Changes in resting-state brain networks after cognitive-behavioral therapy for chronic pain.

BACKGROUND: Cognitive-behavioral therapy (CBT) is thought to be useful for chronic pain, with the pathology of the latter being closely associated with cognitive-emotional components. However, there are few resting-state functional magnetic resonance imaging (R-fMRI) studies. We used the independent component analysis method to examine neural changes after CBT and to assess whether brain regions predict treatment response. METHODS: We performed R-fMRI on a group of 29 chronic pain (somatoform pain disorder) patients and 30 age-matched healthy controls (T1). Patients were enrolled in a weekly 12-session group CBT (T2). We assessed selected regions of interest that exhibited differences in intrinsic connectivity network (ICN) connectivity strength between the patients and controls at T1, and compared T1 and T2. We also examined the correlations between treatment effects and rs-fMRI data. RESULTS: Abnormal ICN connectivity of the orbitofrontal cortex (OFC) and inferior parietal lobule within the dorsal attention network (DAN) and of the paracentral lobule within the sensorimotor network in patients with chronic pain normalized after CBT. Higher ICN connectivity strength in the OFC indicated greater improvements in pain intensity. Furthermore, ICN connectivity strength in the dorsal posterior cingulate cortex (PCC) within the DAN at T1 was negatively correlated with CBT-related clinical improvements. CONCLUSIONS: We conclude that the OFC is crucial for CBT-related improvement of pain intensity, and that the dorsal PCC activation at pretreatment also plays an important role in improvement of clinical symptoms via CBT.

The nature of in vivo cell-killing of deoxyspergualin, and its implication in combination with other antitumor agents.

The mode of in vivo cell-killing by 15-deoxyspergualin (NKT-01) was assessed by measuring change of whole body radioactivity of mice inoculated with 125I-iododeoxyuridine-labeled P388 leukemia cells. Although NKT-01 showed strong life prolonging effect on P388 leukemia-bearing mice, significant excretion of 125I was not observed within 4 days after the start of treatment with NKT-01. Thereafter, the remaining 125I was reduced gradually and reached about half of control level on day 7. Colony forming ability in soft agar media of peritoneal tumor cells taken after completion of 5-day treatment with NKT-01 was markedly reduced to less than 3%. These results suggested that life prolongation of NKT-01 was produced both by a cytostatic effect, which lasts for an extraordinarily long period, and by a subsequent cytotoxic effect. Cell cycle distribution analysis using flow cytometry showed the cytostatic action of NKT-01 caused G0/G1 arrest of the tumor cells. Therefore, the drug-sensitive cycling population of the tumor cells was reduced, and combination with other antitumor agents was antagonistic, if they were administered simultaneously or consecutively with NKT-01. In contrast, if the other drugs such as cyclophosphamide, cisplatin and cytosine arabinoside, were administered prior to NKT-01, a synergistic combination effect was obtained. This synergism might be due to prolongation of the period of cell cycle perturbation caused by other drugs (such as G2 arrest by cisplatin) by the cytostatic effect of NKT-01. Although the precise mechanisms of the cytostatic action of NKT-01 remain unclear, it might play an important role in the combination with other antitumor drugs.

Antitumor spectrum of deoxyspergualin and its lack of cross-resistance to other antitumor agents.

Antitumor activities of 15-deoxyspergualin (NKT-01), an analogue of spergualin (SGL), were examined in cultured tumor cells, transplantable murine tumors, and human tumor xenografts in nude mice. NKT-01 exhibited strong antitumor activity specifically against leukemias both in vitro and in vivo. Moreover, it also showed activity against AH66F hepatoma, M5076 fibrosarcoma and MH134 hepatoma. However, antitumor activity of NKT-01 against other non-leukemic tumors was marginal. Effective dose range of NKT-01 in sensitive tumors was so wide that the largest chemotherapeutic indexes were produced by NKT-01 in P388 and L1210 leukemias among 15 antitumor agents examined. The efficacy of NKT-01 against doxorubicin- and cytosine arabinoside-resistant P388 leukemias was comparable to that against parental sensitive P388 leukemia. NKT-01 also retained activity against other p388 leukemia sublines resistant to cisplatin, 5-fluorouracil or nimustine, although the effect was slightly decreased. In addition, in the in vitro and in vivo experiments using NKT-01-resistant P388 and SGL-resistant L1210(IMC) leukemias, no cross-resistance was observed. Moreover, collateral sensitivity was observed especially to alkylating agents in animal study.

Treatment schedule dependency of antitumor effect of deoxyspergualin.

The effect of treatment schedule on antitumor activity of 15-deoxyspergualin (NKT-01) against P388 leukemia was studied by changing each 2 out of 3 factors of administration schedule (number of injections, injection interval, and injection period) with the rest being constant. The antitumor activity of NKT-01 was shown to be strongly time-dependent; higher efficacy was obtained with prolongation of treatment period and with increasing the number of injections. The dosing interval seemed not to be a dominant factor regarding the activity of NKT-01. The strong dependency on treatment period was also observed in continuous infusion schedules by using Alzet 2001 osmotic minipump. The degree of dependency on infusion period was estimated to be 3- to 4-fold stronger than that on the infused dose by logarithmical plotting of the infusion periods and infused daily doses required to produce 130% of T/C(%). The effective dose range by the continuous infusion was slightly narrower than that by the repeated bolus injections, although slightly higher maximal activity was obtained at the optimal dose. Hyperacute pharmacological toxicity caused by bolus injection of high dose (51.2 mg/kg) of NKT-01 did not occur by continuous infusion method even at much higher dose (409.6 mg/kg/day). Cumulative gastrointestinal toxicity was observed by prolonged continuous infusion as well as repetitive treatment schedule. From these results on antitumor activity and toxicity by various treatment schedules, recommendable clinical modality for NKT-01 seems to be the short-time infusion on every or every other day continuing for a few weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

[Antitumor activity of a novel analog of cytarabine, 4-amino-1-beta-D-arabinofuranosyl-2(1H)-pyrimidinone 5'-(sodium octadecyl phosphate) monohydrate (YNK01)].

4-Amino-1-beta-D-arabinofuranosyl-2(1H)-pyrimidinone 5'-(sodium octadecyl phosphate) monohydrate (YNK01) was an orally active depot form of 1-beta-D-arabinofuranosylcytosine (Ara-C). In the present study, antitumor activity of YNK01 was compared with it of Ara-C in vitro and in vivo. The activity of a main metabolite of YNK01, 5'-carboxypropylphosphate of Ara-C (C-C3PCA), was also studied. Growth inhibitory activity of YNK01 against various cultured tumor cells was 1/32-1/1,100 of that of Ara-C. YNK01 exhibited antitumor activity against L1210 leukemia in mice after i.v., i.p. or p.o. administration. The activity did not depend on the administration routes. Compared with Ara-C, the activity was comparable in both i.v. and i.p. administrations, but greater in p.o. administration. Oral administration of YNK01 showed similar antitumor spectrum to i.p. administration of Ara-C. Oral activity of YNK01 against L1210 leukemia did not depend on the administration schedules but depended on a total administration dose. In contrast, activity of Ara-C greatly depended on the schedules, and the frequent i.p, administration showed greatest activity. Growth inhibitory activity of C-C3PCA against cultured tumor cells was 1/2-1/7 of Ara-C. The metabolite exhibited activity against L1210 leukemia in mice after i.p. administration. These results suggest that YNK01 is a clinically useful drug with p.o. administration for cancers as well as Ara-C.

[Combined effect of CDDP with various types of antitumor drugs against P 388 leukemia].

The combined effect of cisplatin (CDDP) with various types of antitumor drugs was examined in P 388 leukemia in vivo. Three representative drugs were chosen from every group of alkylating agents, antitumor antibiotics, antimetabolites, and plant originated drugs. According to their dependency on administration schedules, the dose-dependent and time-dependent drugs were administered once, and daily 5 times, respectively, before and after the single administration of CDDP. In addition to these sequential combinations, simultaneous treatment with CDDP was examined for the drugs which were singly administered. The combined effect was assessed by comparing ILS (increase in life span) in a combined group with the sum of ILS's of each of the 2 single-treatment groups. Synergistic effect was observed in the combination of CDDP with all drugs except MMC. Among them CYC, CQ, ACNU, ADR, PEP, ET, VCR, and VDS produced synergistic effect in any treatment schedules, irrespective of the combination sequences. In the cases of the combination with antimetabolites, the combined effect was depended on the treatment sequences; prior treatment of 5-FU, and posterior treatment of Ara-C and MTX to CDDP administration exhibited a synergistic effect, but the combination in reverse sequence remained almost additive.

[Antitumor activity of peplomycin against 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors].

Antitumor activity of peplomycin (PEP) against 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors was compared with activities of bleomycin (BLM) and doxorubicin (adriamycin, ADM). Drugs were administered subcutaneously 3 times weekly (24 times in total) starting on 75 days after an intravenous administration of DMBA. PEP strongly inhibited the growth of mammary tumors detected at the start of the treatment, and some of the tumors disappeared and regressed upon the administration of PEP. The number of stable tumors was larger and the number of progressed tumors smaller in the PEP-treated group than in the control group. Moreover, PEP exhibited strong growth inhibitory effect with slight delay of tumor appearance against mammary tumors appeared during the treatment period. These antitumor effects of PEP were greater than those of BLM, a parent compound of PEP, and almost comparable to those of ADM.

Involvement of cytotoxic T-lymphocytes in the antitumor activity of spergualin against L1210 cells.

Spergualin exhibited a strong antitumor effect against L1210(IMC), a tumor cell line which has been maintained in BALB/c X DBA/2 F1 (hereafter called CD2F1) mice in the Institute of Microbial Chemistry. Mice inoculated i.p. with 10(5) cells of L1210(IMC) survived more than 60 days by daily i.p. administration of spergualin for 9 days at 5 mg/kg/day, which was started 1 day after the tumor inoculation. These cured mice rejected a second inoculation of 10(6) cells of L1210(IMC), but they did not reject the inoculation of 10(2) P388 cells. In Winn's tumor neutralization assay and in the 51Cr release assay, the T-cell fraction prepared from the spleens of the cured mice had higher cytotoxic activity against L1210(IMC) than whole spleen cells. The cytotoxic activity of spleen cells was diminished by treatment with anti-Thy-1.2 or anti-Lyt-2.1 antibody and complement. Therefore, the effector cells involved in the immunological rejection should be regarded as cytotoxic T-lymphocytes. The cytotoxic activity of these T-lymphocytes was measured during and after the spergualin administration for 9 days, and high activity was observed from 1 day after the final spergualin administration. The antitumor effect of spergualin against L1210(IMC) was much lower in T-cell-deficient athymic mice. These results suggest that cytotoxic T-lymphocytes are involved in the antitumor action of spergualin against L1210(IMC) in vivo.

Antitumor activity of spergualin, a novel antitumor antibiotic.

Spergualin (SGL), a novel antitumor antibiotic, exhibited strong antitumor activity against transplantable leukemias in mice: L1210, L1210(IMC), P388, P815, C1498, EL-4 and RL male 1. It also exhibited antitumor activity against M5076 fibrosarcoma, AH66 and AH66F rat hepatomas, but not against Meth-A fibrosarcoma, B16 melanoma, Lewis lung carcinoma (LL) and C26 colon adenocarcinoma. The antitumor activity of SGL was administration-schedule dependent. The strongest activity against L1210 was obtained by ip continuous infusion for 7 days or daily ip administration for 9 days. Single ip injection of SGL at 100 mg/kg to mice caused convulsion and death within 15 minutes after injection. Such acute toxicity was not observed by continuous infusion. SGL showed its strongest activity at subtoxic dose against sensitive tumors except for L1210(IMC). Mice implanted ip with L1210(IMC) were cured by treatment with SGL at 3.13 mg/kg/day for 9 days, but died from the tumor at 50 mg/kg/day X 9. The cured mice rejected a second inoculation of up to 10(6) tumor cells. The tumor cells isolated from mice after treatment with the high dose showed resistance to SGL in vivo. Mice implanted sc with L1210(IMC) were also cured by 9 daily ip administrations of SGL at 12.5 mg/kg/day, but solid tumor was observed at the implantation site until 3 days after the final injection of SGL in some cured mice. These results suggest that the therapeutic effect of SGL has a relatively high specificity for leukemias and that the immunological effect is involved in the antitumor activity.

[The antitumor activity of intraperitoneally- or orally-administered etoposide in animals and its administration-schedule dependency].

The antitumor activity of etoposide against a wide variety of transplantable tumors in mice and rats was examined. Etoposide exhibited antitumor activity by both i.p. and p.o. administrations but a much larger effect was obtained in the former case. In addition, the effective dose of etoposide was much less in i.p. administration. In order to further investigate this large difference of etoposide effect the level of etoposide in the blood was followed after administration of 3H-etoposide via i.p. and p.o. routes. Although the maximum levels for both were seen 10 to 20 min after administration, the level in i.p. administration was much higher than that in p.o. administration. For instance, the level seen for i.p. administration at 8 mg/kg was comparable to that for p.o. administration at a much higher dose of 128 mg/kg. The administration schedule dependency of etoposide antitumor activity was examined using L1210 leukemia as the target tumor. When etoposide was administered alone on day, 1, the effect was the smallest obtained in i.p. as well as in p.o. administrations among the schedules examined in this study. Under other schedules where etoposide was administered i.p. and p.o. once a day for 3, 5 and 9 consecutive days from day 1 and on every other day, that is, days 1, 3 and 5, higher antitumor effects were seen.

[Antitumor activity of cis-dichlorodiammineplatinum(II) and its effect on cell cycle progression].

Antitumor activity of cis-dichlorodiammineplatinum(II) (cisplatin) on various mouse transplantable tumors was investigated. Cisplatin was active against a wide variety of the following tumor systems: L1210 leukemia, P388 leukemia, B16 melanoma, colon tumor 38, Ehrlich ascites and solid carcinoma, WHT squamous cell carcinoma, and human stomach cancer G/S heterotransplanted in nude mice. From the comparison of growth inhibitory effect by cisplatin with various other antitumor agents in cultured Ehrlich ascites carcinoma cells, cisplatin was found to be mainly a concentration depending drug, but also time depending, so that it was identified as a type Ib class drug proposed by Shimoyama. Effect of cisplatin on the cell cycle progression of Ehrlich ascites carcinoma cells in mice was studied by flow cytometry of DNA. At an early stage after administration of cisplatin, cell cycle progression was delayed in S phase and blocked in G2 phase. With the elapse of time block in G1 phase or G1-S boundary was observed and the cell population, partially synchronized in G1 phase or G1-S boundary, progressed slowly through S phase to be blocked in G2 phase finally.