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Pregnant Syrian golden hamsters were treated with a single intra-peritoneal injection of ethylnitrosourea (ENU) solution a few hours pre-parturition. Offspring either received no further treatment or from 6 weeks of age, bi-weekly application of ENU solution in acetone for 20 consecutive weeks. Progeny from non, transplacentally treated mothers were also treated topically. Among all treated groups, 8.6% of the animals developed pigmented skin tumors, most of these animals having received the combined treatment. This group also showed a significantly decreased latency period in females compared to males. One of the skin tumors, which was histologically and clinically benign, was transplanted several times and subsequently exhibited malignant features.

A patient in complete remission from malignant melanoma but with refractory anemia after nitrosourea treatment developed acute biphenotypic leukemia. This disease, progression was accompanied by expansion of a cytogenetically abnormal clone. At first cytogenetic analysis, 1 year post discontinuation of chemotherapy, only 25% of the metaphases examined were hypodiploid with monosomy 7. Six months later, all of the metaphases seen were 45,XY,-7. Six months before overt acute leukemia was diagnosed, an additional chromosome abnormality emerged, t(2;3)(q31;q27). Although the translocation was present in all metaphases examined, the patient progressed into an acute leukemia with two components: one TdT-positive, Ia-positive, and the other TdT-negative, Ia-positive, monocytoid antigen-positive. This mixed leukemia was identified by double fluorescence staining for intranuclear TdT and surface labeling with a monocyte-specific monoclonal antibody.

The ocular side effects of cancer chemotherapeutic drugs are relatively uncommon. Patients with cancer may develop ocular problems due to metastases to the eye or central nervous system, side effects and radiotherapy or chemotherapy, or totally independent eye disorders. We present a review of the reported ocular toxicities of chemotherapeutic agents to assist the oncologist caring for such patients.

Thirty-nine previously treated patients received Nimustine in a phase II trial to test the therapeutic activity in refractory small cell lung cancer. Nimustine was given as a direct i.v. injection of 100 mg/m2 with treatments repeated every six weeks. Three partial remissions of 56, 123 and 355 days duration were noted among 34 evaluable patients. Thrombocytopenia was prominent with a median platelet nadir of 47,000/microliter. We conclude that Nimustine has minor antitumor-activity in heavily pretreated patients with small cell lung cancer. The definitive value of Nimustine in the treatment of small cell lung cancer, as well as its superiority over its parent compounds remains to be established.

Increased rate of sister chromatid exchange (SCE) in peripheral lymphocytes has been observed in smokers as compared to nonsmokers and in patients receiving certain cytostatic drugs. The increased SCE frequency in smokers was shown to depend on the number of cigarettes smoked per day, as well as on the duration of smoking. DNA cross-links caused by photochemotherapy against psoriasis, 8-methoxypsoralen plus UVA irradiation (PUVA), as well as by the anti-cancer chemotherapeutic agent CCNU, were shown to be more effective at inducing SCE's than other types of DNA damage caused by these treatments. These observations suggest that SCE analysis may be used as an indicator of genotoxic exposure in vivo, provided that the various types of DNA damage caused by genotoxic agents and the dose, as well as the time of exposure in relation to the time of sampling, are considered.

Teratological study on microgyra is rare, and its morphogenesis is still on dispute. Microgyra associated with cranial meningocele and progressive hydrocephalus were induced in rat siblings by administration of 10 mg/kg.bw of n-methyl n-nitrosourea (MNU) to rat dams on day 9 of gestation. Microgyra were closely similar to human cases. They were formed during progressive stage of hydrocephalus, when the expansion of cranial meningocele was proceeding. This stage was in accord with migratory and postmigratory phase of neuroblasts. The results of this study suggest that the formation of microgyra may be related to the cortical laminar destruction during this critical period of differentiating brain.

The Eastern Cooperative Oncology Group undertook a limited institution phase II study of PCNU in advanced, metastatic breast cancer. The study was limited to patients treated with 1 to 2 prior chemotherapy regimens. Accrual goals were 30 patients but the study was terminated after 10 patients had no response, with a rapid time to progression of 4 weeks, despite considerable hematologic toxicity. Based on this experience and negative results in two prior studies in more heavily pretreated patients, we conclude PCNU is inactive in breast cancer.

The use of drugs in combination for the management of cancer patients aims at the increased therapeutic advantage by elimination the problem of the heterogeneous sensitivity of cancer cells to anticancer drugs, and by delaying or preventing the development of drug resistance within given tumors. Theoretically, the effects of drugs in combination are classified as antagonistic, subadditive, additive and synergistic. Since these results hold for both tumors and hosts, the effects of combined drugs should be considered in terms of therapeutic index. From this viewpoint, the choice and administration schedule of drugs in combination must be synergistic or additive for the tumors and antagonistic or subadditive for the hosts in regard to combined effects. Thus, the rationale for combined drug therapy should be considered from the aspects of biochemical basis, drug resistance, cytokinetic and pharmacologic rationales, and toxicologic basis.

TCNU (1-(2-chloroethyl)-3-[2-(dimethylaminosulphonyl)ethyl]-1-nitrosour ea) is a newly developed water-soluble nitrosourea based on the endogenous aminoethanesulphonic acid taurine. TCNU was in an extended phase I trial given orally every 4-8 weeks using a stepwise dose escalation from 20 to 170 mg/m2. One hundred and thirty-nine patients received a total of 323 courses. Minor haematologic toxicity was observed in 12 patients treated at dose levels less than 70 mg/m2. Thrombocytopenia WHO grades 1-4 occurred in 43% (55/127) and leucopenia WHO grades 1-3 in 45% (57/127) of the patients treated at dose levels greater than or equal to 70 mg/m2. Nausea and vomiting was recorded in about half the patients despite the use of metoclopramide. At the initial dose level 41 patients received greater than or equal to 3 courses of TCNU. Cumulative leucopenia and thrombocytopenia occurred in 3/41 and in 12/41 patients, respectively, while reversible hepatotoxicity was observed in two patients. Antitumour activity was observed in patients with advanced squamous cell, adeno- and large cell carcinoma of the lung. The recommended starting doses for phase II trials with TCNU are as follows: heavily pretreated patients 90 mg/m2, minimally/-moderately pretreated patients 110 mg/m2 and previously untreated patients 130 mg/m2 with TCNU given every 4-5 weeks, the repeated doses and intervals being adjusted to individual tolerance.

Two nitrosourea compounds--1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)--have been used in the treatment of primary and metastatic brain tumors after operation and/or radiotherapy. Hematological and nonhematological toxicity were recorded in 272 patients treated between May 1973 and June 1978. BCNU was given to 135 patients (80 mg/m2 i.v. daily for 3 days) and CCNU was given to 137 patients (130 mg/m2 orally, single dose) every 8 weeks until progression of the primary disease process or for a total of 12 cycles. Radiation therapy (5500 +/- 500 rads in 6 to 7 weeks) was carried out after the first course of chemotherapy. BCNU and CCNU induced the same hematological and clinical toxicity. The bone marrow toxicity seemed to be dose-related, delayed, and cumulative. One case of acute nonlymphoblastic leukemia arising 2 months after the end of CCNU therapy is reported.

Wistar rats given a single intraperitoneal injection of 75 mg cyclophosphamide revealed dental anomalies in the form of shortening or lengthening of incisors, and development of supernumerary teeth. Rats given additionally 5 mg/kg b. w. of a nitrosomethylurea solution over a period of four months showed the same dental anomalies, but with relatively shorter latency times. In a supplementary investigation examining the effects of benzo(a)pyrene and nitrosomethylurea applied locally to the organon dentale, neoplastic lesions and dental dysplasia were seen.

The widely used intracerebral tumor implantation method by freehand injection into parietal or hippocampal areas of the rat brain has proven inadequate for reliable experimental therapeutic studies. Problems include poor intracerebral growth yields and significant rates of spread to extracranial tissues, lungs, and spinal cord. Major variables have been examined experimentally on a model using nitrosourea-induced nervous system tumor cell lines in sygeneic rats. A rapid stereotaxic method greatly improved the consistency of tumor placement. The optimal site was found to be the caudate nucleus. The production of a spheroid intracerebral growth was further facilitated by the use of 1% agar in the cell suspension medium and by an injection volume of 10 mu1 containing at least 10(4) cells. Further improvements involved injection technique and flushing of the operative field. These modifications have resulted in a 99% to 100% yield of intracerebral growth, with a marked reduction in the number and size of extracranial extensions and with distant metastasis rates of 0% to 5%. These results have continually improved with further experience. The method is satisfactory for radiation and chemotherapeutic trials in which survival time as an index of tumor size may be used an an end point.

n-butyl-nitrosourea (BNU), which is highly leukemogenic in adult rats and in young mice, was applied in a single dose of 120 mg/kg body weight to pregnant Wistar rats on day 22 post conceptionem (p.c.). In another group the same dose was injected directly to fetuses of Wistar rats on day 22 p.c. after surgical delivery with subsequent feeding by nurses. The same single dose was given to 1 and 2 days old Wistar rats as well as to 10 and 30 days old Sprague-Dawley rats. In about 50% of the progeny tumors (predominantly neurogenic) developed both after diaplacental and after direct application of the substance on day 22 p.c. After neonatal application, almost exclusively neurogenic tumors were found in greater than 85% of the treated juvenile animals. Comparison of survival time and tumor rates between the rats treated diaplacentally or directly on day 22 p.c. and the rats treated neonatally revealed significant differences. This shows that the nervous tissue of the rat is less sensitive to BNU prenatally than in the neonatal phase of development. After application of BNU on day 10 post partum (p.p.) in Sprague-Dawley rats greater than 95% of the animals developed almost exclusively neurogenic tumors with a high percentage of brain tumors. After a single dose on day 30 p.p. a significant increase in survival time and a significant decrease in the total tumor yield is observed in comparison to the animals treated on day 10. Additionally a decrease in the rate of neurogenic tumors is accompanied by an increase of tumors outside the nervous system. Aftertreatment with single doses of BNU perinatally and on day 10 p.p. only 2 rats out of 154 animals were found to have leukemia. After application of BNU to 30 days old rats, leukemia was diagnosed in 7 out of 40 animals.

During the period from January 1981 to December 1983, two groups of a total of 51 patients (31 malignant astrocytomas, 17 glioblastomas, and 3 others) were treated with radioimmunochemotherapy using nimustine hydrochloride (ACNU) plus Picibanil (OK-432) (group A) and radiochemotherapy with ACNU only (group B) in a randomized controlled study. Group A consisted of 24 patients and group B of 27 patients. The differences in the background of the two groups were not statistically significant. Survival curves of both groups were shown by the Kaplan-Meier method. The postoperative survival rate at 1 year and 3 years was 70% and 30%, respectively, equal in both groups, and the differences between groups A and B were not statistically significant by the Cox-Mantel test. The side effects seen in group B were most prominent in the bone marrow, and severe leukopenia occurred. However, in group A leukopenia was suppressed after 2 months. Immunologic parameters, such as the purified protein derivative skin reaction test, did not change, but the streptococcus pyogenes Su-strain polysaccharide skin-reaction test became more positive after therapy in group A.

The oncogenic effect of ethylnitrosourea (ENU) on rabbits during the organogenesis was studied. ENU, dissolved in sodium phosphate (pH 6.0), was injected in a 50 mg/kg dosis intravenously in pregnant dams between the 8th and 10th day of gestation. From 12 offspring 8 grew up normally and appeared unremarkably until 30--36 months of age when neurologic signs first developed. Six rabbits showed one or more tumors along the peripheral nerves. Two rabbits were bearing brain gliomas in the vicinity of the 3rd ventricle. The tumors of the peripheral nervous system (PNS) were of variable size and soft consistency; they had a cut surface of spongy and even cystic appearance. Histologically, the PNS tumors resemble Schwannomas of the Antoni B type. An ultrastructural study of these neoplasms disclosed cells featuring a basal lamina type of lining characteristics of Schwann cells. These findings demonstrate that the exposure of rabbits to ENU during organogenesis results in the induction of neurogenic tumors which become clinically manifest late in life. It seems, therefore, that the selective oncogenic effect of ENU on the nervous tissues of the exposed animals depends exclusively on the stage of organogenesis at which the drug is brought to bear upon the target organ anlage.

Two patients treated for chronic myeloid leukemia with high doses of CCNU (1100 mg/m2 and 1240 mg/m2, respectively) developed a fatal pulmonary fibrosis. This side effect has never been reported for this nitrosourea but only for BCNU and methyl-CCNU. The responsibility of CCNU in the pathogenesis of pulmonary fibrosis seems very likely. The possibility that the underlying disease or other chemotherapeutic agents may increase the risk of pulmonary toxicity can, however, be discussed. In addition, 13 other adults treated for chronic myeloid leukemia with various doses of CCNU were reviewed. No respiratory symptoms appeared in the ten patients who were given less than 950 mg/m2. Three patients who received more than 1100 mg/m2 developed pulmonary symptoms with the same clinical and radiologic pattern as in the two cases with pathologic documents, and two of them died from acute respiratory failure. Although lung specimens were lacking from these three patients, it is suggested that the pulmonary toxicity of CCNU may be dose-related.

A total of 48 patients with various malignant disorders, mostly from hemopoietic organs, entered to phase I study of MCNU given orally. Fifty-six percent of the patients given MCNU at the doses of 50-125 mg/m2 complained of gastrointestinal symptoms including nausea and vomiting, which were however mild and well tolerated. In the following study employing administration of 50 mg/day of MCNU for consecutive 2-6 days, the gastrointestinal toxicities were reduced to 26.1%, and hematological toxicities of delayed leukopenia and thrombocytopenia were derived 4-6 weeks after oral intake of the drug. The hematological recovery required 1-2 weeks after the nadir of leukocyte and thrombocyte count. A recommended dose for phase II study of MCNU by the route of oral administration was 50 mg/body/day for consecutive 4-6 days in every 8 weeks interval. The peak value of blood concentration of MCNU was obtained 60-120 minutes after p.o. administration at the doses of 50-100 mg. Elimination half-life was estimated to be 40-45 minutes. No concentration of the drug was detected in blood 24 hours after the administration.

This paper has outlined the varied renal and metabolic abnormalities which may occur as complications of antineoplastic chemotherapy. Rapid tumor lysis leading to acute uric acid nephropathy, hyperkalemia and hyperphosphatemia may complicate the treatment of patients with chemotherapy-responsive tumors. Aggressive management with intravenous hydration, urinary alkalinization and administration of allopurinol can ameliorate these complications of therapy. Many commonly used antineoplastic agents, particularly cisplatin, methotrexate, streptozotocin, and nitrosoureas, are nephrotoxic. Careful monitoring of renal function and serum electrolytes are essential during administration of these agents. In addition, intravascular volume depletion, urinary tract infection, and obstructive uropathy must always be considered when renal function deteriorates in patients with cancer. With foresight and aggressive management, many of these derangements can be ameliorated or avoided entirely and the toxicity of effective cancer chemotherapy can be minimized. Patients with established renal failure who require chemotherapy pose a particularly difficult clinical problem. Though a complete discussion of this subject is beyond the scope of this paper, Table 3 is included to provide some guidelines for dose modification in patients with altered renal function.

As the advances in the field of cytostatic substances gain ground, more and more side effects and complications become manifest in the nervous system. Although the neurotoxic effects produced by different cytostatics present a different appearance and are partly of only sporadic or slight clinical importance, there is hardly a cytostatic which does not exercise a side effect on the nervous system. Definition of the side effects in the nervous system which are caused by cytostatics, is often difficult, because the neurotoxic syndromes are similar to disease patterns of different origin, especially those of the neoplastic and paraneoplastic type, both topically and clinico-phenomenologically. However, it is often of vital importance to arrive at the correct diagnosis well in time, because this will help the physician to decide whether the cytostatic should be discontinued or administered as before. For this reason, it may be necessary to employ, besides the neuropsychiatric examination, additional electrophysiological, CSF-diagnostic, CT and bioptic methods.

The nitrosoureas (BCNU, CCNU, methyl CCNU) represent a new class of antineoplastic agents with a broad spectrum of antitumor activity. They are cell-cycle nonspecific cytotoxic agents. Postulated modes of action and pharmacology of these nitrosoureas are reviewed. Their therapeutic effectiveness as single agents and in combinations have been recognized in malignant lymphomas, multiple myeloma, melanoma, glioblastoma multiforme, gastric and colorectal carcionma, and small-cell carcinoma of the lung. The nitrosoureas are administered on an intermittent 6--8-week schedule because of delayed and frequently severe bone marrow toxicity which may be cumulative in nature.

RFCNU or (chloro-2-ethyl)-l-(ribofuranosyl-isopropylidene-2', 3' paranitrobenzoate-5')-3 nitrosourea, a new synthetic nitrosourea derivative, which has been shown to have, in mice, among all nitrosourea derivatives tested, the longest maximallly efficient dose interval (MEDI) and which is not immunosuppressive at the smallest dose of MEDI, gave in a phase II trial on digestive tract tumours (at the dose of 400 mg/m2 per month determined by the phase I trial), 30% objective remissions among which 13% were greater than 50%.

Administration of a number of cytotoxic agents has been associated with interstitial pneumonitis, alveolitis and pulmonary fibrosis. Some (bleomycin, busulfan, methotrexate) are well known to cause this problem, and others (carmustine, semustine, zinostatin, mitomycin, and chlorambucil) have only recently been recognized to do so. We review and update the available information about this form of drug toxicity. Interaction between these drugs and thoracic radiation or high oxygen fractions in inspired air has produced pneumonitis at doses lower than when the drug is used alone. Synergism between the drugs themselves when given concurrently also produces pulmonary toxicity at lower doses. With some drugs and in some patients steroids will diminish the pulmonary abnormalities, but death from hypoxia is a frequent outcome. Since early recognition of the problem and withdrawal of the injurious agent is the best treatment, physician awareness of and alertness to this toxicity and its relative risk is most important. The discovery of analogs of bleomycin with a better therapeutic index, specifically reducing pulmonary damage, is one of the goals of current cancer drug development.

The renal toxicity of antitumoral drugs is an increasingly disturbing problem. These drugs are now prescribed in an ever wider variety of cases, and delayed renal reactions, previously unknown, are revealed by the longer survivals obtained. For a number of years, patients whose cancer had been cured have been placed under haemodialysis on account of drug-induced renal failure. The renal toxicity of cisplatinum, nitrosoureas and methotrexate is well-known, but mitomycin C is also capable of inducing permanent renal failure; the delayed toxicity of this drug explains that it has long been underestimated. This example emphasizes the need for close co-operation between oncologists, nephrologists and pharmacologists in order to determine, for each patient, the most effective treatment with the minimum of side effects.

Forty-six cases of non-surgical malignant glioma were treated by several repeated infusion of non-superselective intra-arterial chemotherapy using HECNU, followed by conventional radiotherapy. Chemotherapy was well tolerated immediately. Good responses rate was 46% for the whole group, but was higher in anaplastic astrocytomas (71%) than in glioblastomas (43%). The median survival for responders was 17 months, and clinical improvement was observed in a large majority of them. Later, neurological or ophthalmological ipsilateral complications of varying severity were observed in 8.7% and 15% of the cases respectively. Despite these complications the treatment was generally well tolerated and gave in responders a longer survival with better comfort.

In a phase I trial, 28 patients with advanced solid tumors were given PCNU daily for 5 days by iv infusion over 20 minutes at 6-week intervals. The total dose for each course ranged from 25 to 150 mg/m2 in six escalation steps. Myelosuppression was dose-limiting, with a platelet count depression regularly observed at doses of greater than or equal to 82.5 mg/m2. Leukopenia occurred only at higher doses. Nausea was uncommon, and vomiting did not occur. There were no adverse drug-related effects on renal or hepatic function. No antitumor activity was observed. A dose range of 100-125 mg/m2 iv for each 5-day course (20-25 mg/m2/day) is recommended for phase II studies.

Pulmonary toxicity caused by antineoplastic drugs is becoming a more frequently recognized entity, and the number of drugs known or suspected of causing this disease is steadily increasing. In general, the initial clinical appearance includes both constitutional signs of malaise and fever, as well as pulmonary complaints. Some clinical signs may suggest a particular drug as the cause. The pathological condition also is generally nonspecific, but some clues may be present histologically that help define the causal agent. This is a review of the antineoplastic drugs that are associated with pulmonary toxicity. Clinical, laboratory, and pathological data are presented as useful information for practicing physicians. Although therapeutic maneuvers are limited, these are discussed with regard to each drug.

Secondary acute leukemias can occur in patients who have been treated with chemotherapy. Several reports have shown that treatment with nitrosoureas can result in secondary leukemia, but this is the first report implicating the investigational drug PCNU as a cause. This case is unique because of the cytogenetic findings, the short latency period between the chemotherapy and the diagnosis of leukemia, and the successful treatment of the leukemia with high-dose cytarabine (ara-C).