Local Cancer Chemotherapy Research Articles

Improved antitumor activity through a tyramidyl maslinic acid derivative. Design and validation as drug-loaded electrospun polymeric nanofibers

Among the most harmful tumors detected in the human body, such as breast, colon, brain or pancreas, breast (BC) and colorectal cancer (CRC) are the first and third most frequent cancer worldwide, respectively. The current existing chemotherapeutic treatments present serious side effects due to their intravenous administration can induce cytotoxicity in healthy cells. Thus, new treatment methods based on drug-loaded polymeric nanofibers (NFs) have gained significant potential for their use in localized cancer chemotherapy. Here, a deep in vitro comparative analysis between maslinic acid (MA) and a tyramine-maslinic acid (TMA) derivative is initially performed. This analysis includes a proliferation, and a cell cycle assay, and a genotoxicity, antiangiogenic and apoptosis study. Then, the TMA derivative has been incorporated into electrospun polymeric NFs obtaining an implantable dressing material with antitumor activity. Two types of patches containing TMA-loaded polymeric NFs of poly(caprolactone) (PCL), and a mixture of polylactic acid/poly(4-vinylpyridine) (PLA/PVP) were fabricated by the electrospinning technique. The characterization of the drug-loaded NFs showed an encapsulation capacity of 0.027 mg TMA/mg PCL and 0.024 mg TMA/mg PLA/PVP. Then, the cytotoxic activity of both polymeric systems was tested in CRC (T84), BC (MCF-7) and a no tumor (L929) cell lines exposed to TMA-loaded NFs and blank NFs for 48 h. Moreover, cell cycle assay, genotoxicity, angiogenesis and apoptosis tests were carried out to study the mechanism of action of TMA. Blank NFs showed no-toxicity in all cell lines tested and both drug-loaded NFs significantly reduced cell proliferation (relative proliferation of ≈44 % and ≈25 % respectively). Therefore, TMA was less genotoxic than maslinic acid (MA), and reduced VEGFA expression in MCF-7 cells (1.32 and 2.12-fold for MA and TMA respectively). These results showed that TMA-loaded NFs could constitute a promising biocompatible and biodegradable nanoplatform for the local treatment of solid tumors such as CRC or BC.

Second-Line Chemotherapy in Gastric Cancer: a Retrospective Study.

Second-line chemotherapy is recommended for patients who have disease progression after first-line chemotherapy and have a good performance status. The aim of our study is thus to determine which chemotherapy regimen is more appropriate for second-line gastric cancer treatment. Patients were included if they met the following inclusion criteria: metastatic gastric adenocarcinoma pathology; no previous treatment for local gastric cancer (surgery, chemotherapy, or radiotherapy); received first-line chemotherapy for metastatic gastric cancer and had the disease progress afterward; had adequate organ functions for second-line chemotherapy; had an Eastern Cooperative Oncology Group (ECOG) score 0-2; and were HER-2 negative. The patients were examined in three groups according to the second-line chemotherapy regimen they received. These three groups were compared in terms of overall and progression-free survival. The three groups were statistically similar in overall survival, which was the primary endpoint of the study; the median overall survival was 5months in the FOLFIRI group (n = 79), 6.5months in the platinum-based group (n = 55), and 5.6months in the taxane-based group (n = 40) (p = 0.554). There was no statistical difference between the groups' progression-free survival either; the median progression-free survival time was 3.43months in the FOLFIRI group, 4months in the platinum-based group, and 2.77months in the taxane-based group (p = 0.546). There was no statistically significant difference between the three irinotecan-based, platinum-based, and taxane-based treatments. According to our study's results, the chemotherapy given in second-line treatment should be decided on an individual basis according to toxicity and cost.

Biodegradable Electrospun Polyester‐Urethane Nanofiber Scaffold: Codelivery Investigation of Doxorubicin‐Ezetimibe and Its Synergistic Effect on Prostate Cancer Cell Line

Electrospun nanofiber‐mediated drug‐delivery systems are extensively applied for the controlled delivery of anticancer agents and localized cancer chemotherapy. In this work, we assessed the synergistic anticancer effect of polyurethane‐polycaprolactone (PU‐PCL) nanofibers (NFs) on prostate cancer cell line (PC3) and evaluate their antitumor activity in vitro. Polyurethane‐polycaprolactone (PU‐PCL) nanofibers were prepared by electrospinning and used for codelivery of doxorubicin hydrochloride (DOX) and ezetimibe (EZ). The morphology, weight loss, and swelling ability of the PU‐PCL nanofibers were characterized. Drug release test was performed by UV‐vis spectroscopy in a phosphate buffer at pH 7.4 at 37°C. The viability of the PC3 prostate cancer cells was evaluated by the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay for the different periods of cell incubation. PC3 prostate cancer cells were treated with different concentrations of 0‐50 μg/ml of DOX, EZ, DOX‐loaded NFs, EZ‐loaded NFs, and DOX‐EZ coloaded NFs for 48 hours. The results demonstrated that electrospun PU‐PCL NFs showed significant synergistic therapeutic efficacy on prostate cancer cells. This study proposes that the DOX‐EZ codelivery using PU‐PCL nanofibrous scaffold could be used as a possible approach for anticancer drug delivery for the treatment of prostate cancer.

ICG/NIR TECHNIQUE IN LYMPH NODE MAPPING IN PATIENTS WITH COLORECTAL CANCER

Most cancers in humans are epithelial in nature and such neoplasms metastasize via lymphatics; therefore, the lymphatic system plays a pivotal role in a significant number of malignancies. The hematologic behavior of metastatic cancer has been extensively studied, but little is known regarding lymphatic metastasis. Sentinel lymph node (SLN) is the first node to receive the drainage directly from a tumor. Detection and pathological examination of the SLN is an important oncological procedure that minimizes morbidity related to extensive nodal dissection. After many years of observation and research on its use in various malignancies SLN biopsy has become the standard surgical treatment in patients with malignant melanoma, breast and cervical cancers.
 Today, the issue of diagnosing lymphogenous metastasis in patients with colorectal cancer remains relevant. Standardized methods for examining lymph nodes do not allow to reliably establish the presence of their metastatic lesions. For a more effective assessment, additional examinations are carried out to identify the sentinel lymph node and its precision study, in particular, one of the newest methods is mapping of sentinel lymph nodes using Indocyanine Green (ICG) using near infrared radiation (NIR). Along with the introduction of new technologies, such as the fluorescent dyes indocyanine green (ICG) and near-infrared fluorescence (NIR), and pathologic ultrastaging, Indocyanine green fluorescence-imaging (ICG-FI) has emerged as a potential tool for increasing the accuracy of staging of patients with primary colorectal cancer (CRC) through the detection of sentinel lymph nodes (SLNs).
 Indocyanine green (ICG) is an inexpensive and safe non-specific fluorescent probe. SLN detection rate has increased and false-negative rate has decreased.Colorectal cancer is the third most common cancer in the Western hemisphere and the incidence increases with increasing age. Surgery is the only curative therapy for localized colorectal cancer and adjuvant chemotherapy is usually recommended for patients with lymph node metastases. Surgery, radiation therapy and chemotherapy are the key components of rectal cancer therapy.
 Local recurrence greatly affects the treatment efficiency and the survival outcomes for patients with rectal cancer. Lateral pelvic lymph node (LPLN) metastasis (LPNM) is an important factor for local recurrence. Accurate staging TNM of colorectal cancer is essential for evaluating the prognosis and developing an optimal treatment strategy. The presence of metastatic lateral pelvic lymph nodes has been shown to portend a worse prognosis for patients with low rectal cancer. SLN biopsy should be used in this patients for evaluating the prognosis and developing an optimal treatment strategy. Only with all of the above diagnostic tools can accurate diagnosis according to TNM and the choice of the right treatment strategy. The article analyzes and summarizes the scientific literature data on the methods for determining the sentinel lymph node. The sensitivity and specificity of the sentinel lymph node detection using ICG/NIR has been demonstrated. The analysis of various techniques for introducing indocyanine green, the rate of SLN identification was carried out.

A Diels-Alder polymer platform for thermally enhanced drug release toward efficient local cancer chemotherapy

ABSTRACT We reports a novel thermally enhanced drug release system synthesized via a dynamic Diels-Alder (DA) reaction to develop chemotherapy for pancreatic cancer. The anticancer prodrug was designed by tethering gemcitabine (GEM) to poly(furfuryl methacrylate) (PFMA) via N-(3-maleimidopropionyloxy)succinimide as a linker by DA reaction (PFMA-L-GEM). The conversion rate of the DA reaction was found to be approximately 60% at room temperature for 120 h. The reversible deconstruction of the DA covalent bond in retro Diels-Alder (rDA) reaction was confirmed by proton nuclear magnetic resonance, and the reaction was significantly accelerated at 90 °C. A PFMA-LGEM film containing magnetic nanoparticles (MNPs) was prepared for thermally enhanced release of the drug via the rDA reaction. Drug release was initiated by heating MNPs by alternating magnetic field. This enables local heating within the film above the rDA reaction temperature while maintaining a constant surrounding medium temperature. The MNPs/PFMA-L-GEM film decreased the viability of pancreatic cancer cells by 49% over 24 h. Our results suggest that DA/rDA-based thermally enhanced drug release systems can serve as a local drug release platform and deliver the target drug within locally heated tissue, thereby improving the therapeutic efficiency and overcoming the side effects of conventional drugs used to treat pancreatic cancer.

A Local and Low-Dose Chemotherapy/Autophagy-Enhancing Regimen Treatment Markedly Inhibited the Growth of Established Solid Tumors Through a Systemic Antitumor Immune Response.

Chemotherapy is one of the main options for the treatment of a variety of malignant tumors. However, the severe side effects resulting from the killing of normal proliferating cells limit the application of cancer-targeting chemotherapeutic drugs. To improve the efficacy of classic systemic chemotherapy, the local delivery of high-dose chemotherapeutic drugs was developed as a method to enhance local drug concentrations and minimize systemic toxicity. Studies have demonstrated that chemotherapy is often accompanied by cancer-associated immunogenic cell death (ICD) and that autophagy is involved in the induction of ICD. To improve the efficacy of local cancer chemotherapy, we hypothesized that the local delivery of chemotherapeutic plus autophagy-enhancing agents would enhance the promotive effects of ICD on the antitumor immune response. Here, we report that a low-dose chemotherapy/autophagy enhancing regimen (CAER) not only resulted in the increased death of B16F10 and 4T1 tumor cells, but also induced higher levels of autophagy in vitro. Importantly, the local delivery of the CARE drugs significantly inhibited tumor growth in B16F10 and 4T1 tumor-bearing mice. Systemic antitumor T-cell immunity was observed in vivo, including neoantigen-specific T-cell responses. Furthermore, bioinformatic analysis of human breast cancer and melanoma tissues showed that autophagy-associated gene expression was upregulated in tumor samples. Increased autophagy and immune cell infiltration in tumor tissues were positively correlated with good prognosis of tumor patients. This work highlights a new approach to improve the effects of local chemotherapy and enhance systemic antitumor immunity.

Drug Delivery of Anticancer Drugs from Injectable 3D Porous Silk Scaffold for Prevention of Gastric Cancer Growth and Recurrence.

Localized cancer chemotherapy through injectable hydrogels is a next-generation advanced substitute for the currently operational systemic route of drug administration. Recently, several hydrogels have been developed for prospective drug delivery applications; however, no in vitro disease model is available to evaluate its long-term bioactivity in real time. In this regard, we have designed a porous silk scaffold that provides a single platform to accommodate both the soft hydrogel and cancer cells together. The stomach cancer (AGS) cells were seeded in the periphery of the silk scaffold, where they sit in the pores and form three-dimensional (3D) spheroids. Furthermore, the anticancer drug cisplatin-loaded nanocomposite injectable silk hydrogel was filled in the central cavity of the scaffold to evaluate its 11 day extended bioactivity. Such an arrangement keeps the released cisplatin in close contact with the spheroids for its sustained therapeutic effects. In an attempt to model cancer recurrence, the AGS cells were reseeded on the second day of treatment. Our data revealed that the shelf life and cytotoxic effects of cisplatin, which was explicitly releasing out from the nanocomposite silk hydrogel, were considerably enhanced. Hence, the reseeded AGS cells did not survive further on the scaffold, which also indicates its ability to inhibit cancer relapse. Conclusively, the current work showed a possible way to evaluate the long-term efficacy and bioactivity of the injectable hydrogel system in vitro for sustained drug delivery application.

Harmonious Biomaterials for Development of In situ Approaches for Locoregional Delivery of Anti-cancer Drugs: Current Trends.

Locoregional drug delivery is a novel approach for the effective delivery of anti-cancer agents as it exposes the tumors to high concentration of drugs. In situ gelling systems have fetched paramount attention in the field of localized cancer chemotherapy due to their targeted delivery, ease of preparation, prolonged or sustained drug release and improved patient compliance. Numerous polymers have been investigated for their properties like swelling along with biodegradation, drug release and physicochemical properties for successful targeting of the drugs at the site of implantation. The polymers such as chitosan, Hyaluronic Acid (HA), poloxamer, Poly Glycolic Lactic Acid (PGLA) and Poly Lactic Acid (PLA) tend to form in situ hydrogels and have been exploited to develop localized delivery vehicles. These formulations are administered in the solution form and on exposure to physiological environment such as temperature, pH or ionic composition they undergo phase conversion into a hydrogel drug depot. The use of in situ gelling approach has provided prospects to increase overall survival and life quality of cancer patient by enhancing the bioavailability of drug to the site of tumor by minimizing the exposure to normal cells and alleviating systemic side effects. Because of its favorable safety profile and clinical benefits, United States Food and Drug Administration (U.S. FDA) has approved polymer based in situ systems for prolonged locoregional activity. This article discusses the rationale for developing in situ systems for targeted delivery of anti-cancer agents with special emphasis on types of polymers used to formulate the in situ system. In situ formulations for locoregional anti-cancer drug delivery that are marketed and are under clinical trials have also been discussed in detail in this article.

Recent advances in electrospun nanofiber-mediated drug delivery strategies for localized cancer chemotherapy.

Nanotechnology empowered localized cancer chemotherapy has indicated a promising performance for targeting and controlled release of anticancer agents over a period of time to eliminate local-regional recurrence of cancers and also to improve the tissue regeneration during/after treatment. Electrospun nanofiber-based implantable drug-delivery systems have been established as one of the most effective approaches for localized cancer treatment, allowing the on-site delivery of anticancer agents and reducing systemic toxicities and side effects to normal cells. The present review aimed to summarize the latest cutting-edge research on applications of electrospun-based systems for local chemotherapy. Meantime, in vitro and in vivo studies conducted using various anticancer agents along with the capability of electrospun nanofibers for combinatorial/synergistic chemotherapy as well as existing challenges and the potential dramatic advances in applying this pioneering approach for clinical transition in localized treatments of cancer is also discussed.

Self-Assembly of Succinated Paclitaxel into Supramolecular Hydrogel for Local Cancer Chemotherapy

In the present study, we reported the generation of a molecular hydrogel of succinated paclitaxel (PTX-SA) by a self-hydrolytic strategy for potential local cancer chemotherapy. Upon self-hydrolysis of the ester bond of PTX-SA in phosphate-buffered saline (pH = 7.4) for 24 h, a PTX-SA supramolecular hydrogel formed spontaneously with a minimal gelation concentration of 0.25 wt%. The formed PTX-SA supramolecular hydrogel displayed a filamentous nanostructure, the nanofibers of which were typically several micrometers in length with a diameter of 10-15 nm. Rheological analysis suggested that the PTX-SA supramolecular hydrogel exhibited dominant elastic and thixotropic properties. Ionization of the carboxylate group together with the self-hydrolysis of the ester bond in PTX-SA are the major driving forces for the hydrogelation, as indicated by Fourier transform infrared spectroscopy (FTIR) analysis. The bioactive drug payload sustainably released from the supramolecular hydrogel over a period of 15 day in an in vitro release study, and the drug-release behavior could be finely controlled by altering the initial PTX-SA concentration. More importantly, the formed PTX-SA supramolecular hydrogel without compromising its pharmacological activity could efficiently inhibit the proliferation of cancer cells (HepG2 and MCF-7 cells) in vitro. Therefore, the generated PTX-SA supramolecular hydrogel might provide great potential as a novel drug-delivery system for local anti-cancer therapy.

Injectable and Biodegradable pH-Responsive Hydrogels for Localized and Sustained Treatment of Human Fibrosarcoma.

Injectable hydrogels are an important class of biomaterials, and they have been widely used for controlled drug release. This study evaluated an injectable hydrogel formed in situ system by the reaction of a polyethylene glycol derivative with α,β-polyaspartylhydrazide for local cancer chemotherapy. This pH-responsive hydrogel was used to realize a sol-gel phase transition, where the gel remained a free-flowing fluid before injection but spontaneously changed into a semisolid hydrogel just after administration. As indicated by scanning electron microscopy images, the hydrogel exhibited a porous three-dimensional microstructure. The prepared hydrogel was biocompatible and biodegradable and could be utilized as a pH-responsive vector for drug delivery. The therapeutic effect of the hydrogel loaded with doxorubicin (DOX) after intratumoral administration in mice with human fibrosarcoma was evaluated. The inhibition of tumor growth was more obvious in the group treated by the DOX-loaded hydrogel, compared to that treated with the free DOX solution. Hence, this hydrogel with good syringeability and high biodegradability, which focuses on local chemotherapy, may enhance the therapeutic effect on human fibrosarcoma.

Krabbamein í ristli og endaþarmi - yfirlitsgrein

Colorectal cancer is the third most common cancer in the Western hemisphere and the incidence increases with increasing age. Most colorectal cancers are localized with or without lymph node metastases. Up to 20% of patients present with metastatic disease, most commonly to the liver. Surgery is the only curative therapy for localized colorectal cancer and adjuvant chemotherapy is usually recommended for patients with lymph node metastases. Surgery, radiation therapy and chemotherapy are the key components of rectal cancer therapy. Selected patients with recurrent and metastatic disease can be salvaged with surgery but chemotherapy remains the mainstay of therapy for advanced colorectal cancer. Substantial progress has been observed in the treatment of metastatic colorectal cancer in recent years.

Water-Dispersed Single-Wall Carbon Nanohorns as Drug Carriers for Local Cancer Chemotherapy

Functional analyses of water-dispersed carbon nanohorns with antitumor activity were performed to explore their potential as a drug carrier for local cancer chemotherapy. Water-dispersed carbon nanohorns were prepared through adsorption of polyethylene glycol-doxorubicin conjugate (PEG-DXR) onto oxidized single-wall carbon nanohorns (oxSWNHs). PEG-DXR-bound oxSWNHs were administered intratumorally to human nonsmall cell lung cancer-cell NCI-H460-bearing mice. When injected intratumorally, PEG-DXR-bound oxSWNHs caused significant retardation of tumor growth associated with prolonged DXR retention in the tumor. In accordance with this DXR retention, a large number of oxSWNH agglomerates was found in the periphery of the tumor. Histological analyses showed migration of oxSWNHs to the axillary lymph node, which is a major site of breast cancer metastasis near the tumor, possibly by means of interstitial lymphatic-fluid transport. These results suggest that water-dispersed oxSWNHs may thus be useful as a drug carrier for local chemotherapy.

Extracellular Protease Activation of Chemotherapeutics from Hydrogel Matrices: A New Paradigm for Local Chemotherapy

A novel paradigm for local cancer chemotherapy, based upon local activation of chemotherapeutic molecules by soluble proteases, is presented. In the presence of matrix metalloproteases, a family of cancer-associated proteases, cisplatin is released from a hydrogel matrix in an active form. In the absence of matrix metalloproteases, cisplatin is released at a much lower rate. The mesh size of the polymer controls metalloprotease-based cisplatin release from the hydrogel matrix with approximate doubling of cisplatin release in the presence of matrix metalloprotease. Overall, this novel paradigm shows much potential for local chemotherapy where local chemotherapeutic release is in response to the invasive properties of the tumor.

Controlled release of adriamycin from silicone elastomer and its antitumor effects on Yoshida Sarcoma

Adriamycin (ADM) -silicone elastomer composite which is a delivery system for an anticancer agent was developed by the authors to facilitate local cancer chemotherapy of recurrent and metastasized tumors and chemoembolization of primary tumors. The characteristics of ADM release from this composite and its antitumor effects on Yoshida sarcoma were investigated in this study.The ADM release in vitro was affected by the external fluids, the amount of ADM embedded in the sillicone elastomer, the surface area of the composite and the temperature of the external fluid, and it was enhanced significantly by the addition of glycine or D-mannitol to the silicone elastomer.After the inoculation of tumor cells the mean survival period of the 10 rats administered with the composite was more than 46.8 days and their rate of survival for 60 days was 40%. However, the survival period of the 10 rats without the composite was 8.5±1.3 days and all of them died in 10 day.Flow cytometric analysis showed that, in the tumor cells of the rats administered with the composite, more than 70% of the cells were in the G1 phase and the S, G2+M phase was decreased relatively. This tendency was seen for 5 days after the administration of the composite. Morphologically, vacuole formation, enlargement and the disappearance of mitosis of the tumor cells were observed. These results show that the antitumor effects of the composite actually remained for along time.

Experimental study on trans-nodal cancer chemotherapy for metastatic lymph nodes.

As complete dissection of metastatic lymph nodes in the upper mediastinum is impossible in conventional surgery for esophageal carcinoma, we devised a form of intraoperative local adjuvant cancer chemotherapy for metastatic lymph nodes of the mediastinum, via tracheal bifurcation lymph nodes located at the anatomical pivot in the upper mediastinal lymph flow. Emulsion type bleomycin (BLM) was injected into the bifurcation lymph nodes of mongrel dogs, and BLM was identified in the pulmotracheal lymph nodes within 20 minutes. When the cervicothoracic lymph nodes in the ipsilateral side were dissected beforehand, the BLM levels in the contralateral side doubled those seen in the controls. In rabbits with VX2 carcinoma, the level of BLM decreased in lymph nodes with metastasis, however, the spread was still evident even when about 75 per cent of the nodes were occupied with metastasis.

Palliative therapy of pelvic tumors by intra-arterial infusion of cytotoxic drugs.

The treatment of patients with inoperable pelvic tumors is a major problem of clinical oncology. In most cases, colorectal or bladder carcinomas cause intractable pain in the pelvic region requiring high-dose analgesic treatment and sometimes even nerve blocks or neurosurgery. There is no curative systemic treatment for these cancers, but palliative therapy can improve the quality of life of symptomatic patients. The best results in the treatment of colorectal cancers were obtained by combination chemotherapy using 5-fluorouracil with nitrosourea derivatives (Queiser and Heim 1981), while adriamycin is the most active single drug for the treatment of bladder cancers. Because of their short half-life and high systemic clearance rate these cytotoxic drugs seem especially suited for local cancer chemotherapy (Chen and Gross 1980).

Intraoperative local adjuvant cancer chemotherapy for carcinoma of the thoracic esophagus.

Two forms of effective, supplemental, intraoperative chemotherapy for carcinoma of the esophagus have been devised, i.e., Bleomycin (BLM)-Spongel aimed at prevention of a local recurrence and trans-lymph-nodal administration of BLM for prevention of recurrence in the intramediastinal lymph nodes. Fifty-one patients given one or both of these local cancer chemotherapy had a lower incidence of local and/or lymph node recurrence in twelve months after surgery than did the controls. As both procedures are simple and there are few adverse effects, further application of this form of chemotherapy is warranted.

Tumors of the skin. XII. Topical 5-Fluorouracil for epidermal neoplasms.

AbstractOur studies have been carried out in over 500 patients with an aggregate of more than 15,000 lesions for observation periods in excess of 5 years. Topical chemotherapy with 5‐FU was shown to result in selective eradication of premalignant and superficial malignant lesions of the skin. Since the action of 5‐FU is selective, it produces minimal or no effects on normal tissues adjacent to tumors. Healing therefore occurs with slight or no apparent scarring. Topical chemotherapy is indicated for solar keratoses and other precancerous lesions as well as for multiple superficial primary skin cancers when standard therapeutic measures are not suitable because large areas of the skin are involved by persistently developing tumors. Topical cancer chemotherapy induces the resolution of premalignant skin lesions and prevents their further development to the malignant stage. Early primary skin cancers and premalignant lesions react to topical antitumor agents before they are otherwise clinically detectable. These tumors can therefore be eradicated before they present significant clinical problems. Early detection and eradication of skin cancers and premalignant skin lesions furthermore result in the reduction of the subsequent incidence of clinically significant tumors. Local chemotherapy therefore appears to have prophylactic value. Local administration of 5‐FU results in high concentrations of the antitumor agent at the tumor site, although the total amount administered and the rate of absorption are relatively low. General toxicity such as bone marrow depression and other systemic side‐effects are therefore not encountered with local cancer chemotherapy. Superficially located neoplasms are suitable model systems for the study of tumor biology. Local chemotherapy indicates that differential and selective chemical effects can be produced in neoplastic cells and their normal counterparts. Studies on local chemotherapy demonstrate that the selective eradication of malignant disease in many by chemical means is feasible.

Toxicity, metabolism, and tissue distribution of carbon 14-labeled N,N′,N″-triethylenethiophosphoramide (Thio-TEPA) in rats

The toxicity, histopathology, tissue distribution, and metabolism of Thio-TEPA were studied following intravenous and intra-arterial injection into adult male Sprague-Dawley rats. The LD 50 30 for all animals injected intravenously or intraarterially with Thio-TEPA was 9.06 ± 0.45 mg per kilogram of body weight. The route of injection did not influence the toxicity and histopathology, nor did it markedly affect the distribution of C 14 activity in the tissues obtained 5 minutes after injection of labeled Thio-TEPA. Fixation of Thio-TEPA in tissues appears to be much slower than fixation of NH2 and resembles that of TEM. At least 95% of the C 14 activity of the drug and its metabolites was excreted in the urine 8 hours after drug injection. Following the intravenous injection of 9.0 mg/kg of Thio-TEPA, 20–30% of the drug was excreted as the metabolite TEPA, while 70–80% of the drug was excreted unchanged. Of the 3 alkylating agents (HN2, TEM, and Thio-TEPA) studied in this laboratory, HN2 would appear to be the drug of choice for local cancer chemotherapy and treatment of cancer by perfusion.