Treatment Of Malignant Solid Tumors Research Articles

Small-molecule inhibitors of the human epidermal receptor family

Background: Small molecule inhibitors of human epidermal receptors (HER) have become an integral part of the armamentarium available to the medical oncologist in the treatment of solid tumor malignancies. At present, there are two small-molecule inhibitors (erlotinib and lapatinib) approved by the FDA in the USA, and a third inhibitor, gefitinib, is approved in other countries. Objective: To summarize the current standards of care for these new agents in solid tumors, and to discuss ongoing clinical trials; to review the known mechanisms of action of these inhibitors as well as to discuss both the known predictive markers for response and likely mechanisms of resistance. Methods: We reviewed key presentations and recent publications on small-molecule inhibitors targeting the HER family in solid tumors. Conclusions: Recent data have highlighted the importance of mutations and amplifications of receptors within the HER family. Amplification of HER2 often translates into responses in anti-HER2 therapy. Mutations either enhance sensitivity or confer resistance to small-molecule inhibitors. Other mechanisms of resistance are being elucidated which should lead to the ability to predict both responses and resistance to HER family inhibitors and should translate into improvements in patient care.

Enhanced cytotoxicity with a novel system combining the paclitaxel-2′-ethylcarbonate prodrug and an HSV amplicon with an attenuated replication-competent virus, HF10 as a helper virus

We previously demonstrated that HF10, which is a natural, non-engineered HSV-1, has potent oncolytic activity in the treatment of solid malignant tumors in vitro and in vivo [H. Takakuwa, F. Goshima, N. Nozawa, T. Yoshikawa, H. Kimata, A. Nakao, et al., Oncolytic viral therapy using a spontaneously generated herpes simplex virus type 1 variant for disseminated peritoneal tumor in immunocompetent mice, Arch. Virol. 148 (2003) 813–825; S. Kohno, C. Lou, F. Goshima, Y. Nishiyama, T. Sata, Y. Ono, Herpes simplex virus type 1 mutant HF10 oncolytic viral therapy for bladder cancer, Urology 66 (2005) 1116–1121; D. Watanabe, F. Goshima, I. Mori, Y. Tamada, Y. Matsumoto, Y. Nishiyama, Oncolytic virotherapy for malignant melanoma with herpes simplex virus type 1 mutant HF10, J. Dermatol. Sci. 50 (2008) 185–196; A. Nawa, C. Luo, L. Zhang, Y. Ushijima, D. Ishida, M. Kamakura, et al., Non-engineered, naturally oncolytic herpes simplex virus HSV1 HF10: applications for cancer gene therapy, Curr. Gene. Ther. 8 (2008) 208–221]. Previous reports have also shown that a combination of HF10 and paclitaxel (TAX) was more efficacious than either regimen alone for some types of malignant tumors [S. Shimoyama, F. Goshima, O. Teshigahara, H. Kasuya, Y. Kodera, A. Nakao, et al., Enhanced efficacy of herpes simplex virus mutant HF10 combined with paclitaxel in peritoneal cancer dissemination models, Hepatogastroenterology 54 (2007) 1038–1042]. In this study, we investigated the efficacy of gene-directed enzyme prodrug therapy (GDEPT) using a novel system that combines the paclitaxel-2′-ethylcarbonate prodrug (TAX-2′-Et) and an HSV amplicon expressing rabbit-carboxylesterase (CES) with HF10 as a helper virus. This GDEPT system aims to produce high level of CES at the tumor site, resulting in efficient local conversion of the TAX-2′-Et prodrug into the active drug TAX [A. Nawa, T. Tanino, C. Lou, M. Iwaki, H. Kajiyama, K. Shibata, et al., Gene directed enzyme prodrug therapy for ovarian cancer: could GDEPT become a promising treatment against ovarian cancer?, Anti-Cancer Agents Med Chem 8 (2008) 232–239]. We demonstrated that the green fluorescent protein (GFP) gene, as a trace maker, was more efficiently introduced by the HSV amplicon compared to the expression vector, pHGCX, and that the HSV amplicon system expressed an active CES enzyme that could convert TAX-2′-Et to TAX in Cos7 cells. Furthermore, although the cytotoxicity of this amplicon system was not enhanced in virus-sensitive tumor cells, it was significantly enhanced in low virus-sensitive tumor cells in the presence of the prodrug in a concentration-dependent manner, compared to the control virus alone ( p < 0.05). These results indicate that the addition of a prodrug converting enzyme may be a feasible approach to further enhance the efficacy of HF10 as a cancer therapeutics in low HF10-sensitive malignancies.

Monoclonal antibody therapies for solid tumors

Background: About 1.4 million new cancer cases are expected to be diagnosed in the US in 2008 and the overall costs of cancer treatment is estimated at > $200 billion per year. Over half a million people will die from cancer each year. Monoclonal antibodies have attracted attention because of their potential clinical benefits. Currently, there are four monoclonal antibodies that have been approved by the FDA for the treatment of solid tumor malignancies. Over 100 other antibodies are in early- and late-phase clinical testing. Objectives/methods: Clinical efficacy of FDA-approved and investigational monoclonal antibody therapies are summarized. Results/conclusions: Anti-tumor responses have been modest. However, the advent of novel antibody engineering and combination therapy strategies has generated much optimism for current and future antibody-based therapeutics in solid tumors.

Clinical study of gamma ray whole body therapeutic system for malignant tumors (report of 643 cases)

Objective To evaluate the feasibility of the whole body gamma knife in the treatment of malignant solid tumors.

Treatment of Solid Malignant Tumors with Microwave Balloon Ablation Catheters and Localized Chemotherapy.

The paper describes a new approach to the treatment of solid malignant tumors. In this approach the tumors are thermally ablated with minimally invasive microwave balloon catheters, and the cavities created in the tumors by the balloon catheters are fllled with anticancer agents that can be forced through the ablated malignant tissues to the margins of the tumors in order to destroy any remaining viable tumor cells. In vivo and in vitro experiments are described that illustrate the ability of microwave balloon ablation catheters to rapidly ablate of large volumes of tissues, to create reservoirs for anticancer agents in the ablated (necrosed) tissues, and to force substances with large molecular weights that are introduced into these reservoirs through the ablated tissues to the margins of the ablation. DOI: 10.2529/PIERS060821120416

Erupción acneiforme secundaria a cetuximab

C225 (cetuximab) is a monoclonal antibody that targets the epidermal growth factor receptor (EGF-R). It is used for the treatment of solid malignant tumors in advanced stages. It works against tumors by inhibiting cell proliferation, angiogenesis and the formation of metastases, as well as by promoting cell apoptosis. We present the case of a 64-year-old male patient affected with a colon neoplasm with hepatic metastases, for which treatment with cetuximab was indicated. He came to our department because of a skin eruption with papules and pustules located on the face, neck, presternal area and upper back, but with no cysts or comedones. The biopsy was compatible with an acneiform eruption. The patient was treated with minocycline, 100 mg/day for 2 weeks, with the clinical symptoms responding favorably. When he was given further doses of cetuximab, he once again presented with new eruptions, but of lesser intensity. Because of the high frequency with which this adverse effect appears, it is recommended that cetuximab be included on the list of drugs causing acneiform eruptions.

Use of high intensity focused ultrasound for treating malignant tumors

Objective To investigate the efficacy and side effects of high intensity focused ultrasound(HIFU) in the treatment of malignant solid tumors.

A novel carbazole topoisomerase II poison, ER-37328: potent tumoricidal activity against human solid tumors in vitro and in vivo.

We have discovered a novel topoisomerase II (topo II) poison, ER-37328 (12,13-dihydro-5-[2-(dimethylamino)ethyl]-4H-benzo[c]pyrimido[5,6,1-jk]carbazole-4,6,10(5H,11H)-trione hydrochloride), which shows potent tumor regression activity against Colon 38 cancer inoculated s.c. Here, we describe studies on the cell-killing activity against a panel of human cancer cell lines and the antitumor activity of ER-37328 against human tumor xenografts. In a cell-killing assay involving 1-h drug treatment, ER-37328 showed more potent cell-killing activity (50% lethal concentrations (LC50s) ranging from 2.9 to 20 microM) than etoposide (LC50s>60 microM) against a panel of human cancer cell lines. ER-37328 induced double-stranded DNA cleavage, an indicator of topo II-DNA cleavable complex formation, within 1 h in MX-1 cells, and the extent of cleavage showed a bell-shaped relationship to drug concentration, with the maximum at 2.5 microM. After removal of the drug (2.5 microM) at 1 h, incubation was continued in drug-free medium, and the amount of cleaved DNA decreased. However, at 10 microM, which is close to the LC50s against MX-1 cells, DNA cleavage was not detected immediately after 1-h treatment, but appeared and increased after drug removal. This result may explain the potent cell-killing activity of ER-37328 in the 1-h treatment. In vivo, ER-37328 showed potent tumor regression activity against MX-1 and NS-3 tumors. Moreover, ER-37328 had a different antitumor spectrum from irinotecan or cisplatin against human tumor xenografts. In conclusion, ER-37328 is a promising topo II poison with strong cell killing activity in vitro and tumor regression activity in vivo, and is a candidate for the clinical treatment of malignant solid tumors.

Cancer treatment by photodynamic therapy combined with adoptive immunotherapy using genetically altered natural killer cell line.

Adoptive immunotherapy mediated by human natural killer (NK) cell line genetically altered to produce interleukin-2 (NK92MI) was evaluated as adjuvant to photodynamic therapy (PDT) of subcutaneous tumors. The combined effect of these two modalities was first examined with SiHa tumors (human cervical squamous cell carcinoma) growing in NOD-scid mice. The most effective protocol for NK92MI cell transfer in conjunction with PDT mediated by photosensitizer mTHPC was the injection of 5 x 10(7) cells (peritumoral or intravenous) given immediately after PDT, which produced a marked improvement in the therapeutic outcome compared with the effect of PDT alone. The same protocol was tested with HT-29 tumor model (human colorectal adenocarcinoma) xenografted in NOD-scid mice. The results demonstrate that the adoptive immunotherapy with NK92MI cells (which when used alone were not effective in controlling tumor growth) significantly improved the cures of PDT-treated HT-29 tumors, whereas such benefit was not observed with the parental cell line NK92 (not producing interleukin-2). Flow cytometry-based analysis revealed a higher percentage of p.t. injected NK92MI cells in PDT-treated than in non-treated HT-29 tumors. Further investigation showed that the NK92MI cell-based adoptive immunotherapy is also a highly effective adjuvant for PDT treatment of murine EMT6 tumors growing in immunocompetent syngeneic BALB/c mice. This result diminishes the concern that adoptively transferred NK92MI cells may be rendered ineffective by an allogenic reaction of the host. The findings of this study suggest that advanced protocols of NK cell-based adoptive immunotherapy can be developed as efficient adjuvants to PDT used for the treatment of solid malignant tumors.

Experimental studies of the protective effect of ginkgo biloba extract (GBE) on cisplatin-induced toxicity in rats

Cisplatin (CDDP) is an effective antineoplastic agent in the treatment of solid malignant tumors. Its clinical use, however, is limited because of various side effects including sensorineural hearing loss. Several agents have been proposed to reduce these side effects. GBE has recently been reported to scavenge superoxide and hydroxyl radicals, resulting in a reduction of lipid peroxidation. GBE is expected to protect against CDDP-induced toxicity because its generative mechanism is thought to be associated with free-radical formation. The purpose of the present study was to evaluate GBE's efficacy as a protective agent against cisplatin-induced ototoxicity. Fisher rats were used in this study and were divided into three treatment groups: 1) animals administered 1.0 mg of CDDP per kg for 10 days (Group I), 2) animals receiving 100 mg of GBE per kg 90 min before administration 1.0 mg of CDDP per kg (Group II) and 3) a vehicle control (Group III). First, the protective effect of GBE on CDDP-induced ototoxicity was investigated. The auditory threshold was evaluated by means of the compound action potential (CAP) recording. After CAP recordings, cochlear sensory epithelia were observed throughout the cochlea by scanning electron microscopy. In Group II, the elevation of CAP thresholds at 12 kHz, 16 kHz, 20 kHz and the missing rate for the outer hair cells were significantly reduced as compared to those in Group I. These data suggest that GBE is effective for otoprotection against CDDP. Second, the protective effect of GBE on CDDP-induced nephrotoxicity was evaluated. Nephrotoxicity was evaluated by means of measurement of serum BUN and creatinine and histopathological examination of the kidney. These were significant differences in serum BUN and creatinine levels between Group I and Group II. Third, the influence of GBE against the antitumor effect of CDDP was researched in the rats inoculated subcutaneously with SCC-158 squamous cell carcinoma cells. There was no difference in tumor growth rate (TGR) between Group I and Group II. The result suggested that the combined administration had no influence on the antitumor activity of CDDP. In conclusion, the co-administration of CDDP with GBE is beneficial to ameliorate CDDP-induced toxicity without attenuation of CDDP antitumor activity.

In vitro and in vivo antitumor activity of a novel nucleoside, 4'-thio-2'-deoxy-2'-methylidenecytidine.

The in vitro and in vivo antitumor activity of a novel nucleoside, 4'-thio-2'-deoxy-2'-methylidenecytidine (4'-thio-DMDC), was examined. 4'-Thio-DMDC inhibited the growth of various cell lines established from human solid cancers, particularly the growth of lung and bladder carcinomas and melanomas. 4'-Thio-DMDC exhibited potent antitumor activity against subcutaneously implanted murine sarcoma S-180 and human fibrosarcoma HT-1080 xenografts. It was shown that 4'-thio-DMDC suppressed cell growth by inhibiting cellular DNA synthesis, and phosphorylation of the 5'-position of its deoxyribose by deoxycytidine kinase was needed for its antitumor activity. 4'-Thio-DMDC is a poor substrate for cytidine deaminase, thus it is a promising agent for the treatment of malignant solid tumors because it will not be converted into its inactive uridine form.

Effect of interleukin-2 on natural killer-cell activity in children with malignant solid tumors

The purpose of the study was to determine the activity of natural killer (NK) cells in children with malignant tumors and the effect of interleukin-2 (IL-2) in enhancing NK-cell activity of these patients in vitro. The NK-cell activity in mononuclear cells of peripheral blood was measured by the 125 IUdR release assay. The mean level of NK-cell activity in children with cancer (16.52%) was significantly lower than that for normal controls (29.75%) and no significant difference of NK-cell activity was found between children with different cancers. After mononuclear cells were incubated with recombinant IL-2 (rIL-2), NK cells from 96% (22/23) of the samples showed augmented cytotoxicity. The levels of NK-cell activity of patients, either prior to therapy or with treatment (operation or chemotherapy), were very low (1.36%–30.69%; 6.17%–33.64%, respectively) before rIL-2 stimulation and significantly increased (15.41%–65.80%; 23.85%–49.36%, respectively) after stimulation, suggesting a potential therapeutic role for rIL-2 in the treatment of malignant solid tumors of childhood and providing a rationale for the clinical use of rIL-2.

Targeting cancer chemotherapeutic agents by use of lipiodol contrast medium

Arterially administered Lipiodol Ultrafluid contrast medium selectively remained in various malignant solid tumors because of the difference in time required for the removal of Lipiodol contrast medium from normal capillaries and tumor neovasculature. Although blood flow was maintained in the tumor, even immediately after injection Lipiodol contrast medium remained in the neovasculature of the tumor. To target anti-cancer agents to tumors by using Lipiodol contrast medium as a carrier, the characteristics of the agents were examined. Anti-cancer agents had to be soluble in Lipiodol, be stable in it, and separate gradually from it so that the anti-cancer agents would selectively remain in the tumor. These conditions were found to be necessary on the basis of the measurement of radioactivity in VX2 tumors implanted in the liver of 16 rabbits that received arterial injections of 14C-labeled doxorubicin. Antitumor activities and side effects of arterial injections of two types of anti-cancer agents were compared in 76 rabbits with VX2 tumors. Oily anti-cancer agents that had characteristics essential for targeting were compared with simple mixtures of anti-cancer agents with Lipiodol contrast medium that did not have these essential characteristics. Groups of rabbits that received oily anti-cancer agents responded significantly better than groups that received simple mixtures, and side effects were observed more frequently in the groups that received the simple mixtures. These results suggest that targeting of the anti-cancer agent to the tumor is important for treatment of solid malignant tumors.

Natural killer cells in children with malignant solid tumors. Effect of recombinant interferon-alpha and interleukin-2 on natural killer cell function against tumor cell lines.

Natural killer (NK) cells and NK cell activity were determined in three groups (newly diagnosed [n = 21], on therapy [n = 21], and off therapy [n = 18]) of children with various types of malignant solid tumors and in a control group (n = 26) by means of Leu-7 and Leu-11b monoclonal antibodies and a 4-hour 51Cr-release assay, respectively. The erythroleukemia cell line K562 was used as a target cell. The newly diagnosed group included eight patients with localized disease (Stage I-II), ten with bulky but nonmetastatic disease (Stage III), and three with metastases (Stage IV). The mean percent of NK cell activity in the newly diagnosed group was significantly higher than that of the control group. Children with Stage III tumors at diagnosis had higher mean NK cell function than those with Stage I-II and Stage IV. On therapy patients had significantly fewer NK cells and lower NK cell cytotoxicity than those in the other groups studied. We also studied the following: (1) the in vitro effect of recombinant interferon-alpha (rIFN-alpha) and recombinant interleukin-2 (rIL-2) on NK cell function of peripheral blood lymphocytes (PBL) from children with solid malignancies; and (2) the susceptibility of neuroblastoma-derived (CHP-126 and SKNSH) and rhabdomyosarcoma-derived (A-204) cell lines to NK cell lysis. Both rIFN-alpha and rIL-2 enhanced NK cell activity of PBL from children with malignancies and healthy children against K562 and solid tumor cell lines. The enhancing effect or rIL-2 was greater than that of rIFN-alpha. CHP-126 and SKNSH cell lines were susceptible to NK cell lysis mediated by the PBL of children with neuroblastoma and the control group. The A-204 cell line was less sensitive than K562 to NK cell cytotoxicity. Our results suggest a potential therapeutic role for both cytokines in the treatment of malignant solid tumors of childhood.

Techniques for avoiding surgical complications in chemotherapy-treated cancer patients.

With the development of more effective antineoplastic drugs for the treatment of solid malignant tumors, the use of systemic chemotherapy in the perioperative period has become increasingly attractive. Strategies have evolved for administering chemotherapy preoperatively to render large tumors more easily resected, intraoperatively in isolation-perfusion systems (often in combination with hyperthermia), and postoperatively as an adjuvant or to treat residual disease. It is possible, however, that the benefits of perioperative chemotherapy may be offset by an increase in the incidence of complications, particularly with respect to wound healing. The well-known toxic effects of chemother-apeutic agents on actively replicating normal cells suggest that antineoplastic drugs could easily lead to wound problems such as infection or dehiscence.

Perspectives for the use of high-dose chemotherapy in the treatment of solid malignant tumors

Perspectives for the use of high-dose chemotherapy in the treatment of solid malignant tumors

Effects of induced total-body hyperthermia on phosphorus metabolism in humans

The effects of total-body hyperthermia on phosphorus homeostasis are controversial. To evaluate the problem, 10 clearance studies were performed in seven patients undergoing total-body hyperthermia as an adjunct to the treatment of solid malignant tumors. Total-body hyperthermia was associated with significant reduction in plasma phosphorus concentration from a baseline value of 3.51 ± 0.18 to 0.6 ± 0.1 mg/dl (p < 0.001), returning to baseline following cessation of total-body hyperthermia. The clearance of phosphorus increased from 15.2 ± 2.5 to 26.1 ± 3.1 ml per minute (p < 0.01), and the fractional excretion of phosphorus increased from 11.37 ± 2.2 to 47.68 ± 9.7 percent (p < 0.01). The reduction in plasma phosphorus during total-body hyperthermia was also associated with a significant reduction in the renal threshold phosphorus concentration from 3.17 ± 0.16 to 0.38 ± 0.08 (p < 0.001). The changes in phosphorus homeostasis during total-body hyperthermia were independent of changes in circulating parathyroid hormone level, urinary cyclic AMP excretion, and arterial carbon dioxide tension.

The effect of prior cisplatin therapy on the pharmacokinetics of high-dose methotrexate.

The pharmacokinetics of high-dose methotrexate (MTX, 5-15 g/m2) were evaluated in 11 children and adolescents who had previously received two to eight doses of cisplatin (90 mg/m2) in the treatment of malignant solid tumors. The half-life for disappearance of MTX from serum during the first 24 hours after infusion was determined from serum samples obtained at the end of a six-hour infusion and six, 12, and 24 hours after infusion. These values were compared to a mean half-life of 2.83 (+/- 0.34) hours following 489 courses administered to 71 patients who had not received cisplatin. Stepwise multiple linear regression analysis of patient variables revealed cumulative cisplatin dosage and time from last cisplatin dose as the best predictors of MTX half-life (r2 = 65.4%, p less than 0.001). The best predictors of 24-hour serum concentration were cumulative cisplatin dosage and MTX dosage (r2 = 54.2%, p less than 0.001) in the multiple linear regression model. Patients with delayed MTX clearance received additional leucovorin and experienced no severe toxicity. Patients receiving up to 270 mg/m2 of cisplatin appear to have minimal increases in MTX half-life, while the likelihood of delayed clearance increases in patients who have received 360 mg/m2 or more of cisplatin. All patients who have previously received cisplatin should be treated cautiously with high-dose MTX and prospective pharmacokinetic monitoring should be routinely performed.

Photoradiation Therapy in Advanced Carcinoma of the Trachea and Bronchus

Photoradiation therapy is a new technique being investigated for the treatment of solid malignant tumors. In this study, 17 patients with advanced, recurrent, biopsy-proven malignant lesions of the trachea or main-stem bronchus were treated by photoradiation therapy. Patients received hematoporphyrin derivative intravenously three days prior to light therapy. The light was delivered from a fiberoptic fiber attached to the output beam of a dye laser (633 +/- 3 nm). The fiber was passed through the large channel of a bronchoscope (Olympus BF 2T). Of the 17 patients, two had no measurable response to the photoradiation therapy, six had partial necrosis of the tumor, seven patients had a greater than 50 percent reduction in the intraluminal volume of tumor, and two were lost to follow-up. Survival ranged from 5 to 210 days (median survival, 40 days). Complications of the treatment were significant in this group of advanced-stage patients and included excessive secretions, fever, pneumonia, and abscess formation.

Doxorubicin in treatment of malignant solid tumors in children.

Doxorubicin (adriamycin) was administered to 35 children with malignant solid tumors to further evaluate its usefulness and toxicity. Two dosage schedules were used: 25 mg/sq m of body surface area weekly, and 25 mg/sq m on two consecutive days and then every two weeks. The agent produced tumor regression in 17 children; the tumors included osteosarcoma, neuroblastoma, Wilms tumor, reticulum cell (histiocytic) lymphoma, and hepatoblastoma. Toxic reactions including alopecia, hematopoietic depression, vomiting, mucosal ulcerations, and weight loss were similar with each schedule. Administration of doxorubicin in a dosage of 50 mg/sq m at two-week intervals allows time for detection of toxic reactions and evaluation of tumor response before administration of subsequent doses.