Vinca alkaloids Mitomycin

Several of the naturally occurring indoles also have clinical importance. The dimeric vinca alkaloid vincristine and closely related compounds were among the first of the anti-mitotic class of chemotherapeutic agents for cancer[14]. The mitomycins[15] and derivatives of ellipticine[16] are other examples of compounds having anti-tumour activity. Reserpine, while not now a major drug, was one of the first compounds to show beneficial effects in treatment of mental disorders[17]... 

MITOMYCIN CYTOTOXICS-VINCA ALKALOIDS t risk of abrupt onset of pulmonaiy toxicity in 3-6% of patients, when two courses of these drugs are administered concurrently Mechanism is uncertain possible additive pulmonary toxic effects Monitor clinically and with lung function tests for pulmonary toxicity. Advise patients to report immediately symptoms such as shortness of breath and wheezing... 

Acute shortness of breath and bronchospasm have been reported after the administration of vinca alkaloids, for example vinblastine and vindesine (30-34). The respiratory effects, including abrupt onset of progressive dyspnea, non-productive cough, pleuritic chest pain, profound wheezing, and diffuse basal crackles, were more common when mitomycin was used concomitantly. The onset of symptoms can be rapid (for... 

Prestifilippo J, Lewin D. Dyspnea following vinblastine or vindesine administration in patients receiving mitomycin plus vinca alkaloid combination therapy. Cancer Treat Rep 1984 68(7-8) 1029-31. 

Chemotherapy drugs can directly or indirectly cause acute pneumonitis (bleomycin, carmustine, gemcita-bine, methotrexate, mitomycin, procarbazine, and vinca alkaloids) pulmonary fibrosis (bleomycin, carmustine, cyclophosphamide, methotrexate, and mitomycin) hypersensitivity pneumonitis (bleomycin, methotrexate, and procarbazine) noncardiogeneic pulmonary edema (cytarabine, cyclophosphamide, methotrexate, mitomycin, and teniposide). Docet-axel is associated with fluid retention, which may result in pulmonary edema or pleural effusion. Some of these conditions respond to corticosteroid therapy but some cases of pulmonary fibrosis are fatal. 

Rarely, azathioprine and its major metabohte 6-mercaptopurine have been reported to produce an acute restrictive lung disease. Procarbazine, a methylhydrazine associated more commonly with Loef-fler s syndrome, rarely has been associated with pulmonary fibrosis. The vinca alkaloids vinblastine and vindesine have been reported to produce severe respiratory toxicity in association with mitomycin. The incidence with the combination is 39% and may represent a true synergistic effect between these agents. ... 

Mitomycin is administered IV in the treatment of disseminated adenocarcinoma of the stomach or pancreas, and it has been used intravesically in superficial bladder cancer. Biotransformation pathways are saturable, and approximately 10% of an administered dose is eliminated unchanged via the kidneys. Myelosuppression is the major use-limiting side effect of this drug, which is slow to manifest but quite prolonged in duration. Severe skin necrosis can occur on extravasation, and potentially fatal pulmonary toxicities have been noted as well. Mitomycin can induce hemolytic uremia accompanied by irreversible renal dysfunction and thrombocytopenia, and the drug should not be administered to patients with serum creatinine levels greater than 1.7 mg/dL. Severe bronchospasm also has been noted in patients treated with vinca alkaloids who also are receiving (or who have previously received) mitomycin. 

Among all ABC transporters, P-gp, also known as MDRl protein, ABCBl or CD243, is probably the most studied and characterized member. It was first found as a 170-kDa ATP-dependent membrane glycoprotein that acts as a drug efflux pump [15], P-gp is a broad-spectrum transporter, capable of transporting several structurally and functionally unrelated substrate molecules. Its substrates are typically hydrophobic, amphipathic products, including many chemotherapeutic compounds used for cancer treatment, e.g., vinca alkaloids (vincristine, vinblastine), taxanes (paclitaxel, docetaxel), epipodophyllotoxins (etoposide, teniposide), anthracyclines (doxorubicin, daunorubicin, epirubicin), topotecan, dactinomycin, and mitomycin-C [37]. 

The potential hazards of combining these drugs should be recognised, and in view of the unpredictability ofthe reaction, close observation of patients receiving this combination is recommended. If the reaction occurs, supportive measures such as supplemental oxygen and mechanical ventilation may be needed. Corticosteroids are also often used in an attempt to treat the acute symptoms, and to possibly decrease the risk of chronic respiratory impairment. In patients who have developed acute pulmonary toxicity, the use of both mitomycin and vinca alkaloids should subsequently be avoided. ... 

Rivera MP, Kris MG, Gralla RJ, White DA. S3fndrome of acute d3fspnea related to combined mitomycin plus vinca alkaloid chemodierapy.z4mJCfi>iO <7o/(1995) 18, 245-50. 

Dyke RW. Acute broncho jasm after a vinca alkaloid in patients pieviousty treated with mitomycin. NEnglJMed( 9 A) 310,389. 

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