancer care collaborative hospitals, among other things, mention the necessity of establishing regional networks for cancer and reproductive medical care and the need to participate in such networks. In this article, we discuss the fundamentals of cancer and reproductive medical care, along with the challenges they present. We emphasize the importance of transitioning from information provision to decision-making support and delve into the current status and issues surrounding the establishment of cancer and reproductive medical care networks. Furthermore, we address the efforts of the Japan Society of Cancer and Reproductive Medicine in resolving these issues and advancing the field.

Intracellular ferritin heavy chain plays the key role in artesunate-induced ferroptosis in ovarian serous carcinoma cells.

Artesunate, an antimalarial drug, induces ferroptosis, but the mechanism is still unclear. In the present study, we investigated how Artesunate induces ferroptosis in ovarian serous carcinoma. Experiments were performed using the ovarian serous carcinoma cell lines CaOV3 and SKOV3ip1, and the sensitivity of CaOV3 to Artesunate was higher than that of SKOV3ip1. Ferroptosis inhibitors inhibited Artesunate-induced intracellular lipid peroxi-dation and cell death. However, unlike class 1 ferroptosis inducer erastin, Artesunate had no effect on intracellular glutathione-SH levels. We found that Artesunate-induced changes in lysosomal Fe|2+ were parallel to the induction of ferroptosis. Therefore, ferritin, which oxidizes and binds intracellular Fe|2+, may have an inhibitory effect on ferroptosis. Knockdown of nuclear coactivator 4, a key molecule of ferritinophagy (ferritin-specific autophagy), suppressed Artesunate-induced cell death. Knockdown of ferritin heavy chain by siRNA greatly enhanced the sensitivity to Artesunate, and overexpression of ferritin heavy chain greatly reduced the sensitivity of ovarian cancer cell lines to Artesunate. These results can explain the differential sensitivity of CaOV3 and SKOV3ip1 to Artesunate. In conclusion, enhancement of ferritinophagy is an important step involved in the mechanism of Artesunate-induced ferroptosis, and ferritin heavy chain levels may contribute to the regulation of sensitivity in Artesunate-induced ferroptosis in ovarian serous carcinoma cells.

Control and Risk Factors of Nausea and Vomiting in Patients With Cervical Cancer Receiving Radiotherapy.

BACKGROUND/AIM: Nausea and vomiting are two of the most distressing adverse events of cancer radiotherapy. The aim of this study was to examine the control rate and risk factors associated with nausea and vomiting in patients with cervical cancer receiving radiotherapy. PATIENTS AND METHODS: This retrospective study examined patients with cervical cancer who received radiotherapy alone or with concomitant cisplatin. Patients who received radiotherapy alone were not administered antiemetic premedication, while patients who received radiotherapy with concomitant weekly cisplatin (40 mg/m2) were administered antiemetic therapy comprising granisetron and dexamethasone. Risk factors for non-complete response (CR) were identified using multivariate logistic regression analysis. RESULTS: Multivariate analysis indicated that younger age and concomitant weekly cisplatin were significant factors associated with non-CR across 5 weeks of treatment in patients who received radiotherapy. The proportion achieving CR among younger patients (<65 years) who received radiotherapy alone or with concomitant cisplatin was significantly lower than that among older patients (≥65 years) (Concomitant cisplatin: 27% vs. 67%, p=0.049; Radiotherapy alone: 62% vs. 91%, p=0.166). However, the proportion of patients achieving CR across 5 weeks of treatment was insufficient in all groups except for those aged ≥ 65 years who received radiotherapy alone. CONCLUSION: Antiemetic prophylaxis should be considered for younger patients with cervical cancer undergoing radiotherapy alone. Further, neurokinin-1 receptor antagonist should be added to 5-hydroxytryptamine type-3 receptor antagonist and dexamethasone as antiemetic prophylactic therapy for patients with cervical cancer undergoing radiotherapy with concomitant weekly doses of 40 mg/m2 cisplatin.

Paclitaxel-carboplatin and bevacizumab combination with maintenance bevacizumab therapy for metastatic, recurrent, and persistent uterine cervical cancer: An open-label multicenter phase II trial (JGOG1079).

OBJECTIVE: This multicenter, open-label, phase II study aimed to evaluate the efficacy and safety of paclitaxel-carboplatin, bevacizumab, and bevacizumab-based maintenance therapy for metastatic, recurrent, and persistent uterine cervical cancer. METHODS: Patients with measurable diseases that were not adapted to regional therapies, such as surgery or radiotherapy, and were systematic chemotherapy-naïve were eligible. The participants received paclitaxel (175 mg/m2), carboplatin (AUC 5), and bevacizumab (15 mg/m2) every three weeks until disease progression or unacceptable adverse events occurred. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall response rate (ORR), overall survival (OS), safety, and time to treatment failure. RESULTS: Sixty-nine patients were analyzed using our protocol. The median paclitaxel- carboplatin therapy duration was six cycles; 40% of patients received bevacizumab maintenance therapy. The median PFS was 11.3 months. The median OS was not reached; the median time to treatment failure was 5.9 months. The ORR was 79.7% [95% confidence interval (CI) 63.8-88.4]; 16 patients (23.2%) showed complete response (CR) and 39 patients (56.5%) showed partial response (PR). The median PFS was 14.3 months (95% CI 7.3-17 months) for the 25 patients who received maintenance therapy and 7.4 months (95% CI 6.1-11 months) for nonrecipients (p = 0.0449). Gastrointestinal perforation/fistulas occurred in four patients (5.6%), all of whom had a history of radiation therapy. CONCLUSIONS: Paclitaxel-carboplatin and bevacizumab therapy is an acceptable and tolerable treatment for advanced or recurrent cervical cancer.

[Promotion of Equal Access to Medical Services for Children, Adolescent and Young Adult(CAYA)Cancer Patients with Reproductive Problems-A Nationwide Expansion of the Regional Oncofertility Network in Japan].

OBJECTIVES: Fertility preservation is important for Children, Adolescent and Young Adult(CAYA)cancer patients. Although a regional oncofertility network was established in Japan in 2012, regional inequality persists. This study was aimed at expanding the oncofertility network throughout Japan. METHODS: Oncologists, reproductive medicine specialists, and administrative officials from 24 regions, currently without a regional oncofertility network, conferred to discuss problems and strategies for network expansion. RESULTS: Regional oncofertility networks had already been established in 4 of 24 regions. Consultation and support and a collaboration system between facilities and individual doctors were found in 13 and 14 regions, respectively. Regarding which organization should lead the network operation, the regions(number)chose the prefecture (10), prefectural cancer centers(10), and OB/GYN department of hospitals specializing in cancer treatment(9). Obstacles to establishing a regional oncofertility network were the lack of manpower(21), budget(19), know-how(16), and specialists( 12). DISCUSSION: CAYA cancer patients need equal access to oncofertility networks, and a public support system is essential for preserving the fertility of cancer patients. We should organize a oncofertility network in association with prefectural administration. Medical staff training and supply of materials using the Oncofertility Consortium Japan system are required to promote the oncofertility network throughout Japan.

Investigation of clinicopathological features of vulvar cancer in 1068 patients: A Japanese Gynecologic Oncology Group (JGOG) nationwide survey study.

OBJECTIVE: Vulvar cancer is a rare malignancy in the aging population, and optimizing treatment strategies requires large-scale investigation of the clinicopathological features of this disease. In Japan, no such surveys have been conducted in the past 30 years. This large-scale retrospective multi-center study aimed to examine the clinicopathological features of vulvar cancer in Japan. METHODS: Upon obtaining ethical approval by the participating institutions' review boards, the medical records of patients with vulvar cancer, who were treated between 2001 and 2010 were reviewed. The impact of clinicopathological factors on overall survival (OS) was investigated using a multivariate Cox regression model. RESULTS: After applying the inclusion and exclusion criteria, 1068 patients treated in 108 centers were included. The median age was 72 years. The disease was in stage I in 402 patients (37.6%), stage II in 249 patients (23.3%), stage III in 252 patients (23.6%), and stage IV in 165 patients (15.4%). Squamous cell carcinoma, Paget's disease, adenocarcinoma, and other diseases were diagnosed in 773 (72.4%), 154 (14.4%), 59 (5.5%), and 82 (7.7%) patients, respectively. Positive inguino-femoral lymph nodes were found in 265 (24.8%) patients. The 5-year OS rate for stage I, II, III, and IV vulvar cancer were 85.6%, 75.1%, 48.8%, and 40.0%, respectively. CONCLUSION: Our study shows that advanced age, disease stage, histological diagnosis, tumor diameter, and lymph node metastases significantly affect the OS of patients with vulvar cancer in Japan.

Efficacy and safety of 5 mg olanzapine combined with aprepitant, granisetron and dexamethasone to prevent carboplatin-induced nausea and vomiting in patients with gynecologic cancer: A multi-institution phase II study.

PURPOSE: The aim of this study was to investigate the efficacy and safety of prophylactic administration of 5 mg olanzapine (OLZ) combined with neurokinin 1 receptor antagonist (NK1RA), 5-hydroxytryptamine type-3 receptor antagonist (5-HT3RA), and dexamethasone (DEX) to prevent nausea and vomiting in carboplatin (CBDCA) combination therapy for patients with gynecological cancer. METHODS: We conducted a single-arm, multi-institution, phase II study. Gynecological cancer patients scheduled to receive AUC ≥4 mg/mL/min CBDCA were enrolled. All patients received 5 mg OLZ (once daily after supper on days 1-4) combined with NK1RA, 5-HT3RA, and DEX. The primary end point was complete response (CR; no emesis and rescue therapy) during overall phase (120 h after the start of carboplatin administration). RESULTS: Between May 2018 and June 2019, 60 patients were enrolled from 3 institutions in Japan. A total of 57 patients who met the criteria were included in the efficacy and safety analysis. The CR rate for the overall phase was 78.9%. Acute (0-24 h) and delayed phases (24-120 h) were 96.5% and 80.7%, respectively. Somnolence was observed in 73.7% patients. However, somnolence of grade 2 or higher was observed in only 3.5% of cases. There were no grade 3 or 4 toxicities associated with OLZ. CONCLUSIONS: Preventive use of OLZ combined with standard triplet therapy had promising activity with manageable safety, suggesting that this combination could be an effective standard treatment option for patients with AUC ≥4 mg/mL/min CBDCA combination therapy.

Management of ovarian hyperstimulation syndrome with abdominal compartment syndrome, based on intravesical pressure measurement.

There are few reports on abdominal compartment syndrome that are caused by ovarian hyperstimulation syndrome (OHSS). Here, a case of a 29 year old woman is reported in which intravesical pressure measurement was useful in the management of severe OHSS that had been complicated by abdominal compartment syndrome. The patient's urinary output and general condition did not improve after the initial treatment. The woman's intra-abdominal pressure was evaluated indirectly, based on her intravesical pressure, and was found to be significantly elevated. The patient's urinary volume increased after a 14 mm Hg decrease in the intravesical pressure was achieved by the drainage of ascitic fluid. Intravesical pressure measurement was useful in the management of the general condition of this patient with OHSS.

Iron regulatory protein 2 in ovarian endometrial cysts.

Ovarian endometrial cysts cause some kinds of ovarian cancer, and iron is considered as one factor of carcinogenesis. In contrast, hypoxia is associated with progression, angiogenesis, metastasis, and resistance to therapy in cancer. We investigated hypoxia-induced perturbation of iron homeostasis in terms of labile iron, iron deposition, and iron regulatory protein (IRP) in ovarian endometrial cysts. Iron deposition, expression of IRPs, and a protein marker of hypoxia in human ovarian endometrial cysts were analyzed histologically. The concentration of free iron and the pO2 level of the cyst fluid of human ovarian cysts (n = 9) were measured. The expression of IRP2 under hypoxia was investigated in vitro by using Ishikawa cells as a model of endometrial cells. Iron deposition and the expression of IRP2 and Carbonic anhydrase 9 (CA9) were strong in endometrial stromal cells in the human ovarian endometrial cysts. The average concentration of free iron in the cyst fluid was 8.1 ± 2.9 mg/L, and the pO2 was 22.4 ± 5.2 mmHg. A cell-based study using Ishikawa cells revealed that IRP2 expression was decreased by an overload of Fe(II) under normoxia but remained unchanged under hypoxia even in the presence of excess Fe(II). An increase in the expression of IRP2 caused upregulation of intracellular iron as a result of the response to iron deficiency, whereas the protein was degraded under iron-rich conditions. We found that iron-rich regions existed in ovarian endometrial cysts concomitantly with the high level of IRP2 expression, which should generally be decomposed upon an overload of iron. We revealed that an insufficient level of oxygen in the cysts is the main factor for the unusual stabilization of IRP2 against iron-mediated degradation, which provides aberrant uptake of iron in ovarian endometrial stromal cells and can potentially lead to carcinogenesis.

An evaluation of the Gifu Model in a trial for a new regional oncofertility network in Japan, focusing on its necessity and effects.

Purpose: We evaluated our 2-year experience of the regional oncofertility network in Gifu Prefecture (GPOFS) in order to establish a more sophisticated regional oncofertility networking model in Japan. Methods: Questionnaires were distributed twice in January 2013 to 57 departments in 35 hospitals that provide cancer treatment in Gifu Prefecture, before the establishment of the regional oncofertility network. The number and type of disease of the referred adolescent and young adult (AYA) cancer patients who visited the oncofertility clinic in Gifu University Hospital via the GPOFS were analyzed. Results: The majority of regional oncologists are aware of the need to provide information about oncofertility to their patients, but they cannot provide sufficient information due to their lack of knowledge about reproductive medicine. Eighty-one AYA patients were referred to our clinic for oncofertility counseling in the first 2 years after the establishment of the GPOFS. Conclusions: The GPOFS as the first regional oncofertility network in Japan has just started and may be working to help both AYA cancer patients and their oncologists. The nationwide establishment of the regional oncofertility network model could help both AYA cancer patients and oncologists.

Exploratory study of pre-surgical medications with dienogest or leuprorelin in laparoscopic cystectomy of endometrial cysts.

AIM: The aim of this study was to compare the effects of pre-surgical medication with dienogest or leuprorelin on post-surgical ovarian function. MATERIAL AND METHODS: We conducted an exploratory study in two centers in Japan that comprised 30 patients with ovarian endometrial cysts for whom surgical excision was planned. Patients were enrolled and divided into pre-surgical medication groups with dienogest or leuprorelin for 12 weeks. Thereafter, patients were treated by laparoscopic cystectomy. The primary outcome was ovarian function post-surgery, as assessed by serum anti-Müllerian hormone (AMH) level, antral follicle count (AFC) and resumption of menses. Secondary outcome was the effect of pre-surgical medication, as assessed by the size of endometrial cysts and visual analog scale (VAS) score. Serum AMH, AFC, size of endometrial cysts, and VAS scores were measured at baseline (before medication), after medication (1 day before surgery), and at 4 and 12 weeks post-surgery. RESULTS: Serum AMH levels did not change after pre-surgical medication with either dienogest or leuprorelin. Although AMH decreased after surgery, it recovered by 12 weeks post-surgery in both groups with no statistically significant difference. Mean AFC did not change after surgery in either group. Menses returned by 12 weeks post-surgery in all patients except for those who were pregnant. The rate of reduction of endometrial cyst volume did not differ between the groups. Both dienogest and leuprorelin were associated with substantial reductions in VAS scores. CONCLUSION: There were no statistically significant differences between pre-surgical medication with dienogest and leuprorelin in post-surgical ovarian function. Both medications were effective in reducing endometrial cyst volume and VAS score.

Amnioinfusion before 26 weeks' gestation for severe fetal growth restriction with oligohydramnios: preliminary pilot study.

AIM: The prognosis for severe fetal growth restriction (FGR) with severe oligohydramnios before 26 weeks' gestation (WG) is currently poor; furthermore, its management is controversial. We report the innovative new management of FGR, such as therapeutic amnioinfusion and tocolysis. MATERIAL AND METHODS: For FGR and severe oligohydramnios before 26 WG complicated with absent or reversed umbilical artery end-diastolic flow velocity and/or deceleration by ultrasonography, we performed transabdominal amnioinfusion with tocolysis. Cases with multiple anomalies were excluded. Survival rate and long-term prognosis were analyzed. RESULTS: Among 570 FGR cases, 18 were included in the study. Mean diagnosis and delivery were at 22.6 ± 2.0 and 28.7 ± 3.3 WG. Median birthweight was 625 g (-4.2 standard deviation). Final survival rate was 11/13 (85%). There were five fetal deaths. In seven cases, oligohydramnios improved. Growth was detected in 10/18 fetuses. Furthermore, 8/8 decelerations, 4/12 cases of reversed umbilical artery end-diastolic flow velocity, 7/14 cases of brain-sparing effect, and 6/13 venous Doppler abnormalities were improved. When we detected umbilical cord compression, 8/10 cases were rescued. Eleven infants were followed up for an average of 5 years; one case of cerebral palsy with normal development and 10 cases with intact motor functions without major neurological handicap were confirmed. CONCLUSIONS: In cases of extremely severe FGR before 26 WG with oligohydramnios and circulatory failure, amnioinfusion might be a promising, innovative tool.

Vasopressin phosphorylates HSP27 in aortic smooth muscle cells.

Administration of arginine vasopressin (AVP) time-dependently induced the phosphorylation of heat shock protein 27 (HSP27) at Ser-15 and Ser-85 in smooth muscle of aorta in vivo. The AVP-induced phosphorylation of HSP27 at Ser-15 and Ser-85 was inhibited by a V1a receptor antagonist but not by a V2 receptor antagonist. In cultured aortic smooth muscle A10 cells, AVP markedly stimulated the phosphorylation of HSP27 at Ser-15 and Ser-85. The AVP-induced phosphorylation of HSP27 was attenuated by SB203580 and PD169316, inhibitors of p38 mitogen-activated protein (MAP) kinase, but not by PD98059, a MEK inhibitor. These results strongly suggest that AVP phosphorylates HSP27 via p38 MAP kinase in aortic smooth muscle cells.

Interleukin (IL)-17 enhances tumor necrosis factor-alpha-stimulated IL-6 synthesis via p38 mitogen-activated protein kinase in osteoblasts.

Inflammatory cytokines are well known to play crucial roles in the pathogenesis of rheumatoid arthritis. Among them, interleukin (IL)-17 is a cytokine that is mainly synthesized by activated T cells and its receptors are present in osteoblasts. The synthesis of IL-6, known to stimulate osteoclastic bone resorption, is reportedly responded to bone resorptive agents such as tumor necrosis factor-alpha (TNF-alpha) in osteoblasts. It has been reported that IL-17 enhances TNF-alpha-stimulated IL-6 synthesis in osteoblast-like MC3T3-E1 cells. We previously showed that sphingosine 1-phosphate (S1-P) mediates TNF-alpha-stimulated IL-6 synthesis in these cells. In the present study, we investigated the mechanism of IL-17 underlying enhancement of IL-6 synthesis in MC3T3-E1 cells. IL-17 induced phosphorylation of p38 mitogen-activated protein (MAP) kinase. SB203580 and PD169316, specific inhibitors of p38 MAP kinase, significantly reduced the enhancement by IL-17 of TNF-alpha-stimulated IL-6 synthesis. IL-17 also amplified S1-P-stimulated IL-6 synthesis, and the amplification by IL-17 was suppressed by SB203580. Anisomycin, an activator of p38 MAP kinase, which alone had no effect on IL-6 level, enhanced the IL-6 synthesis stimulated by TNF-alpha. SB203580 and PD169316 inhibited the amplification by anisomycin of the TNF-alpha-induced IL-6 synthesis. Taken together, our results strongly suggest that IL-17 enhances TNF-alpha-stimulated IL-6 synthesis via p38 MAP kinase activation in osteoblasts.

Platelet-derived growth factor-BB phosphorylates heat shock protein 27 in cardiac myocytes.

It is recognized that heat shock protein 27 (HSP27) is highly expressed in heart. In the present study, we investigated whether platelet-derived growth factor (PDGF) phosphorylates HSP27 in mouse myocytes, and the mechanism underlying the HSP27 phosphorylation. Administration of PDGF-BB induced the phosphorylation of HSP27 at Ser-15 and -85 in mouse cardiac muscle in vivo. In primary cultured myocytes, PDGF-BB time dependently phosphorylated HSP27 at Ser-15 and -85. PDGF-BB stimulated the phosphorylation of p44/p42 mitogen-activated protein (MAP) kinase, p38 MAP kinase, and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) among the MAP kinase superfamily. SB203580, a specific inhibitor of p38 MAP kinase, reduced the PDGF-BB-stimulated phosphorylation of HSP27 at both Ser-15 and -85, and phosphorylation of p38 MAP kinase. However, PD98059, a specific inhibitor of MEK, or SP600125, a specific inhibitor of SAPK/JNK, failed to affect the HSP27 phosphorylation. These results strongly suggest that PDGF-BB phosphorylates HSP27 at Ser-15 and -85 via p38 MAP kinase in cardiac myocytes.

Simvastatin stimulates VEGF release via p44/p42 MAP kinase in vascular smooth muscle cells.

It has been shown that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) modulate vascular smooth muscle cell functions. In the present study, we investigated the effect of simvastatin on vascular endothelial growth factor (VEGF) release, and the underlying mechanism, in a rat aortic smooth muscle cell line, A10 cells. Administration of simvastatin increased the VEGF level in rat plasma in vivo. In cultured cells, simvastatin significantly stimulated VEGF release in a dose-dependent manner. Simvastatin induced the phosphorylation of p44/p42 MAP kinase but not p38 MAP kinase or SAPK (stress-activated protein kinase)/JNK (c-Jun N-terminal kinase). PD98059 and U-0126, inhibitors of the upstream kinase that activates p44/p42 MAP kinase, significantly reduced the simvastatin-induced VEGF release in a dose-dependent manner. The phosphorylation of p44/p42 MAP kinase induced by simvastatin was reduced by PD98059 or U-0126. Moreover, a bolus injection of PD98059 truly suppressed the simvastatin-increased VEGF level in rat plasma in vivo. These results strongly suggest that p44/p42 MAP kinase plays a role at least partly in the simvastatin-stimulated VEGF release in vascular smooth muscle cells.