[A case of adult primitive neuroectodermal tumor(PNET)with multiple lung metastases effectively treated with ADM, IFM(AI)regimen].

The patient was a 48-year-old male with a right subclavicular tumor. The pathological diagnosis showed primitive neuroectodermal tumor(PNET)because of the rosette formation and the positive neurogenic marker.Radiation was administered at a total dose of 50 Gy, because surgical resection would induce the loss of right arm function. CT examination demonstrated a reduction of the primary tumor and new multiple lung metastases. The patient received intravenous AI regimen(ADM and IFM). After the 7th course, both the primary tumor and multiple lung metastases decreased. AI regimen might be effective for PNET.

Prophylactic surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC CO2) versus standard surgery in colorectal carcinoma at high risk of peritoneal carcinomatosis: short-term and long-term outcomes from the CHECK study - protocol for a randomised, multicentre, phase 3 trial.

INTRODUCTION: Up to one-fifth of patients with colorectal cancer will develop peritoneal metastases, frequently without other districts' involvement. Despite the recent unsuccesses of hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer peritoneal metastases treatment, the rationale in the prophylactic setting remains strong. Several clinical and pharmacokinetic data suggest that the efficacy of intraperitoneal chemotherapy is highest when the disease is microscopic. However, robust evidence demonstrating whether the addition of HIPEC for high-risk colorectal cancers offers better control of local recurrence is lacking. METHODS AND ANALYSIS: This is a multicentre randomised phase 3 trial comparing prophylactic surgery plus HIPEC CO2 with mitomycin, over standard surgical excision in patients with colorectal cancer at high risk of peritoneal carcinomatosis; 388 patients will be included in this study. The primary objective is to compare the efficacy of prophylactic surgery (radical colorectal resection, omentectomy, appendectomy, round ligament of the liver resection and bilateral adnexectomy) plus HIPEC CO2 with mitomycin and standard surgery in terms of local recurrence-free survival. The main secondary endpoints are disease-free survival (DFS), overall survival (OS) and safety. The primary endpoint will be described with a cumulative incidence function and will be analysed with Grey test to take account of the competing risks. DFS and OS will be described with the Kaplan-Meier method. ETHICS AND DISSEMINATION: This trial has been evaluated by the Italian Medicines Agency, local ethics committees and will be submitted to the Ministry of Health to notify the start of the trial according to the regulation of trials on devices with CE mark/certification.The results will be submitted for presentation at academic meetings and for publication in a peer-reviewed journal, whatever the findings. TRIAL REGISTRATION NUMBER: NCT03914820.

Suppression of murine leukemias by L-asparaginase. Incidence of sensitivity among leukemias of various types: comparative inhibitory activities of guinea pig serum L-asparaginase and Escherichia coli L-asparaginase.

A survey of 109 recently derived leukemias of the mouse revealed that sensitivity to suppression by guinea pig serum is a common property of transplanted leukemias of certain classes. The sensitive leukemias included five that arose spontaneously in mice of strains with a low incidence of leukemia and 21 that were induced by X-radiation. Two GPS-sensitive leukemias were not more sensitive than a GPS-resistant leukemia to a range of standard chemotherapeutic agents. The effectiveness of L-asparaginase EC-2 from Escherichia coli in suppression of the GPS-sensitive leukemia EARAD1 depends upon the conditions of assay. Whereas it is not inhibitory when administered as a single dose at the time of inoculation of the leukemia it is considerably more effective than GPS when used in the treatment of established leukemia. Permanent cures of 7-day generalized transplants of EARAD1 can be effected by the administration of 2000 or more units of EC-2. Immunological factors apparently do not contribute to cure as treated survivors are fully susceptible to rechallenge with minimal numbers of cells from the same leukemia. Reinoculated survivors with progressively growing transplants have been successfully retreated with EC-2. The blood clearance of EC-2 L-asparaginase injected into mice is much more rapid than that of GPS L-asparaginase. After intraperitoneal inoculation of the EC-1 L-asparaginase, which does not have leukemia-inhibitory activity, only very low levels of enzyme activity could be detected in the serum. The effectiveness of EC-2 from E. coli and its availability from a virtually limitless source will make it possible to extend the study of inhibition of leukemias and other tumors by L-asparaginase to species other than small rodents.

[Clinicopathologic analysis of 57 cases of primary pulmonary mucinous adenocarcinoma].

OBJECTIVE: To summarize the clinicopathological characteristics and prognostic factors of primary pulmonary mucinous adenocarcinoma (PPMA). METHODS: The clinicopathological manifestations and radiological appearances of 57 PPMA patients surgically treated and pathologically proved between Jan. 2001 and Dec. 2006 were retrospectively analyzed. The cumulated survival rate was calculated by life table method. RESULTS: There were no specific clinical manifestations in PPMA patients, while the tumors were radiologically pleomorphologic. Of these 57 patients, 5 were in stage Ia, 20 in stage Ib, 1 in stage IIb, 11 in stage IIIa, 6 in stage IIIb and 14 in stage IV. The cumulated 1-, 3- and 5-year survivals of those with complete resection were 88.0%, 55.0% and 55.0%, respectively. CONCLUSION: The final correct diagnosis of primary pulmonary mucinous adenocarcinoma should be made by pathology. Though the treatment is not different, the prognosis of the patients with primary pulmonary mucinous adenocarcinoma is better than that of those with adenocarcinoma.

The evolving role of DNA inter-strand crosslinks in chemotherapy.

DNA crosslinking agents make up a broad class of chemotherapy agents that target rapidly dividing cancer cells by disrupting DNA synthesis. These drugs differ widely in both chemical structure and biological effect. In cells, crosslinking agents can form multiple types of DNA lesions with varying efficiencies. Inter-strand crosslinks (ICLs) are considered to be the most cytotoxic lesion, creating a covalent roadblock to replication and transcription. Despite over 50 years in the clinic, the use of crosslinking agents that specialize in the formation of ICLs remains limited, largely due to high toxicity in patients. Current ICL-based therapeutics have focused on late-stage and drug-resistant tumors, or localized treatments that limit exposure. In this article, we review the development of clinical crosslinking agents, our understanding of how cells respond to different lesions, and the potential to improve ICL-based chemotherapeutics in the future.

Reduced toxicity and superior therapeutic activity of a mitomycin C lipid-based prodrug incorporated in pegylated liposomes.

PURPOSE: A lipid-based prodrug of mitomycin C [MMC; 2,3-(distearoyloxy)propane-1-dithio-4'-benzyloxycarbonyl-MMC] was designed for liposome formulation. The purpose of this study was to examine the in vitro cytotoxicity, pharmacokinetics, in vivo toxicity, and in vivo antitumor activity of this new lipid-based prodrug formulated in polyethylene glycol-coated (pegylated) liposomes. EXPERIMENTAL DESIGN: MMC was released from the MMC lipid-based prodrug (MLP) by thiolytic-induced cleavage with a variety of thiol-containing reducing agents. MLP was incorporated with nearly 100% efficiency in cholesterol-free pegylated liposomes with hydrogenated phosphatidylcholine as the main component and a mean vesicle size of approximately 90 nm. This formulation was used for in vitro and in vivo tests in rodents. RESULTS: In vitro, the cytotoxic activity of pegylated liposomal MLP (PL-MLP) was drastically reduced compared with free MMC. However, in the presence of reducing agents, such as cysteine or N-acetyl-cysteine, its activity increased to nearly comparable levels to those of free MMC. Intravenous administration of PL-MLP in rats resulted in a slow clearance indicating stable prodrug retention in liposomes and long circulation time kinetics, with a pharmacokinetic profile substantially different from that of free MMC. In vivo, PL-MLP was approximately 3-fold less toxic than free MMC. The therapeutic index and absolute antitumor efficacy of PL-MLP were superior to that of free MMC in the three tumor models tested. In addition, PL-MLP was significantly more active than a formulation of doxorubicin in pegylated liposomes (DOXIL) in the M109R tumor model, a mouse tumor cell line with a multidrug-resistant phenotype. CONCLUSIONS: Delivery of MLP in pegylated liposomes is a potential approach for effective treatment of multidrug-resistant tumors while significantly buffering the toxicity of MMC.

A new approach to cancer chemotherapy: selective enhancement of tumor blood flow with angiotensin II.

Elevation of the mean arterial blood pressure to approximately 150 mmHg by infusion of angiotensin II resulted in an approximate 5.7-fold selective increase in blood flow in tumor tissue without increasing blood flow in normal tissue. This finding of no autoregulation of blood flow in tumor tissue was made in an experiment on inbred DONRYU rats with sc transplanted AH109A solid tumors (Yoshida ascites hepatoma). Changes in tissue blood flow were measured by a thermoelectrical method. In another experiment in which DONRYU rats with sc transplanted AH272 solid tumors were used, the chemotherapeutic effect of mitomycin C on main tumors and lymph node metastatic foci was markedly enhanced in rats with angiotensin-induced hypertension, as compared to its effect in rats without angiotensin-induced hypertension. Thus a new approach to cancer chemotherapy has been demonstrated in which the delivery to tumor tissue of systemically administered anticancer drugs can be selectively enhanced.

Effects of mitomycin C alone and in combination with X-rays on EMT6 mouse mammary tumors in vivo.

The effects of mitomycin C alone and in combination with radiation on the cells of EMT6 mouse mammary tumors in BALB/cKaRw mice were examined. At doses near the toxic level, approximately 98% of the tumor cells were killed by a single injection of mitomycin C. Both proliferating and quiescent cells and both hypoxic and aerobic cells were killed by the drug. Cytotoxicity with mitomycin C occurred rapidly and was apparently complete within 30 minutes after injection of the drug . No evidence was found for repair of potentially lethal mitomycin C damage or sublethal mitomycin C damage by the tumor cells. Mitomycin C and radiation in combination produced an additive cytotoxicity; neither agent was found to alter significantly the shape of the dose-response curve for the other agent. The cytotoxicity of mitomycin C and radiation in combination depended on the sequence and timing of the treatments; additive toxicities were obtained when mitomycin C was given just after, just before, or up to 24 hours before irradiation, but the combination was less effective when mitomycin C was given 2-12 hours after irradiation.

Hydralazine-induced tumor hypoxia: a potential target for cancer chemotherapy.

Currently available cancer chemotherapeutic agents have been designed to exploit subtle differences in proliferation and biochemistry that are known to exist between host and malignant cells. However, chemotherapeutic agents may also be used to exploit physiological differences between cancer and normal tissue. The present study was conducted to determine whether the reduction in blood flow to the tumor (and thus oxygen delivery) induced by the vasodilator hydralazine would increase the cytotoxicity of drugs known to be more toxic in regions of reduced oxygenation. Results obtained with three murine tumor models clearly demonstrate that hydralazine potentiates the tumor cytotoxicity of such agents to a greater extent than it does their systemic toxicity. This study indicates a potential strategy for increasing the efficacy of certain cancer chemotherapeutic agents in solid tumors.

Regression of established tumors and induction of tumor immunity by intratumor chemotherapy.

The inoculation of a mixture of drugs and guinea pig hepatoma cells (line-10) induced tumor-specific immunity in about 20% of guinea pigs. When guinea pigs with established intradermal tumors were given various drugs ip, no cures were observed; in contrast, multiple intralesional injections of actinomycin D, 1,3-bis(2-chlorethyl)-1-nitrosourea, adriamycin, mitomycin C, and melphalan were effective in curing animals of their intradermal tumors at a time when there were tumor cells in the draining lymph nodes; dimethyl-triazenoimidazole carboxamide, methotrexate, 5-fluorouracil, and 6-mercaptopurine were not effective. More than 80% of the cured animals were immune to rechallenge with 10(6) line-10 tumor cells.

Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on Radiation Therapy Oncology Group study no. 8314.

Following documented evidence of the synergism of 5-fluorouracil (5-FU) and radiation therapy and an additive effect with mitomycin and irradiation, pilot studies have demonstrated the potential for definitive radiation therapy in the management of squamous cell and basaloid carcinomas of the anal canal, allowing sphincter preservation. Our study explored the long-term effectiveness of combined therapy at this disease site and examined the feasibility of a Radiation Therapy Oncology Group study involving concomitant radiation therapy and chemotherapy. Between 1983 and 1987, 79 assessable patients with any primary tumor stage of anal canal carcinoma were treated by external-beam irradiation combined with mitomycin given by bolus iv injection and 5-FU given by continuous infusion. Radiation was delivered to the perineum and pelvis to a total dose of 4,080 cGy in 4.5-5 weeks. The inguinal nodal areas received 4,080 cGy, calculated at a 3-cm depth in the center of the nodal area. A 96-hour infusion of 5-FU was started on days 2 and 28 of the irradiation at a dose of 1,000 mg/m2 over 24 hours, and a bolus injection of mitomycin was administered on day 2 at a dose of 10 mg/m2. The overall survival rates are 97% at 1 year and 73% at 3 years. Patients with lesions less than 3 cm in diameter and those treated strictly according to the protocol did significantly better than those with larger lesions and those whose treatment did not comply with the protocol. The interim outcome of the study demonstrates that this combined therapy is effective for patients with anal cancer and allows preservation of the sphincter and of sexual function.

Gastric cancer: current status of treatment.

While carcinomas of the stomach is decreasing in incidence in the Dnited States, it is still a major cause of cancer death. But gastric neoplasms are not decreasing in some other geographic areas. According to some studies, 30% of all cancer in the U.S.S.R. originates in the stomach. The rate of gastric neoplasms is greatest in Japan, and over 54% of all cancer in the male population arises in the stomach. The peak age for development of stomach cancer is between 70 and 80 years; over 60% of all stomach cancer is diagnosed in patients between the ages of 60 and 70, while more than 10% is found in those over 80. The main hope for cure at this time rests with surgical treatment. However, despite increased use of surgery, the 5-year survival rate of approximately 13% for patients diagnosed during 1955-59 has not improved to any degree since that time. The major drugs commonly used to treat gastric cancer are 5-fluorouracil (5-FU) and mitomycin C. Controversy still exists concerning the optimum method for administering 5-FU, the most frequently used drug in the United States. The standard loading-course method was attended by a high risk of severe toxicity and drug-related deaths. Several variations of the loading course have evolved. Currently, the Mayo Clinic group uses a 5-day course of 13.5 mg 5-FU/kg repeated every 5 weeks, with therapy interrupted if stomatitis or diarrhea develops; with this regimen the drug-related mortality rate was reported to be less than 1%. Studies have shown that 5-FU plus radiotherapy can enhance survival in patients with locally unresectable diseases. The overall objective with 5-FU is 20-25% with an average of 4-5 months' duration of response. Despite the many patients treated with 5-FU, rarely has a systematic analysis been done of factors such as age, sex, disease-free interval, histologic grade of the tumor, or sites or metastases, which might predispose to a favourable or unfavorable response. In Japan the most commonly used drug for treatment of gastric cancer is mitomycin C, the second most frequently used drug in the United States. The overall objective response rate with mitomycin C is between 20 and 30%, with the higher response rates being reported in the Japanese data. The average duration of response ranges from 1 to 3 months. The nitrosoureas [1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1,3-cis(2-chloroethyl)-1-nitrosourea (CCNU), and methyl CCNU (MeCCNU)] have shown some evidence of activity against gastric cancer. BCNU has yielded an objective response rate of 18% (6/33) and an average duration of response of 4.5 months in gastric cancer patients, most of whom had no prior therapy. Adriamycin recently has been shown to have some antitumor activity, with an approximate response rate of 25%. Combination approaches have been more successful in stomach cancer than in any other gastrointestinal neoplasm. The Japanese have reported higher response rates with a combination of 5-FU, mitomycin C, and cytosine arabinoside...

[Expression of MDR1 and GST-pi in osteosarcoma and soft tissue sarcoma and their correlation with chemotherapy resistance].

OBJECTIVE: To explore the expression of multidrug resistance gene 1 ( MDR1), glutathione-S-transferases-pi (GST-pi) in osteosarcoma and soft tissue sarcoma tissues from 34 patients and their correlation with chemotherapy resistance. METHODS: MDR1 and GST-pi expressions were analyzed by real-time fluorescence quantitative polymerase chain reaction (FQ-PCR) and flow cytometry (FCM) at mRNA and protein levels, respectively. Chemotherapy sensitivity on adriamycin, cisplatinum, fluorouracil, mitomycin C, dacarbazine, vincristine, methotrexate in tumor tissues were detected by MTT assay. RESULTS: The nonsensitive rates on adriamycin, cisplatinum, fluorouracil, mitomycin C, dacarbazine, vincristine, methotrexate in tumor tissues were 41.18%, 17.7%, 47.1%, 50.0%, 76.5%, 61.8% and 52.9%, respectively. The expression of P-glycoprotein (P-gp) and GST-pi in tumor tissues was 1.54 and 2.58 (relative fluorescence intensity). Chi2 analysis showed that there was a positive correlation between P-gp expression and drug resistance on ADM, GST-pi expression and resistance on ADM, DDP and MMC (P < 0.05). There was not seen obvious correlation between expression of MDR1, GST-pi and age, gender, pathological type, tumor size in osteosarcoma and soft tissue sarcoma patients (P > 0.05). The expression of GST-pi was increased in patients receiving preoperative chemotherapy. The rate of postoperative recurrence was higher in patients with higher GST-pi expression level than those with lower GST-pi expression level before operation (P < 0.05). CONCLUSION: Individual differences exist in chemotherapy sensitivity and expression of MDR1 and GST-pi in osteosarcoma and soft tissue sarcomas patients. Chemotherapy can induce up-regulation of GST-pi protein expression. Primary high expression of GST-pi is the main mechanism of resistance of osteosarcoma and soft tissue sarcomas to chemotherapy and is related to poor prognosis.

Treatment of implanted peritoneal cancer in rats by continuous hyperthermic peritoneal perfusion in combination with an anticancer drug.

To study the feasibility of combined hyperthermic and anticancer drug treatment for peritoneal cancer, we devised a continuous hyperthermic peritoneal perfusion system in combination with mitomycin C. The model uses i.p.-transplantable rat ascites hepatoma 100B cells. Hyperthermic peritoneal perfusion alone or combined with mitomycin C was performed after i.p. inoculation of the tumor cells into rats. In rats treated with combined peritoneal perfusion (41.5 degrees) and mitomycin C, the mean survival times were significantly prolonged as compared to those of rats treated with peritoneal perfusion at 41.5 degrees alone. Our results suggest that combined hyperthermic peritoneal perfusion and mitomycin C treatment may represent a therapeutic and prophylactic treatment for peritoneal metastasis after gastric cancer surgery in humans.

Effects of total-body hyperthermia on metastases from experimental mouse tumors.

To study the effects of total-body hyperthermia (TBH) on metastases from malignant tumors, Lewis lung carcinoma (LLC)-bearing C57BL/6 mice and mouse ascites hepatoma 134-bearing C3H/He mice were immersed in a heated water bath. Rectal temperature was maintained for 30 min at 40 degrees C or 42 degrees C. After treatment, the incidence of lung metastasis was analyzed in LLC-inoculated mice, and the presence or absence of metastasis in affiliated lymph nodes was determined in mouse ascites hepatoma 134-inoculated mice. A significant inhibition in primary tumor growth in LLC- and mouse ascites hepatoma 134-bearing mice treated with 42 degrees C TBH was noted. The incidence of lung metastasis was increased from the control level of 1.6 +/- 0.63 (SD) to 2.4 +/- 0.98 in the 42 degrees C TBH (P less than 0.01) groups but not in the 40 degrees C TBH group. Metastasis to affiliated lymph nodes was similar for the controls and the 40 degrees C and 42 degrees C TBH groups. The increase in lung metastasis in LLC-treated mice subjected to 42 degrees C TBH could be prevented by the combined use of anticancer drugs such as cis-diamminedichloroplatinum(II) (1.0, 3.0 mg/kg) or mitomycin C (0.3, 1.0 mg/kg). Furthermore, the combined use of 42 degrees C TBH and anticancer drugs showed the inhibition of primary tumor growth to a greater degree than did 42 degrees C TBH alone or anticancer drugs alone. Since 42 degrees C TBH may induce tumor metastasis, especially hematogenous metastasis, it seems advisable to use anticancer drugs in combination with clinical thermal applications.

Therapeutic attack of hypoxic cells of solid tumors: presidential address.

Hypoxic cells of solid tumors are relatively resistant to therapeutic assault. Studies have demonstrated that oxygen-deficient tumor cells exist in an environment conducive to reductive reactions making hypoxic cells particularly sensitive to bioreductive alkylating agents. Mitomycin C, the prototype bioreductive alkylating agent available for clinical use, is capable of preferentially killing oxygen-deficient cells both in vitro and in vivo. This phenomenon is at least in part the result of differences in the uptake and metabolism of mitomycin C by hypoxic and oxygenated tumor cells, with the ultimate critical lesion being the cross-linking of DNA by the mitomycin antibiotic. The combination of mitomycin C with X-irradiation, to attack hypoxic and oxygenated tumor cell populations, respectively, has led to enhanced antitumor effects in mice bearing solid tumor implants and in patients with cancer of the head and neck. More efficacious kill of hypoxic tumor cells may be possible by the use of dicoumarol in combination with mitomycin or by the use of the related antibiotic porfiromycin. The findings support the use of an agent with specificity for hypoxic tumor cells in potentially curative regimens for solid tumors.

A bioassay to measure cytotoxicity of plasma from patients treated with mitomycin C.

The unpredictable clinical toxicity observed in patients treated with mitomycin C and the observation that this agent must be reduced to an active form before alkylating target molecules have led to the development of a bioassay which is capable of detecting biologically active forms of mitomycin C in the plasma of drug-treated patients. The bioassay makes use of a repair-deficient mutant of Chinese hamster ovary cells, UV-20, which is 40 to 60 times more sensitive to mitomycin C than its wild-type parent. A standard curve relating in vitro cell colony-forming ability of UV-20 versus drug concentration in the plating medium has been determined. Mitomycin C levels in patient plasma as low as 1 ng/ml can be detected, compared to the 5-ng/ml limit of detection obtained with a high-pressure liquid chromatography assay for the parent compound. This assay has been utilized to detect active drug in plasma obtained from patients with colorectal cancer treated with mitomycin C as a single agent. At the completion of drug injection, serial blood samples were collected in heparinized tubes, and aliquots of plasma were extracted and assayed for mitomycin C levels by high-pressure liquid chromatography, diluted and assayed directly for their toxicity for UV-20 cells, or frozen at -20 degrees C to be assayed at a later time. The activity detected by immediate bioassay was stable up to 2 mo in frozen samples. Plasma pharmacokinetics determined by the bioassay in seven patients were no different than those determined by high-pressure liquid chromatography. No stable, cytotoxic species other than the parent compound were detected by the bioassay in the plasma of patients treated with mitomycin C.

Intratumor chemoimmunotherapy with mitomycin C and components from mycobacteria in regression of line 10 tumors in guinea pigs.

Intratumor chemotherapy with the use of mitomycin C and/or immunotherapy caused regression of line 10 carcinomas in strain 2 guinea pigs and resulted in development of tumor-specific immunity. The immunotherapeutic preparation consisted of oil-in-water emulsions containing Mycobacterium cell walls or residues of cell walls termed cell wall skeletons. The latter preparations were combined with trehalose dimycolate, which was isolated by microparticulate chromatography from whole cells of mycobacteria. Reducing mitomycin C to a single intratumor injection of 50 microgram produced little necrotizing effect and a mean tumor regression rate of 17%. Intratumor immunotherapy 1 day after treatment with 50 microgram of mitomycin C resulted in regression of 90% of the treated tumors as compared to mean regression rates of 30 to 50% for immunotherapy alone. In addition, chemoimmunotherapy was more effective than either chemotherapy or immunotherapy alone in producing regression of relatively large, as well as smaller, tumors.

Pharmacokinetics of mitomycin C in humans.

This paper describes an investigation into the pharmacokinetic behavior of mitomycin C (MMC) in 36 patients receiving either single-agent chemotherapy (10 to 20 mg/sq m), or a combination regimen including MMC (5 to 10 mg/sq m). A high-performance liquid chromatographic assay of MMC was applied for the analysis of plasma, urine, bile, and ascites fluid samples. The detection limit is 1 ng/ml sample. Most patients were given short-term i.v. infusion, although other methods of administration were used as well. Most plasma concentration-time curves fit a two-compartment model. Pharmacokinetic parameters revealed large interindividual variations. Median terminal half-lives in single-agent chemotherapy and combination chemotherapy were 50 and 42 min, respectively. The apparent volume of the central compartment was 7 liters/sq m in both groups. The volume of distribution was 22 liters/sq m in single-agent chemotherapy, and 25 litres/sq m in combination chemotherapy. Linear regression analysis of the area under the plasma concentration-time curve versus the dose did not produce any evidence that the pharmacokinetics was dose dependent. However, differences were observed between patients receiving MMC alone and those on combination chemotherapy, in particular with regard to the total body clearance: 18 liters/hr/sq m for single-agent chemotherapy and 28 liters/hr/sq m for combination chemotherapy. Urinary recovery was limited to a maximum of 15% of the administered dose. In one patient studied, MMC was found to be present in the bile. There is evidence for enterohepatic circulation of MMC, and MMC was also found to penetrate into the ascites fluid.

Sensitivity of xenografts of human pancreatic adenocarcinoma in nude mice to heat and heat combined with chemotherapy.

The sensitivity of two human pancreatic adenocarcinomas (Capan-1 and Capan-2) to heat and heat combined with chemotherapy was studied using xenografts of the tumors in the foot of athymic nude mice. Heat was applied by immersion of the tumor in a water bath at 43.5 degrees for 1 hr. A single i.p. dose of mitomycin C, cisplatin, 5-fluorouracil, or 0.9% NaCl solution was given at 1 hr prior to treatment. Heat treatment alone significantly suppressed tumor growth (p less than 0.001), with 35% of the tumors showing complete regression. Combined treatment using heat plus chemotherapy yielded significantly greater suppression of tumor growth (p less than 0.05) with mitomycin for both tumors and with cisplatin or 5-fluorouracil for Capan-1. Combined treatment also gave higher rates of complete tumor regression: 55 and 64%, respectively, for Capan-1 and Capan-2 as compared with 18 and 47% for the respective tumors treated by heat alone. These observations suggest that human pancreatic carcinomas are sufficiently sensitive to heat combined with chemotherapeutic treatment to warrant a clinical trial of these modalities.